Fluoxetine versus other types of pharmacotherapy for depression

  • Review
  • Intervention

Authors

  • Laura R Magni,

    1. Istituto di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio, Fatebenefratelli, Psychiatric Unit, Brescia, Italy
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  • Marianna Purgato,

    1. University of Verona, Department of Public Health and Community Medicine, Section of Psychiatry, Verona, Italy
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  • Chiara Gastaldon,

    1. University of Verona, Department of Public Health and Community Medicine, Section of Psychiatry, Verona, Italy
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  • Davide Papola,

    1. University of Verona, Department of Public Health and Community Medicine, Section of Psychiatry, Verona, Italy
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  • Toshi A Furukawa,

    1. Kyoto University Graduate School of Medicine / School of Public Health, Department of Health Promotion and Human Behavior, Kyoto, Japan
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  • Andrea Cipriani,

    1. University of Verona, Department of Public Health and Community Medicine, Section of Psychiatry, Verona, Italy
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  • Corrado Barbui

    Corresponding author
    1. University of Verona, Department of Public Health and Community Medicine, Section of Psychiatry, Verona, Italy
    • Corrado Barbui, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Policlinico "G.B.Rossi", Pzz.le L.A. Scuro, 10, Verona, 37134, Italy. corrado.barbui@univr.it.

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Abstract

Background

Depression is common in primary care and is associated with marked personal, social and economic morbidity, thus creating significant demands on service providers. The antidepressant fluoxetine has been studied in many randomised controlled trials (RCTs) in comparison with other conventional and unconventional antidepressants. However, these studies have produced conflicting findings. Other systematic reviews have considered selective serotonin reuptake inhibitor (SSRIs) as a group which limits the applicability of the findings for fluoxetine alone. Therefore, this review intends to provide specific and clinically useful information regarding the effects of fluoxetine for depression compared with tricyclics (TCAs), SSRIs, serotonin-noradrenaline reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and newer agents, and other conventional and unconventional agents.

Objectives

To assess the effects of fluoxetine in comparison with all other antidepressive agents for depression in adult individuals with unipolar major depressive disorder.

Search methods

We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group Controlled Trials Register (CCDANCTR) to 11 May 2012. This register includes relevant RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL) (all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). No language restriction was applied. Reference lists of relevant papers and previous systematic reviews were handsearched. The pharmaceutical company marketing fluoxetine and experts in this field were contacted for supplemental data.

Selection criteria

All RCTs comparing fluoxetine with any other AD (including non-conventional agents such as hypericum) for patients with unipolar major depressive disorder (regardless of the diagnostic criteria used) were included. For trials that had a cross-over design only results from the first randomisation period were considered.

Data collection and analysis

Data were independently extracted by two review authors using a standard form. Responders to treatment were calculated on an intention-to-treat basis: dropouts were always included in this analysis. When data on dropouts were carried forward and included in the efficacy evaluation, they were analysed according to the primary studies; when dropouts were excluded from any assessment in the primary studies, they were considered as treatment failures. Scores from continuous outcomes were analysed by including patients with a final assessment or with the last observation carried forward. Tolerability data were analysed by calculating the proportion of patients who failed to complete the study due to any causes and due to side effects or inefficacy. For dichotomous data, odds ratios (ORs) were calculated with 95% confidence intervals (CI) using the random-effects model. Continuous data were analysed using standardised mean differences (SMD) with 95% CI.

Main results

A total of 171 studies were included in the analysis (24,868 participants). The included studies were undertaken between 1984 and 2012. Studies had homogenous characteristics in terms of design, intervention and outcome measures. The assessment of quality with the risk of bias tool revealed that the great majority of them failed to report methodological details, like the method of random sequence generation, the allocation concealment and blinding. Moreover, most of the included studies were sponsored by drug companies, so the potential for overestimation of treatment effect due to sponsorship bias should be considered in interpreting the results. Fluoxetine was as effective as the TCAs when considered as a group both on a dichotomous outcome (reduction of at least 50% on the Hamilton Depression Scale) (OR 0.97, 95% CI 0.77 to 1.22, 24 RCTs, 2124 participants) and a continuous outcome (mean scores at the end of the trial or change score on depression measures) (SMD 0.03, 95% CI -0.07 to 0.14, 50 RCTs, 3393 participants). On a dichotomous outcome, fluoxetine was less effective than dothiepin or dosulepin (OR 2.13, 95% CI 1.08 to 4.20; number needed to treat (NNT) = 6, 95% CI 3 to 50, 2 RCTs, 144 participants), sertraline (OR 1.37, 95% CI 1.08 to 1.74; NNT = 13, 95% CI 7 to 58, 6 RCTs, 1188 participants), mirtazapine (OR 1.46, 95% CI 1.04 to 2.04; NNT = 12, 95% CI 6 to 134, 4 RCTs, 600 participants) and venlafaxine (OR 1.29, 95% CI 1.10 to 1.51; NNT = 11, 95% CI 8 to 16, 12 RCTs, 3387 participants). On a continuous outcome, fluoxetine was more effective than ABT-200 (SMD -1.85, 95% CI -2.25 to -1.45, 1 RCT, 141 participants) and milnacipran (SMD -0.36, 95% CI -0.63 to -0.08, 2 RCTs, 213 participants); conversely, it was less effective than venlafaxine (SMD 0.10, 95% CI 0 to 0.19, 13 RCTs, 3097 participants). Fluoxetine was better tolerated than TCAs considered as a group (total dropout OR 0.79, 95% CI 0.65 to 0.96; NNT = 20, 95% CI 13 to 48, 49 RCTs, 4194 participants) and was better tolerated in comparison with individual ADs, in particular amitriptyline (total dropout OR 0.62, 95% CI 0.46 to 0.85; NNT = 13, 95% CI 8 to 39, 18 RCTs, 1089 participants), and among the newer ADs ABT-200 (total dropout OR 0.18, 95% CI 0.08 to 0.39; NNT = 3, 95% CI 2 to 5, 1 RCT, 144 participants), pramipexole (total dropout OR 0.12, 95% CI 0.03 to 0.42, NNT = 3, 95% CI 2 to 5, 1 RCT, 105 participants), and reboxetine (total dropout OR 0.60, 95% CI 0.44 to 0.82, NNT = 9, 95% CI 6 to 24, 4 RCTs, 764 participants).

Authors' conclusions

The present study detected differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain. Moreover, the assessment of quality with the risk of bias tool showed that the great majority of included studies failed to report details on methodological procedures. Of consequence, no definitive implications can be drawn from the studies' results. The better efficacy profile of sertraline and venlafaxine (and possibly other ADs) over fluoxetine may be clinically meaningful, as already suggested by other systematic reviews. In addition to efficacy data, treatment decisions should also be based on considerations of drug toxicity, patient acceptability and cost.

摘要

背景

Fluoxetine及其他種類藥物治療憂鬱症的比較

憂鬱症是一種在臨床照護上常見的疾病,且它會造成個人、社會及經濟病態,造成照護提供者工作量明顯增加。治療主要是以藥物或心理治療,選擇性血清回收抑制抗鬱劑(SSRIs)的第一個藥物Fluoxetine,已在很多隨機對照臨床試驗中被使用來和三環類抗鬱劑(TCA),多環類抗鬱劑,相關的其他抗鬱劑或者其他的選擇性血清回收抑制抗鬱劑(SSRIs)來做比較研究。這些比較研究提供了對比的結果。除此之外,有系統的回顧隨機對照臨床試驗一直視選擇性血清回收抑制抗鬱劑(SSRIs)為一組,而證據適用於這組藥物未必單獨適用於fluoxetine,此系統回顧研究評估fluoxetine和三環類抗鬱劑(TCA),其他選擇性血清回收抑制抗鬱劑(SSRIs)及新抗鬱劑比較的效用及耐受性資料。

目標

以確認fluoxetine和其他抗鬱劑比較的效用,解除急性憂鬱症狀的效果及回顧其備接受度。

搜尋策略

相關試驗是從Cochrane Collaboration Depression,Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL), Medline(1966年到2004年)及Embase(1974年到2004年)搜尋。非英文的文章也會被納入。

選擇標準

只有隨機對照試驗會被納入,試驗設計若是用互換設計則只有在第一次被隨機分配試驗的結果會被採納。

資料收集與分析

資料由兩位回顧作者使用標準化模式獨立擷取,對治療有反應者是以治療意向分析法為基礎,退出試驗的個案也會被納入分析,當退出試驗個案資料被進一步使用且納入在效用評估時,他們會根據原始的設計組別被分析,當試驗個案從初期試驗的任何評估被排除,他們被視為治療失敗,連續性的結果的分數包括患者的最後評估,或者以最近一次觀察進行分析。耐受性數據分析是看整體隨機病人中,多少比例的病人未能完成研究以及多少比例經驗了不良反應。基本的分析是使用固定效應模式,以Peto勝算比(PetoOR)及標準平均差異(SMD)來呈現。

主要結論

在二分法結果中,fluoxetine比dothiepin效果不佳(PetoOR:2.09,95%CI 1.08 to 4.05),比sertraline效果不佳(PetoOR:1.40,95%CI 1.11 to 1.76),比mirtazapine效果不佳(PetoOR:1.64,95%CI 1.01 to 2.65),比venlafaxine效果不佳(Peto OR:1.40,95%CI 1.15 to 1.70)。在連續性資料結果上,fluoxetine優於ABT200(標準平均差異(SMD)隨機效應:  1.85,95%CI  2.25 to  1.45),優於milnacipran(標準平均差異(SMD)隨機效應:  0.38,95% CI  0.71 to  0.06),但相對的比venlafaxine效果不佳(標準平均差異(SMD)隨機效應: 0.11,95% CI 0.00 to 0.23),然而這些數字為邊緣統計學意義。Fluoxetine比三環類抗鬱劑(TCA)這一類別藥物有較佳的耐受性(Peto OR:0.78,95%CI 0.68 to 0.89),個別的比較也是有較佳的耐受性,特別是amitriptyline(Peto OR:0.64,95%CI 0.47 to 0.85)及imipramine(Peto OR:0.79,95%CI 0.63 to 0.99),在新的抗鬱劑中,比ABT200(Peto OR:0.21,95%CI 0.10 to 0.41),pramipexole(Peto OR:0.20,95%CI 0.08 to 0.47)及reboxetine(Peto OR: 0.61,95%CI 0.40 to 0.94)有較佳的耐受性。

作者結論

在效用及耐受性方面,fluoxetine跟其他特定抗鬱劑,有統計上顯著的差異,但這些差異在臨床上的意義還不清楚,並無法得出確切臨床操作的影響,從臨床角度看抗鬱劑安全性的分析(副作用及自殺風險)這些成果是必要的,仍然是關鍵重要和較可靠的數據。等待更有力的證據,處理決定應當根據考慮臨床病史,藥物毒性,病人的可接受度和成本。我們需要大型的,務實的試驗,納入異質性憂鬱症患者產生臨床相關資料,關於比較藥理選擇的優點及缺點。從隨機試驗個案做統合分析顯然是必要的。

翻譯人

本摘要由彰化基督教醫院許文郁翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

在急性治療憂鬱疾病,fluoxetine及其他抗鬱劑(三環類、異環類及新抗鬱劑)效用及耐受性的比較。一共找到132個隨機控制試驗,把這些試驗結果統合起來,在效用及耐受性方面,fluoxetine跟一些抗鬱劑,有統計上顯著的差異,然而,難以得出明確的臨床有意義的結論,更可靠關於抗鬱劑的安全性數據是必要的。如果沒有更有力的證據,研究人員認為,治療的決定是基於考慮藥物的毒性,患者對藥物接受性和成本。

Résumé scientifique

Comparaison de la fluoxétine à d'autres types de pharmacothérapie dans la dépression

Contexte

Les cas de dépression sont fréquents dans les soins primaires et sont liés à une morbidité personnelle, sociale et économique marquée, ce qui crée une demande importante au niveau des fournisseurs de services. La fluoxétine antidépressive a été étudiée dans de nombreux essais contrôlés randomisés (ECR) et comparée à d'autres antidépresseurs conventionnels et non conventionnels. Toutefois, ces études ont généré des résultats contradictoires. D'autres revues systématiques ont examiné des inhibiteurs sélectifs de recapture de la sérotonine (ISRS) comme groupe limitant l'applicabilité des résultats relatifs à la fluoxétine seule. Par conséquent, cette revue vise à fournir des informations spécifiques et cliniquement utiles en comparant les effets de la fluoxétine aux tricycliques (ATC) sur la dépression, aux ISRS, aux inhibiteurs de recapture de la sérotonine-noradrénaline (IRSN), aux inhibiteurs de la monoamine oxydase (IMAO), à de nouveaux agents et à d'autres agents conventionnels et non conventionnels.

Objectifs

Évaluer les effets de la fluoxétine par rapport à tous les autres agents antidépresseurs sur la dépression chez l'adulte souffrant de troubles dépressifs majeurs unipolaires.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais contrôlés du groupe thématique the Cochrane Collaboration sur la dépression, l'anxiété et la névrose (CCDANCTR) jusqu'au 11 mai 2012. Ce registre contient des ECR pertinents provenant du registre Cochrane des essais contrôlés (CENTRAL) (toutes les années), de MEDLINE (de 1950 à aujourd'hui), d'EMBASE (de 1974 à aujourd'hui) et de PsycINFO (de 1967 à aujourd'hui). Aucune restriction de langue n'a été appliquée. Les listes bibliographiques des articles pertinents et des revues systématiques antérieures ont fait l'objet de recherches manuelles. Le laboratoire pharmaceutique commercialisant la fluoxétine et des experts dans le domaine ont été contactés afin d'obtenir des données supplémentaires.

Critères de sélection

Tous les ECR comparant la fluoxétine à tout autre antidépresseur (notamment des agents non conventionnels, comme l'hypéricum) chez des patients souffrant de troubles dépressifs majeurs unipolaires (quels que soient les critères de diagnostic utilisés) ont été inclus. Pour les essais ayant une conception croisée, seuls les résultats issus de la première période de randomisation ont été pris en compte.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment extrait des données à l'aide d'un formulaire standard. Les répondants au traitement ont été calculés en intention de traiter : les sorties d'étude étaient toujours incluses dans cette analyse. Lorsque les données concernant les sorties d'étude étaient reportées et incluses dans l'évaluation d'efficacité, elles ont été analysées conformément aux études primaires ; lorsque les sorties d'étude étaient exclues de toute évaluation dans les études primaires, elles étaient considérées comme des échecs de traitement. Les scores des résultats continus ont été analysés en incluant les patients avec une évaluation finale ou avec une dernière observation reportée. Les données de tolérance ont été analysées en calculant la proportion de patients n'ayant pas terminé l'étude pour des causes diverses et en raison d'effets secondaires ou de son inefficacité. Pour les données dichotomiques, les odds ratios (OR) ont été calculés avec leurs intervalles de confiance (IC) à 95 % à l'aide d'un modèle à effets aléatoires. Les données continues ont été analysées en utilisant des différences moyennes standardisées (DMS) avec un IC à 95 %.

Résultats principaux

Au total, 171 études ont été incluses dans cette analyse (24 868 participants). Les études incluses ont été réalisées entre 1984 et 2012. Elles présentaient des caractéristiques homogènes en termes de conception, d'intervention et de critères de jugement. L'évaluation de la qualité méthodologique à l'aide de l'outil d'évaluation des risques de biais révélait que la grande majorité d'entre elles ne rapportaient aucun détail méthodologique, comme la méthode de génération de séquences aléatoires, l'assignation secrète et la mise en aveugle. De plus, la plupart des études incluses étaient parrainées par des laboratoires pharmaceutiques, le potentiel de surestimation des effets du traitement dû au biais de parrainage devait donc être pris en compte lors de l'interprétation des résultats. La fluoxétine était aussi efficace que les ATC lorsqu'elle était considérée comme groupe dans le cas de résultats dichotomiques (diminution d'au moins 50 % sur l'échelle de dépression d'Hamilton) (OR 0,97, IC à 95 % 0,77 à 1,22, 24 ECR, 2 124 participants) et de résultats continus (scores moyens à la fin de l'essai ou score de variation des mesures de la dépression) (DMS 0,03, IC à 95% - 0,07 à 0,14, 50 ECR, 3 393 participants). Dans le cas de résultats dichotomiques, la fluoxétine était moins efficace que la dothiépine ou la dosulépine (OR 2,13, IC à 95 % 1,08 à 4,20 ; nombre de sujets à traiter (NST) = 6, IC à 95 % 3 à 50, 2 ECR, 144 participants), la sertraline (OR 1,37, IC à 95 % 1,08 à 1,74 ; NST = 13, IC à 95 % 7 à 58, 6 ECR, 1 188 participants), la mirtazapine (OR 1,46, IC à 95 % 1,04 à 2,04 ; NST = 12, IC à 95 % 6 à 134, 4 ECR, 600 participants) et la venlafaxine (OR 1,29, IC à 95 % 1,10 à 1,51 ; NST = 11, IC à 95 % 8 à 16, 12 ECR, 3 387 participants). Dans le cas de résultats continus, la fluoxétine était plus efficace que l'ABT-200 (DMS - 1,85, IC à 95 % - 2,25 à - 1,45, 1 ECR, 141 participants) et le milnacipran (DMS - 0,36, IC à 95 % - 0,63 à - 0,08, 2 ECR, 213 participants). Cependant, elle était moins efficace que la venlafaxine (DMS 0,10, IC à 95 % 0 à 0,19, 13 ECR, 3 097 participants). La fluoxétine était mieux tolérée que les ATC considérés comme groupe (OR des sorties d'étude totales 0,79, IC à 95 % 0,65 à 0,96 ; NST = 20, IC à 95 % 13 à 48, 49 ECR, 4 194 participants) et mieux tolérée par rapport aux AD individuels, surtout l'amitriptyline (OR des sorties d'étude totales 0,62, IC à 95 % 0,46 à 0,85 ; NST = 13, IC à 95 % 8 à 39, 18 ECR, 1 089 participants) et, parmi les nouveaux AD, l'ABT-200 (OR des sorties d'étude totales 0,18, IC à 95 % 0,08 à 0,39 ; NST = 3, IC à 95 % 2 à 5, 1 ECR, 144 participants), le pramipexole (OR des sorties d'étude totales 0,12, IC à 95 % 0,03 à 0,42, NST = 3, IC à 95 % 2 à 5, 1 ECR, 105 participants) et la réboxétine (OR des sorties d'étude totales 0,60, IC à 95 % 0,44 à 0,82, NST = 9, IC à 95 % 6 à 24, 4 ECR, 764 participants).

Conclusions des auteurs

La présente étude a détecté des différences en termes d'efficacité et de tolérance entre la fluoxétine et certains AD, mais la signification clinique des ces différences est incertaine. De plus, l'évaluation de la qualité à l'aide de l'outil d'évaluation des risques de biais montrait que la grande majorité des études incluses ne donnaient aucune information concernant les procédures méthodologiques. Par conséquent, les résultats des différentes études ne nous permettent de tirer aucune conclusion définitive. L'amélioration du profil d'efficacité de la sertraline et de la venlafaxine (et éventuellement d'autres AD) par rapport à la fluoxétine peut être cliniquement important, comme il a été précédemment suggéré par d'autres revues systématiques. Outre les données d'efficacité, les décisions de traitement doivent également se baser sur des considérations de toxicité du médicament, d'acceptabilité du patient et de coût.

Resumo

Fluoxetina versus outros tipos de farmacoterapias para depressão

Introdução

A depressão é comum no tratamento primário e é associada com morbidade pessoal, social e econômica, criando assim demandas significativas sobre os prestadores de serviço. A fluoxetina tem sido estudada em muitos ensaios clínicos randomizados (ECRs) em comparação com outros antidepressivos convencionais e não convencionais. Contudo, estes estudos têm produzido descobertas conflitantes. Outras revisões sistemáticas têm considerado o inibidor seletivo da recaptação da serotonina (ISRS) como um grupo que limita a aplicabilidade dos achados sobre a fluoxetina isolada. Desta forma, esta revisão pretende fornecer informações específicas e clinicamente úteis sobre os efeitos da fluoxetina para a depressão comparada com os tricíclicos (TC), ISRS, inibidores de recaptação de serotonina-noradrenalina, inibidores de monoamina oxidase (IMAO) e agentes mais novos, além de outros agentes convencionais e não convencionais.

Objetivos

Para avaliar os efeitos da fluoxetina em comparação com outros agentes antidepressivos para depressão em indivíduos adultos com transtorno depressivo unipolar.

Métodos de busca

Nós pesquisamos na the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group Controlled Trials Register (CCDANCTR) até 11 de Maio de 2012. Este registo inclui ensaios clínicos randomizados relevantes do the Cochrane Central Register of Controlled Trials (CENTRAL) (de todos os anos), MEDLINE (1950 até o presente), EMBASE (1974 até o presente) e PsycINFO (1967 até o presente). Não foi aplicada restrição de idioma. Listas de referências de artigos relevantes e revisões sistemáticas anteriores foram buscadas manualmente. A empresa farmacêutica que comercializa a fluoxetina e os especialistas neste campo foram contatados para dados complementares.

Critério de seleção

Todos os ensaios clínicos randomizados que compararam a fluoxetina com qualquer outro antidepressivo (incluindo agentes não convencionais, como hypericum) para pacientes com transtorno depressivo unipolar (independentemente dos critérios diagnósticos utilizados) foram incluídos. Para os ensaios clínicos que apresentaram um desenho do tipo cross-over, apenas os resultados do primeiro período de randomização foram considerados.

Coleta dos dados e análises

Os dados foram extraídos independentemente por dois autores da revisão usando um formulário padrão. Resultados do tratamento foram calculados com base na intenção por tratar: desistências foram sempre incluídas nesta análise. Quando os dados sobre os desistentes foram incluídos na avaliação da eficácia, foram analisados ​​de acordo com os estudos primários; quando desistências foram excluídas de qualquer avaliação dos estudos primários, eles foram considerados como falhas do tratamento. Dezenas de resultados contínuos foram analisados, incluindo pacientes com uma avaliação final ou com a última observação levada adiante. Tolerabilidade dos dados foram analisadas por meio do cálculo da proporção de pacientes que não conseguiram concluir o estudo devido a quaisquer causas e devido a efeitos colaterais ou ineficácia. Para dados dicotômicos, a razão de chances (odds ratio (OR)) foram calculados com intervalo de confiança (IC) de 95%, utilizando o modelo de efeito randômico. Os dados contínuos foram analisados ​​por meio de diferença de média padronizada (DMP) com 95%.

Principais resultados

Um total de 171 estudos foram incluídos na análise (24.868 participantes). Os estudos incluídos foram realizados entre 1984 e 2012. Estudos tinham características homogéneas em termos de desenho, de intervenção e resultado. A avaliação da qualidade, com o risco de viés, revelou que a grande maioria deles não informou detalhes metodológicos, como o método de geração de sequência aleatória e a ocultação da alocação. Além disso, a maioria dos estudos incluídos foram patrocinados por empresas farmacêuticas, de modo que o potencial para a superestimação do efeito do tratamento devido ao patrocínio deve ser considerado na interpretação dos resultados. A fluoxetina foi tão eficaz quanto os TC tanto no desfecho dicotômico (redução de pelo menos 50% na Escala de Depressão de Hamilton) (OR 0,97, IC 95% 0,77-1,22, 24 estudos, 2.124 participantes) quanto no resultado contínuo (escores médios no final do estudo ou pontuação nas medidas de depressão) (DMP 0,03 IC 95% -0,07 a 0,14, 50 estudos, 3.393 participantes). Em um desfecho dicotômico, a fluoxetina foi menos eficaz do que a dotiepina ou dosulepina (OR 2,13 IC 95% 1,08-4,20; número necessário para tratar (NNT) de 6, IC 95%: 3-50, dois estudos, 144 participantes), sertralina (OR 1,37 IC 95% 1,08-1,74; NNT de 13, IC 95% 7 a 58, seis estudos, 1.188 participantes), mirtazapina (OR 1,46, IC 95% 1,04-2,04; NNT de 12, IC 95% 6-134, quatro estudos, 600 participantes) e venlafaxina (OR 1,29, IC 95% 1,10-1,51; NNT de 11, IC 95% 8 a 16, 12 estudos, 3.387 participantes). ). Nos resultados contínuos, a fluoxetina foi mais eficaz do que a milnacipran (DMP -0,36 IC 95% - 0,63 a -0,08, dois estudos, 213 participantes); inversamente, foi menos eficaz do que a venlafaxina (DMP 0,10, IC 95% 0-0,19, 13 estudos, 3.097 participantes). A fluoxetina foi mais bem tolerada do que os TC (total de abandono: 0,79 IC 95% 0,65-0,96; NNT de 20 IC 95% 13 a 48, 49 estudos, 4.194 participantes); e também foi mais bem tolerada em comparação com relato do paciente, em relação a amitriptilina (total de abandono: 0,62, IC 95% 0,46-0,85; NNT de 13, IC 95% 8-39, 18 estudos, 1.089 participantes), entre os mais novos antidepressivos ABT-200 (total de abandono: 0,18 IC 95% 0,08-0,39; NNT de 3, IC 95% 2-5, um estudo, 144 participantes), pramipexol (total de abandono: 0,12, IC 95% 0,03-0,42, NNT de 3, IC 95% 2-5, um estudo, 105 participantes) e reboxetina (total de abandono: 0,60 IC 95% 44-82, NNT de 9 IC 95% 6-24, quatro estudos, 764 participantes).

Conclusão dos autores

O presente estudo detectou diferenças em termos de eficácia e tolerabilidade entre a fluoxetina e alguns antipressivos, mas o significado clínico destes achados ainda é incerto. Além disso, a avaliação da qualidade do risco de viés mostrou que a grande maioria dos estudos incluídos não informou detalhes sobre os procedimentos metodológicos. Em conseqüência, não tem implicações definitivas que possam ser tiradas a partir dos resultados dos estudos. O perfil de melhor eficácia da sertralina e venlafaxina (e possivelmente outros antidepressivos) sobre a fluoxetina pode ser clinicamente significativo, como já foi sugerido por outros autores. Além dos dados de eficácia, as decisões de tratamento também devem ser baseadas em considerações de toxicidade da droga, aceitabilidade do paciente e custo.

Notas de tradução

Traduzido por: Cristiane de Cássia Bergamaschi, Universidade de Sorocaba- Uniso; Unidade de Medicina Baseada em Evidências da Unesp, Brasil Contato: portuguese.ebm.unit@gmail.com

Plain language summary

Fluoxetine compared with other antidepressants for depression in adults

Depression is a severe mental illness characterised by a persistent low mood and loss of all interest and pleasure, usually accompanied by a range of symptoms such as appetite change, sleep disturbance and poor concentration. The predominant treatment options for depression are drugs and psychological therapies, but antidepressant drugs are the most common treatment for moderate to severe depression. Fluoxetine, one of the first new generation antidepressants, is an extremely popular drug treatment for depression. However, findings from studies comparing fluoxetine with other antidepressants are controversial. In this systematic review, the efficacy and tolerability of fluoxetine was compared with other antidepressants for the acute treatment of depression.

In May 2012 we searched, in a wide-ranging way, for all the useful studies (randomised controlled trials, or RCTs) we could find which compared fluoxetine with any other antidepressant in treating people with depression. One hundred and seventy-one RCTs were included, with 24,868 people in the analyses. Combining the results from all the trials, fluoxetine was similarly effective, but better tolerated, than older generation (tricyclic) antidepressants. In comparison with other new generation antidepressants, important differences in efficacy and in tolerability were found between fluoxetine and some of the antidepressants, for example, fluoxetine was less effective than sertraline and mirtazapine but better tolerated than reboxetine. These differences might have a clinical impact in everyday practice. However, when interpreting these differences it is important to bear in mind that the studies were short in duration (eight weeks or less) and that the average size of each trial was small (each included around 100 people). Moreover, most of the included studies were sponsored by drug companies, which could potentially have led to an overestimation of treatment effect. As a consequence, it is difficult to draw clear, clinically meaningful conclusions. More reliable information is needed about the respective safety profiles of antidepressants.

Résumé simplifié

Comparaison de la fluoxétine à d'autres antidépresseurs dans la dépression chez l'adulte

La dépression est une maladie mentale grave qui se caractérise par une déprime persistante et la perte de tout intérêt et de tout plaisir. Elle s'accompagne généralement d'un éventail de symptômes, comme des problèmes d'appétit, des troubles du sommeil et de la concentration. Les principales options de traitement contre la dépression sont les traitements médicamenteux et psychologiques, mais les traitements à base d'antidépresseurs sont les plus courants dans le cas d'une dépression modérée à grave. La fluoxétine, l'un des premiers antidépresseurs nouvelle génération, est un médicament couramment prescrit pour le traitement de la dépression. Toutefois, les résultats d'études comparant la fluoxétine à d'autres antidépresseurs sont contestés. Dans cette revue systématique, l'efficacité et la tolérance de la fluoxétine étaient comparées à d'autres antidépresseurs pour le traitement aigu de la dépression.

En mai 2012, nous avons effectué de vastes recherches dans toutes les études utiles (essais contrôlés randomisés ou ECR) que nous avons pu trouver et qui comparaient la fluoxétine à n'importe quel autre antidépresseur dans le traitement de personnes dépressives. Cent soixante-et-onze ECR ont été inclus, totalisant 24 868 personnes dans les analyses. En combinant les résultats de tous les essais, la fluoxétine était tout aussi efficace, mais mieux tolérée, que les antidépresseurs de la génération précédente (tricycliques). Par rapport aux autres antidépresseurs nouvelle génération, d'importantes différences en termes d'efficacité et de tolérance ont été identifiées entre la fluoxétine et certains antidépresseurs. Par exemple : la fluoxétine était moins efficace que la sertraline et la mirtazapine, mais mieux tolérée que la réboxetine. Ces différences peuvent avoir des effets cliniques sur la pratique courante. Toutefois, lors de l'interprétation de ces différences, il est important de ne pas oublier que ces études étaient de courte durée (huit semaines maximum) et que la taille moyenne de chaque essai était réduite (environ 100 personnes par essai). De plus, la majorité des études incluses étaient sponsorisées par des laboratoires pharmaceutiques, ce qui pouvait alors conduire à une surestimation des effets du traitement. Par conséquent, il est difficile de tirer des conclusions claires et cliniquement significatives. D'autres informations fiables concernant les profils d'innocuité respectifs des antidépresseurs seront nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 4th September, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Laički sažetak

Usporedba fluoksetina i ostalih lijekova za depresiju

Depresija je teška mentalna bolest. Simptomi depresije su dugotrajna potištenost, gubitak interesa za život i gubitak interesa za stvari koje su pacijenta ranije usrećivale, a često postoji i niz dodatnih simptoma kao što su promjena apetita, poremećaj spavanja i lošija koncentracija. Glavni oblik liječenja depresije su lijekovi i psihološka terapija. Za liječenje umjerene do teške depresije najčešće se koriste lijekovi antidepresivi. Fluoksetin, jedan od prvih lijekova nove generacije antidepresiva, iznimno je popularan lijek za liječenje depresija. Međutim, rezultati istraživanja u kojima je fluoksetin uspoređen s drugim antidepresivima su kontroverzni. U ovom Cochrane sustavnom pregledu su učinkovitost i podnošljivost fluoksetina uspoređene s drugim antidepresivima za akutno liječenje depresije.

Autori su u svibnju 2012. napravili sveobuhvatno pretraživanje medicinske literature kako bi pronašli sve kliničke studije (randomizirana kontrolirana istraživanja) u kojima je učinjena usporedba između fluoksetina i bilo kojeg drugog antidepresiva za liječenje depresije. U sustavni pregled uključena je 171 studija s ukupno 24.868 ispitanika. Nakon sabiranja rezultata iz svih istraživanja, pokazalo se da fluoksetin ima sličnu učinkovitost, ali se bolje podnosi nego lijekovi starije generacije (tricikličkih) antidepresiva. U usporedbi s drugim antidepresivima nove generacije, uočene su važne razlike u učinkovitosti i podnošljivosti između fluoksetina i nekih antidepresiva. Primjerice, fluoksetin je bio manje učinkovit nego setralin i mirtazapin, ali se bolje podnosio nego reboksetin. Te razlike mogu imati klinički značaj u svakodnevnoj praksi. Međutim, prilikom interpretacija tih razlika važno je imati na umu da su istraživanja kratko trajala (osam tjedana ili manje) i da je prosječna veličina svake studije bila malena (svaka je uključila oko 100 ljudi). Nadalje, većinu uključenih istraživanja sponzorirala je farmaceutska industrija, što potencijalno može dovesti do preuveličavanja učinka lijeka. Zbog toga je teško izvući jasne zaključke koji bi bili korisni za praksu. Potrebno nam je više pouzdanih informacija o sigurnosti antidepresiva.

Bilješke prijevoda

Prevoditelj:: Croatian Branch of the Italian Cochrane Centre

Resumo para leigos

Fluoxetina versus outros tipos de farmacoterapias para depressão

A depressão é uma doença mental grave caracterizada por um mau humor persistente e perda de todo o interesse e prazer, geralmente acompanhada de uma série de sintomas como alteração do apetite, distúrbios do sono e falta de concentração. As opções de tratamento para a depressão são fármacos e terapias psicológicas, sendo o uso de os antidepressivos o tratamento mais comum para a depressão moderada a grave. A fluoxetina, um dos primeiros novos antidepressivos, é um fármaco extremamente popular tratamento para a depressão. No entanto, os resultados de estudos comparando a fluoxetina com outros antidepressivos são controversos. Nesta revisão sistemática, a eficácia e a tolerabilidade da fluoxetina foi comparada com outros antidepressivos para o tratamento agudo da depressão.

Em maio de 2012, procuramos de uma maneira mais abrangente, para todos os estudos utéis (ensaios clínicos randomizados ou ECRs) pudessemos encontrar comparações da fluoxetina com qualquer outro antidepressivo no tratamento de pessoas com depressão171 ECRs foram incluídos, com 24.868 pessoas nas análises. Combinando os resultados de todos os ensaios clínicos, a fluoxetina foi igualmente eficaz, mas é mais bem tolerada do que a geração os TC. Em comparação com outros antidepressivos de nova geração, foram encontradas diferenças importantes na eficácia e na tolerabilidade entre a fluoxetina e alguns dos antidepressivos; por exemplo, a fluoxetina foi menos eficaz do que a sertralina e mirtazapina, mas melhor tolerada do que a reboxetina. Estas diferenças podem ter um impacto clínico na prática diária. No entanto, ao interpretar essas diferenças, é importante ter em mente que os estudos apresentaram curta duração (oito semanas ou menos) e que o tamanho médio de cada estudo era pequeno (cada ensaio clínico incluiu cerca de 100 pessoas). Além disso, a maioria dos estudos incluídos foram patrocinados por empresas farmacêuticas, o que poderia ter levado a uma superestimação do efeito do tratamento. Como consequência, é difícil tirar conclusões claras e clinicamente significativas. Informação mais confiável é necessária sobre os respectivos perfis de segurança dos antidepressivos.

Notas de tradução

Traduzido por: Cristiane de Cássia Bergamaschi, Universidade de Sorocaba- Uniso; Unidade de Medicina Baseada em Evidências da Unesp, Brasil Contato: portuguese.ebm.unit@gmail.com

Summary of findings(Explanation)

Summary of findings for the main comparison. Fluoxetine compared to TCAs
  1. 1 Limitations in study design: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to TCAs
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: TCAs
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
TCAs Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

471 per 1000 463 per 1000
(406 to 520)
OR 0.97
(0.77 to 1.22)
2124
(24 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.03 higher
(0.07 lower to 0.14 higher)
 3393
(50 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero
Failure to complete - total - 335 per 1000 284 per 1000
(246 to 326)
OR 0.79
(0.65 to 0.96)
4194
(49 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 193 per 1000 116 per 1000
(87 to 152)
OR 0.55
(0.40 to 0.75)
3647
(40 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 68 per 1000 87 per 1000
(66 to 112)
OR 1.29
(0.96 to 1.72)
2911
(33 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Fluoxetine compared to ABT-200

Summary of findings 2. Fluoxetine compared to ABT-200
  1. 1 Limitations in study design: no details on randomisation procedures and allocation concealment. Blinding stated but not tested. Only one study included in the analysis.

Fluoxetine compared to ABT 200
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: ABT 200
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ABT 200 Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

  0 per 1000
(0 to 0)
Not estimable0 (0)  

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
1.85 standard deviations lower
(2.25 to 1.45 lower)
 141
(1 study)
⊕⊕⊝⊝
low 1
This corresponds to a large effect according
to conventions proposed
by Cohen 1992. However, only one study contributed to this analysis
Failure to complete - total - 528 per 1000 167 per 1000
(82 to 304)
OR 0.18
(0.08 to 0.39)
144
(1 study)
⊕⊕⊝⊝
low 1
 
Failure to complete - inefficacy - 56 per 1000 14 per 1000
(2 to 115)
OR 0.24
(0.03 to 2.20)
144
(1 study)
⊕⊕⊝⊝
low 1
 
Failure to complete - side effects - 361 per 1000 43 per 1000
(11 to 132)
OR 0.08
(0.02 to 0.27)
144
(1 study)
⊕⊕⊝⊝
low 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Fluoxetine compared to agomelatine

Summary of findings 3. Fluoxetine compared to agomelatine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

    2 Only one study included in this analysis.

Fluoxetine compared to agomelatine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: agomelatine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Agomelatine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

282 per 1000 361 per 1000
(280 to 450)
OR 1.44
(0.99 to 2.09)
515
(1 study)
⊕⊕⊝⊝
low 1,2
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.02 standard deviations higher
(0.18 lower to 0.23 higher)
 1213
(3 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero
Failure to complete - total - 135 per 1000 170 per 1000
(122 to 233)
OR 1.31
(0.89 to 1.94)
785
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 55 per 1000 59 per 1000
(23 to 142)
OR 1.08
(0.41 to 2.88)
785
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 34 per 1000 50 per 1000
(25 to 97)
OR 1.51
(0.74 to 3.07)
785
(2 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 Fluoxetine compared to amineptine

Summary of findings 4. Fluoxetine compared to amineptine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to amineptine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: amineptine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Amineptine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

719 per 1000 486 per 1000
(249 to 727)
OR 0.37
(0.13 to 1.04)
63
(1 study)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0 standard deviations higher
(0 to 0 higher)
 0 (0) No data available on this outcome
Failure to complete - total - 210 per 1000 140 per 1000
(43 to 370)
OR 0.61
(0.17 to 2.21)
232
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 94 per 1000 97 per 1000
(19 to 366)
OR 1.04
(0.19 to 5.57)
63
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - (Copy) 84 per 1000 46 per 1000
(3 to 418)
OR 0.52
(0.03 to 7.82)
232
(2 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 5 Fluoxetine compared to amisulpride

Summary of findings 5. Fluoxetine compared to amisulpride
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested. Only one study included in the analysis.

Fluoxetine compared to amisulpride
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: amisulpride
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Amisulpride Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

  0 per 1000
(0 to 0)
Not estimable0 (0)  

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.17 standard deviations higher
(0.07 lower to 0.41 higher)
 268
(1 study)
⊕⊕⊝⊝
low 1
This corresponds to a very small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 225 per 1000 288 per 1000
(191 to 409)
OR 1.39
(0.81 to 2.38)
281
(1 study)
⊕⊕⊝⊝
low 1
 
Failure to complete - inefficacy - 56 per 1000 65 per 1000
(25 to 156)
OR 1.16
(0.43 to 3.10)
281
(1 study)
⊕⊕⊝⊝
low 1
 
Failure to complete - side effects - 92 per 1000 72 per 1000
(32 to 155)
OR 0.77
(0.33 to 1.82)
281
(1 study)
⊕⊕⊝⊝
low 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 6 Fluoxetine compared to bupropion

Summary of findings 6. Fluoxetine compared to bupropion
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to bupropion
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: bupropion
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Bupropion Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

493 per 1000 447 per 1000
(318 to 582)
OR 0.83
(0.48 to 1.43)
436
(2 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0 standard deviations higher
(0 to 0 higher)
 0 (0) No data available on this outcome
Failure to complete - total - 356 per 1000 356 per 1000
(270 to 450)
OR 1.00
(0.67 to 1.48)
436
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 23 per 1000 0 per 1000
(0 to 87)
OR 1.16
(0.33 to 4.10)
436
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 59 per 1000 60 per 1000
(28 to 124)
OR 1.01
(0.45 to 2.25)
436
(2 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 7 Fluoxetine compared to citalopram

Summary of findings 7. Fluoxetine compared to citalopram
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

    2 Only one study included in the analysis and less than 100 patients.

Fluoxetine compared to citalopram
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: citalopram
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Citalopram Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

379 per 1000 268 per 1000
(109 to 522)
OR 0.60
(0.20 to 1.79)
59
(1 study)
⊕⊝⊝⊝
very low 1,2
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.06 standard deviations higher
(0.10 lower to 0.21 higher)
 661
(3 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero
Failure to complete - total - 211 per 1000 189 per 1000
(138 to 254)
OR 0.87
(0.60 to 1.27)
732
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 75 per 1000 66 per 1000
(37 to 112)
OR 0.87
(0.48 to 1.56)
732
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 75 per 1000 49 per 1000
(27 to 89)
OR 0.64
(0.34 to 1.20)
732
(3 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 8 Fluoxetine compared to Crocus sativus

Summary of findings 8. Fluoxetine compared to Crocus sativus
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested. Only one study included in the analysis and less than 50 patients.

Fluoxetine compared to Crocus sativus
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: Crocus sativus
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Crocus sativus Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

250 per 1000 150 per 1000
(35 to 464)
OR 0.53
(0.11 to 2.60)
40
(1 study)
⊕⊝⊝⊝
very low 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0 standard deviations higher
(0 to 0 higher)
 0 (0) No data available on this outcome
Failure to complete - total - 50 per 1000 50 per 1000
(3 to 475)
OR 1.00
(0.06 to 17.18)
40
(1 study)
⊕⊝⊝⊝
very low 1
 
Failure to complete - inefficacy -  0 per 1000
(0 to 0)
Not estimable0 (0)  
Failure to complete - side effects -  0 per 1000
(0 to 0)
Not estimable0 (0)  
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 9 Fluoxetine compared to duloxetine

Summary of findings 9. Fluoxetine compared to duloxetine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

    2 Only one study included in the analysis.

Fluoxetine compared to for duloxetine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: duloxetine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
  Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

400 per 1000 485 per 1000
(289 to 684)
OR 1.41
(0.61 to 3.25)
103
(1 study)
⊕⊕⊝⊝
low 1,2
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0 standard deviations higher
(0 to 0 higher)
 0 (0) No data available on this outcome
Failure to complete - total - 281 per 1000 260 per 1000
(171 to 372)
OR 0.90
(0.53 to 1.52)
532
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 15 per 1000 47 per 1000
(14 to 152)
OR 3.33
(0.93 to 12.11)
432
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 66 per 1000 19 per 1000
(5 to 80)
OR 0.28
(0.07 to 1.23)
532
(2 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 10 Fluoxetine compared to escitalopram

Summary of findings 10. Fluoxetine compared to escitalopram
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

    2 Only one study included in the analysis.

Fluoxetine compared to escitalopram
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: escitalopram
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Escitalopram Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

236 per 1000 239 per 1000
(147 to 363)
OR 1.02
(0.56 to 1.85)
240
(1 study)
⊕⊕⊝⊝
low 1,2
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.07 standard deviations higher
(0.19 lower to 0.33 higher)
 231
(1 study)
⊕⊕⊝⊝
low 1,2
This effect approaches zero
Failure to complete - total - 148 per 1000 210 per 1000
(148 to 292)
OR 1.53
(1.00 to 2.37)
578
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 13 per 1000 23 per 1000
(6 to 82)
OR 1.74
(0.46 to 6.53)
578
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 77 per 1000 89 per 1000
(51 to 151)
OR 1.17
(0.64 to 2.12)
578
(2 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 11 Fluoxetine compared to fluvoxamine

Summary of findings 11. Fluoxetine compared to fluvoxamine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

    2 Only one study included in the analysis.

Fluoxetine compared to fluvoxamine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: fluvoxamine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Fluvoxamine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

605 per 1000 592 per 1000
(443 to 727)
OR 0.95
(0.52 to 1.74)
177
(1 study)
⊕⊕⊝⊝
low 1,2
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0 standard deviations higher
(0 to 0 higher)
 0 (0) No data available on this outcome
Failure to complete - total - 170 per 1000 936 per 1000
(69 to 219)
OR 071
(0.36 to 1.37)
284
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy -  0 per 1000
(0 to 0)
Not estimable0 (0)  
Failure to complete - side effects - 39 per 1000 41 per 1000
(6 to 239)
OR 1.04
(0.14 to 7.71)
100
(1 study)
⊕⊕⊝⊝
low 1,2
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 12 Fluoxetine compared to hypericum

Summary of findings 12. Fluoxetine compared to hypericum
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to hypericum
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: hypericum
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Hypericum Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

490 per 1000 485 per 1000
(346 to 625)
OR 0.98
(0.55 to 1.73)
717
(6 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.13 standard deviations higher
(0.02 lower to 0.29 higher)
 648
(5 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a very small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 129 per 1000 133 per 1000
(88 to 189)
OR 1.04
(0.65 to 1. 68)
679
(5 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy -   OR 4.70
(0.22 to 99.39)
401
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 35 per 1000 42 per 1000
(20 to 88)
OR 1.21
(0.56 to 2.64)
679
(5 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 13 Fluoxetine compared to maprotiline

Summary of findings 13. Fluoxetine compared to maprotiline
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to maprotiline
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: maprotiline
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Maprotiline Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

398 per 1000 563 per 1000
(984 to 734)
OR 1.95
(0.91 to 4.18)
163
(2 studies)
⊕⊕⊕⊝
moderate
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.04 standard deviations higher
(0.15 lower to 0.23 higher)
 433
(5 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero
Failure to complete - total - 92 per 1000 151 per 1000
(84 to 257)
OR 1.75
(0.90 to 3.41)
351
(4 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 67 per 1000 36 per 1000
(11 to 121)
OR 0.53
(0.15 to 1.93)
209
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 19 per 1000 47 per 1000
(6 to 279)
OR 2.54
(0.33 to 19.9)
209
(3 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 14 Fluoxetine compared to mianserin

Summary of findings 14. Fluoxetine compared to mianserin
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

    2 Only one study included in the analysis and less than 100 patients.

Fluoxetine compared to mianserin
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: mianserin
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Mianserin Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

593 per 1000 538 per 1000
(282 to 776)
OR 0.80
(0.27 to 2.38)
53
(1 study)
⊕⊝⊝⊝
very low 1,2
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.43 standard deviations higher
(0.38 lower to 1.23 higher)
 128
(3 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 362 per 1000 263 per 1000
(93 to 560)
OR 0.63
(0.18 to 2.25)
93
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 74 per 1000 154 per 1000
(30 to 522)
OR 2.27
(0.38 to 13.63)
53
(1 study)
⊕⊝⊝⊝
very low 1,2
 
Failure to complete - side effects - 148 per 1000 154 per 1000
(38 to 450)
OR 1.05
(0.23 to 4.70)
53
(1 study)
⊕⊝⊝⊝
very low 1,2
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 15 Fluoxetine compared to milnacipran

Summary of findings 15. Fluoxetine compared to milnacipran
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to milnacipran
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: milnacipran
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Milnacipran Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

473 per 1000 518 per 1000
(412 to 623)
OR 1.20
(0.78 to 1.84)
370
(2 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.36 standard deviations lower
(0.63 to 0.08 lower)
 213
(2 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 411 per 1000 406 per 1000
(322 to 497)
OR 0.98
(0.68 to 1.42)
560
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 137 per 1000 165 per 1000
(97 to 267)
OR 1.25
(0.68 to 2.30)
560
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 71 per 1000 103 per 1000
(59 to 175)
OR 1.50
(0.81 to 2.76)
560
(3 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 16 Fluoxetine compared to mirtazapine

Summary of findings 16. Fluoxetine compared to mirtazapine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

    2 Only one study included in the analysis and less than 100 patients.

Fluoxetine compared to mirtazapine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: Fluoxetine
Comparison: mirtazapine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Mirtazapine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

354 per 1000 444 per 1000
(363 to 527)
OR 1.46
(1.04 to 2.04)
600
(4 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.57 standard deviations higher
(0.15 lower to 1.29 higher)
 31
(1 study)
⊕⊝⊝⊝
very low 1,2
This corresponds to a medium effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 327 per 1000 304 per 1000
(211 to 416)
OR 0.90
(0.55 to 1.47)
301
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 44 per 1000 62 per 1000
(31 to 119)
OR 1.45
(0.71 to 2.96)
600
(4 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 98 per 1000 93 per 1000
(56 to 151)
OR 0.95
(0.55 to 1.64)
600
(4 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 17 Fluoxetine compared to moclobemide

Summary of findings 17. Fluoxetine compared to moclobemide
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to moclobemide
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: moclobemide
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Moclobemide Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

436 per 1000 496 per 1000
(416 to 575)
OR 1.27
(0.92 to 1.75)
721
(7 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.13 standard deviations higher
(0.04 lower to 0.30 higher)
 540
(6 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a very small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 207 per 1000 209 per 1000
(155 to 275)
OR 1.01
(0.70 to 1.45)
721
(7 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 62 per 1000 44 per 1000
(21 to 93)
OR 0.70
(0.32 to 1.56)
679
(6 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 86 per 1000 91 per 1000
(57 to 144)
OR 1.07
(0.64 to 1.80)
721
(7 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 18 Fluoxetine compared to nefazodone

Summary of findings 18. Fluoxetine compared to nefazodone
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to nefazodone
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: nefazodone
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Nefazodone Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

  0 per 1000
(0 to 0)
Not estimable0 (0)  

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.06 standard deviations lower
(0.30 lower to 0.18 higher)
 271
(4 studies)
⊕⊕⊕⊝
moderate 1
This effects approaches zero
Failure to complete - total - 220 per 1000 132 per 1000
(58 to 269)
OR 0.54
(0.22 to 1.31)
161
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 24 per 1000 17 per 1000
(1 to 211)
OR 0.71
(0.05 to 10.71)
161
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 96 per 1000 75 per 1000
(33 to 161)
OR 0.76
(0.32 to 1.81)
286
(4 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 19 Fluoxetine compared to paroxetine

Summary of findings 19. Fluoxetine compared to paroxetine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to paroxetine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: paroxetine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Paroxetine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

426 per 1000 477 per 1000
(408 to 550)
OR 1.23
(0.93 to 1.65)
1574
(9 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.01 standard deviations lower
(0.25 lower to 0.24 higher)
 2061
(11 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero
Failure to complete - total - 317 per 1000 313 per 1000
(273 to 358)
OR 0.98
(0.81 to 1.20)
1848
(10 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 52 per 1000 39 per 1000
(22 to 71)
OR 0.75
(0.41 to 1.39)
1005
(4 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 133 per 1000 115 per 1000
(87 to 151)
OR 0.85
(0.62 to 1.16)
1509
(9 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 20 Fluoxetine compared to phenelzine

Summary of findings 20. Fluoxetine compared to phenelzine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested. Only one study included in the analysis and less than 50 patients.

Fluoxetine compared to phenelzine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: phenelzine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Phenelzine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

150 per 1000 200 per 1000
(45 to 564)
OR 1.42
(0.27 to 7.34)
40
(1 study)
⊕⊝⊝⊝
very low 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.05 standard deviations lower
(0.67 lower to 0.57 higher)
 40
(1 study)
⊕⊝⊝⊝
very low 1
This effect approaches zero
Failure to complete - total - 100 per 1000 20 per 1000
(1 to 308)
OR 0.18
(0.01 to 4.01)
40
(1 study)
⊕⊝⊝⊝
very low 1
 
Failure to complete - inefficacy -  0 per 1000
(0 to 0)
Not estimable0 (0)  
Failure to complete - side effects - 50 per 1000 17 per 1000
(1 to 303)
OR 0.32
(0.01 to 8.26)
40
(1 study)
⊕⊝⊝⊝
very low 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 21 Fluoxetine compared to pramipexole

Summary of findings 21. Fluoxetine compared to pramipexole
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested. Only one study included in the analysis.

Fluoxetine compared to pramipexole
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: pramipexole
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Pramipexole Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

657 per 1000 513 per 1000
(315 to 707)
OR 0.55
(0.24 to 1.26)
105
(1 study)
⊕⊕⊝⊝
low 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0 standard deviations higher
(0 to 0 higher)
 0 (0) No data available on this outcome
Failure to complete - total - 443 per 1000 87 per 1000
(23 to 250)
OR 0.12
(0.03 to 0.42)
105
(1 study)
⊕⊕⊝⊝
low 1
 
Failure to complete - inefficacy - 57 per 1000 29 per 1000
(3 to 215)
OR 0.49
(0.05 to 4.51)
105
(1 study)
⊕⊕⊝⊝
low 1
 
Failure to complete - side effects - 314 per 1000 27 per 1000
(5 to 186)
OR 0.06
(0.01 to 0.50)
105
(1 study)
⊕⊕⊝⊝
low 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 22 Fluoxetine compared to reboxetine

Summary of findings 22. Fluoxetine compared to reboxetine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to reboxetine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: reboxetine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Reboxetine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

566 per 1000 501 per 1000
(418 to 589)
OR 0.77
(0.55 to 1.10)
721
(3 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.04 standard deviations higher
(0.31 lower to 0.40 higher)
 205
(2 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero
Failure to complete - total - 361 per 1000 253 per 1000
(199 to 316)
OR 0.60
(0.44 to 0.82)
764
(4 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 88 per 1000 82 per 1000
(43 to 146)
OR 0.92
(0.47 to 1.77)
464
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 129 per 1000 57 per 1000
(22 to 139)
OR 0.41
(0.15 to 1.09)
211
(2 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 23 Fluoxetine compared to sertraline

Summary of findings 23. Fluoxetine compared to sertraline
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to sertraline
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: sertraline
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Sertraline Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

416 per 1000 494 per 1000
(435 to 554)
OR 1.37
(1.08 to 1.74)

1188

(6 studies)

⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.09 standard deviations higher
(0.03 lower to 0.20 higher)
 1160
(7 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a very small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 229 per 1000 258 per 1000
(217 to 307)
OR 1.17
(0.93 to 1.49)
1591
(9 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 70 per 1000 76 per 1000
(49 to 118)
OR 1.09
(0.68 to 1.77)
1056
(5 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 110 per 1000 134 per 1000
(102 to 174)
OR 1.25
(0.92 to 1.70)
1591
(9 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 24 Fluoxetine compared to tianeptine

Summary of findings 24. Fluoxetine compared to tianeptine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to tianeptine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: tianeptine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Tianeptine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

534 per 1000 562 per 1000
(462 to 657)
OR 1.12
(0.75 to 1.67)
387
(3 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.15 standard deviations lower
(0.40 lower to 0.10 higher)
 730
(3 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a very small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 225 per 1000 218 per 1000
(167 to 279)
OR 0.96
(0.69 to 1.33)
830
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 47 per 1000 39 per 1000
(13 to 110)
OR 0.82
(0.27 to 2.53)
830
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 91 per 1000 101 per 1000
(66 to 152)
OR 1.13
(0.71 to 1.80)
830
(3 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 25 Fluoxetine compared to trazodone

Summary of findings 25. Fluoxetine compared to trazodone
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to trazodone
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: trazodone
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Trazodone Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

642 per 1000 467 per 1000
(189 to 769)
OR 0.49
(0.13 to 1.86)
110
(3 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.25 standard deviations lower
(0.76 lower to 0.26 higher)
 203
(4 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 250 per 1000 145 per 1000
(71 to 274)
OR 0.51
(0.23 to 1.13)
230
(4 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 147 per 1000 38 per 1000
(7 to 207)
OR 0.23
(0.04 to 1.51)
70
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 151 per 1000 105 per 1000
(34 to 280)
OR 0.66
(0.20 to 2.19)
110
(3 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 26 Fluoxetine compared to venlafaxine

Summary of findings 26. Fluoxetine compared to venlafaxine
  1. 1 Limitations in studies designs: no details on randomisation procedures and allocation concealment. Blinding stated but not tested.

Fluoxetine compared to venlafaxine
Patient or population: patients with depression
Settings: in- and outpatients
Intervention: fluoxetine
Comparison: venlafaxine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Venlafaxine Fluoxetine

Failure to respond

(reduction ≥ 50% on HDRS)

341 per 1000 400 per 1000
(363 to 439)
OR 1.29
(1.10 to 1.51)
3387
(12 studies)
⊕⊕⊕⊝
moderate 1
 

Endpoint score

(HDRS or MADRS)

 The mean endpoint score in the intervention groups was
0.10 standard deviations higher
(0.0 to 0.19 higher)
 3097
(13 studies)
⊕⊕⊕⊝
moderate 1
This corresponds to a very small effect according
to conventions proposed
by Cohen 1992
Failure to complete - total - 256 per 1000 234 per 1000
(203 to 267)
OR 0.89
(0.74 to 1.06)
2683
(14 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - inefficacy - 43 per 1000 56 per 1000
(40 to 79)
OR 1.31
(0.91 to 1.89)
2640
(13 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to complete - side effects - 116 per 1000 87 per 1000
(69 to 110)
OR 0.72
(0.56 to 0.94)
2640
(13 studies)
⊕⊕⊕⊝
moderate 1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Major depression is generally diagnosed when a persistent and unreactive low mood or loss of interest and pleasure, or both, are accompanied by a range of symptoms including appetite loss, insomnia, fatigue, loss of energy, poor concentration, psychomotor symptoms, inappropriate guilt and morbid thoughts of death (APA 1994). It was the third leading cause of burden among all diseases in the year 2004 and it is expected to be the greatest cause in 2030 (WHO 2006). This condition is associated with marked personal, social and economic morbidity, loss of functioning and productivity, and creates significant demands on service providers in terms of workload (APA 2000; NICE 2010). Although pharmacological and psychological interventions are both effective for major depression, in primary and secondary care settings antidepressant (AD) drugs remain the mainstay of treatment in moderate to severe major depression (APA 2006; NICE 2010). Amongst ADs many different agents are available, including tricyclics (TCAs); monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); serotonin-noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine, duloxetine and milnacipran; and other agents (mirtazapine, reboxetine, bupropion). Over the last 20 years prescribing ADs has dramatically risen in Western countries, mainly because of the increasing number of prescriptions for SSRIs, which have progressively become the most commonly prescribed ADs (Ciuna 2004). The selective action of SSRIs is purported to be the rationale for potential advantages over other existing therapies. Rather than a breakthrough in pharmacology, the development of SSRIs may be seen as a process of refining the action of existing and commonly used alternatives and this process may be clinically important (Freemantle 2000). SSRIs are generally more acceptable than TCAs, and there is evidence of similar efficacy (NICE 2010). However, head-to-head comparisons have provided contrasting findings (Cipriani 2006a).

Description of the intervention

Fluoxetine hydrochloride (3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine HCl; Lilly (LY) 110140) was first described in a scientific journal in 1974 as a selective serotonin (5-hydroxytryptamine or 5-HT)-uptake inhibitor (Wong 2005). It was marketed as an AD in December 1987 and went off patent in August 2001. From its marketing fluoxetine quickly became the most prescribed AD in the United States (Marshall 2009) and, despite the availability of newer agents, it remains extremely popular in the pharmacological treatment of major depression and in the treatment of several anxiety disorders.

How the intervention might work

Fluoxetine’s presumed mechanism of action is through inhibiting the reuptake of serotonin. It is not clear, however, if reuptake inhibition correlates with clinical effect, either between patients or over time.

The bioavailability of fluoxetine is relatively high, and peak plasma concentrations are reached in six to eight hours. It is highly bound to plasma proteins, mostly albumin. Fluoxetine is metabolised in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. Only one metabolite of fluoxetine, norfluoxetine (N-demethylated fluoxetine), is biologically active. The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other ADs. With time, fluoxetine and norfluoxetine inhibit their own metabolism so the fluoxetine elimination half-life changes from one to three days after a single dose to four to six days after long-term use.

Why it is important to do this review

In 2000 Geddes and colleagues (Geddes 2000) completed a Cochrane systematic review comparing the group of SSRIs with all other ADs and concluded that there were no large differences between the AD drug classes; however it was suggested that differences may emerge when single, head-to-head drug comparisons were considered. Starting from this consideration, and with the aim to shed light on the field of AD trials and treatment of major depression, a group of researchers agreed to join forces under the rubric of the Meta-Analyses of New Generation Antidepressants Study Group (MANGA Study Group) to systematically review all available evidence for each specific newer AD. We have up to now completed individual reviews on sertraline (Cipriani 2009a), escitalopram (Cipriani 2009b), milnacipran (Nagakawa 2009), fluvoxamine (Omori 2010), mirtazapine (Watanabe 2011), duloxetine (Cipriani 2012a) and citalopram (Cipriani 2012b), and a number of other reviews are now underway. A systematic review comparing fluoxetine with TCAs, heterocyclics, MAOIs, SSRIs, SNRIs and other antidepressants was first published in 2005 (Cipriani 2005) but since then new randomised evidence has been produced. We therefore sought to update that review with the aim of providing the ‘best available’ and most up-to-date evidence on the efficacy and acceptability of fluoxetine in individuals with unipolar major depression.

Objectives

To assess the effects of fluoxetine in comparison with all other antidepressive agents for depression in adult individuals with unipolar major depressive disorder. Specifically:

  1. To determine the efficacy of fluoxetine in comparison with other ADs in alleviating the acute symptoms of unipolar major depressive disorder in adults; and

  2. Review the acceptability of treatment with fluoxetine in comparison with other ADs.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing fluoxetine with all other active ADs as monotherapy in the acute phase treatment of unipolar depression were included. We included RCTs with a cross-over design but only used the results from the first randomisation period.

We excluded quasi-randomised trials, such as those allocating participants by using alternate days of the week.

Types of participants

The review included participants 18 years or older, of both sexes, with a primary diagnosis of unipolar major depression according to standardised criteria, DSM-III, DSM-III-R, DSM-IV (APA 2000), ICD-10 (WHO 1992), Feighner criteria (Feighner 1972) or Research Diagnostic Criteria (Spitzer 1972). Studies using ICD-9 were excluded as it only lists disease names and does not have diagnostic criteria.

We included participants with the following subtypes of depression: chronic, with catatonic features, with melancholic features, with atypical features, with postpartum onset, and with a seasonal pattern. We included studies in which up to 20% of participants presented with depressive episodes in bipolar affective disorder. We also included participants with a concurrent secondary diagnosis of another psychiatric disorder.

We excluded participants with a concurrent primary diagnosis of Axis I or II disorders and participants with a serious concomitant medical illness.

Types of interventions

We examined fluoxetine in comparison with conventional pharmacological treatments for acute depression. We also examined fluoxetine in comparison with non-conventional ADs (hypericum or other non-conventional ADs). We excluded trials in which fluoxetine was compared to another type of psychopharmacological agent (that is anxiolytics, anticonvulsants, antipsychotics or mood-stabilisers) and trials in which fluoxetine was used as an augmentation strategy.

Experimental intervention

Fluoxetine (as monotherapy). No restrictions on dose, frequency, intensity and duration were applied.

Comparator interventions

Conventional antidepressive agents:

  1. tricyclics (TCAs);

  2. heterocyclics;

  3. SSRIs;

  4. SNRIs;

  5. MAOIs or newer ADs; and

  6. other conventional psychotropic drugs.

Non-conventional antidepressive agents:

  1. hypericum; and

  2. other non-conventional antidepressive agents (e.g. Crocus sativus).

No restrictions on dose, frequency, intensity and duration were applied.

Types of outcome measures

Primary outcomes
Efficacy

Efficacy was evaluated using the following outcome measures.

(1) Dichotomous outcome

Number of participants who responded to treatment at the end of the trial by showing a reduction of at least 50% on the Hamilton Depression Scale (HDRS) (Hamilton 1960) out of the total number of randomised participants (intention-to-treat analysis).

(2) Continuous outcome

Group mean scores at the end of the trial or change scores on HDRS, or Montgomery-Asberg Depression Scale (MADRS) (Montgomery 1979), or any other depression scale. If both endpoint and change scores were available, we considered endpoint scores.

Secondary outcomes
Acceptability
(3) Failure to complete due to any reason

Number of participants who dropped out during the trial as a proportion of the total number of randomised participants.

(4) Failure to complete due to inefficacy

Number of participants who dropped out during the trial due to inefficacy as a proportion of the total number of randomised participants.

(5) Failure to complete due to side effects

Number of participants who dropped out during the trial due to side effects as a proportion of the total number of randomised participants.

Search methods for identification of studies

CCDAN's Specialized Register (CCDANCTR) 
The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) maintains two clinical trials registers at their editorial base in Bristol, UK, a references register and a studies based register. The CCDANCTR-References Register contains over 31,500 reports of randomised controlled trials in depression, anxiety and neurosis. Approximately 65% of these references have been tagged to individual, coded trials. The coded trials are held in the CCDANCTR-Studies Register and records are linked between the two registers through the use of unique Study ID tags. Coding of trials is based on the EU-Psi coding manual. Please contact the CCDAN Trials Search Coordinator for further details. Reports of trials for inclusion in the Group's registers are collated from routine (weekly), generic searches of MEDLINE (1950-), EMBASE (1974-) and PsycINFO (1967-); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review specific searches of additional databases. Reports of trials are also sourced from international trials registers c/o the World Health Organization’s trials portal (ICTRP), ClinicalTrials.gov, drug companies, the hand-searching of key journals, conference proceedings and other (non-Cochrane) systematic reviews and meta-analyses.

Details of CCDAN's generic search strategies can be found on the Group's website.

Electronic searches

The CCDANCTR-Studies Register was searched by the Trials Search Co-ordinator (TSC) using the following search strategy:
Diagnosis = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood Disorder*" or "Affective Disorder*" or "Affective Symptoms"
and
Intervention = Fluoxetine

The CCDANCTR-References Register was searched using similar terms to identify additional untagged/uncoded references:
Keyword = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood Disorder*" or "Affective Disorder" or "Affective Symptoms"
and
Free-Text = (Fluoxetin* or Prozac)

Searches were conducted to 11 May 2012. No language restrictions were applied.

Other trial registers

The CCDAN TSC also searched Clinicalstudyresults.org to December 2011 (before this website was phased out) together with ClinicalTrials.gov and the WHO ICTRP to 16 July 2012 for additional published, unpublished or ongoing studies.

We searched trial databases of the following drug-approving agencies: the Food and Drug Administration (FDA) in the USA, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, the European Medicines Agency (EMA) in the EU, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the Therapeutic Goods Administration (TGA) in Australia. We also searched ongoing trial registers: ClinicalTrials.gov in the USA, Controlled-Trials.com (ISRCTN) in the UK, the Nederland's Trial Register, the European Union Drug Regulating Authorities Clinical Trials register (EudraCT), UMIN-CTR in Japan and the Australian New Zealand Clinical Trials Registry (ACTRN). These searches were undertaken in November 2010.

Searching other resources

Handsearches

Appropriate journals and conference proceedings relating to fluoxetine treatment for depression have already been handsearched and incorporated into the CCDANCTR databases.

Personal communication

Pharmaceutical companies and experts in this field were asked if they knew of any study that met the inclusion criteria of this review.

Reference checking

Reference lists of the included studies, previous systematic reviews and major textbooks of affective disorder that were written in English were checked for published reports and citations of unpublished research (Trespidi 2011).

Data collection and analysis

Selection of studies

Two independent review authors (LRM, MP) checked to ensure that studies relating to fluoxetine generated by the search of the CCDANCTR-References Register and the other complementary searches met the rough inclusion criteria, firstly based on the titles and abstracts. All studies that were rated as possible candidates by either of the two review authors were added to a preliminary list, and the full text articles were then retrieved. LRM, CG, MP and AC assessed the full text articles to see if they met the strict inclusion criteria. If the raters disagreed, the final rating was made by consensus with the involvement of another member of the review group (CB). Considerable care was taken to group multiple publications to the main study to which they related.

Data extraction and management

Two review authors, working independently and in duplicate (LRM and MP), extracted data from the included studies. Again, any disagreement was discussed with other authors, and decisions were documented. If necessary, we contacted authors of studies for clarification. We extracted the following data from the included studies:

(i) participant characteristics (age, depression diagnosis, comorbidity, depression severity, antidepressant treatment history for the index episode, study setting);
(ii) intervention details (intended dosage range, mean daily dosage actually prescribed, sponsorship); and
(iii) outcome measures of interest.

The results were compared with those in the completed reviews of individual antidepressants in The Cochrane Library.

We considered the following comparisons:

  • fluoxetine versus TCAs;

  • fluoxetine versus the heterocyclics maprotiline, mianserin;

  • fluoxetine versus the SSRIs citalopram, escitalopram, fluvoxamine, paroxetine, sertraline;

  • fluoxetine versus the SNRIs duloxetine, milnacipran, venlafaxine;

  • fluoxetine versus the MAOIs or newer ADs agomelatine, mirtazapine, moclobemide, phenelzine, reboxetine;

  • fluoxetine versus other conventional psychotropic drugs amineptine, bupropion, pramipexole, tianeptine, trazodone; and

  • fluoxetine versus the other non-conventional AD agents Crocus sativus, hypericum.

In the analysis TCAs were pooled as data have shown that drugs belonging to the TCA group are similar in terms of efficacy and tolerability, while drugs belonging to the other classes have rather different efficacy and tolerability profiles (Cipriani 2011).

Assessment of risk of bias in included studies

Two independent review authors independently assessed trial quality in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This set of criteria is based on evidence of associations between effect overestimation and a high risk of bias in an article, such as sequence generation, allocation concealment, blinding (of participants and personnel, outcome assessment), incomplete outcome data, selective reporting and other source of bias. The categories are defined as:

  • low risk of bias;

  • high risk of bias; and

  • unclear risk of bias.

If the raters disagreed, the final rating was made by consensus with the involvement of another member of the review group.

Non-congruence in quality assessment was reported as percentage disagreement. The ratings were also compared with those in the completed reviews of individual antidepressants in The Cochrane Library. If there were any discrepancies, they were fed back to the authors of the completed reviews.

Measures of treatment effect

All comparisons were performed between fluoxetine and comparator ADs as individual ADs. Additionally, fluoxetine was compared with TCAs considered as a class.

Skewed data and non-quantitative data were presented descriptively. An outcome was considered skewed when the mean was smaller than twice the SD. In terms of change score, data were difficult to depict as skewed or not as the possibility existed for negative values; therefore, we entered all of the results of the outcome into the meta-analysis.

Dichotomous data

For dichotomous, or event-like, data, odds ratios (ORs) were calculated with their 95% confidence intervals (CI). For statistically significant results, we calculated the number needed to treat to provide benefit (NNT).

Continuous data

For continuous data we calculated the standardised mean differences (SMD) with 95% CI.

Unit of analysis issues

Cross-over trials

A major concern of cross-over trials is the carry-over effect. It occurs if an effect (for example pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase the participants can differ systematically from their initial state, even with a wash-out phase. For the same reason, cross-over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in major depression, we only used data from the first phase of the cross-over studies.

Cluster-randomised trials

Studies increasingly employ 'cluster randomisation’ (such as randomisation by clinician or practice) but analysis and pooling of clustered data pose problems (Barbui 2011b). They are commonly analysed as if the randomisation was performed on the individuals rather than the clusters. In this case, approximately correct analyses were performed by dividing the binary data (the number of participants and the number experiencing the event) as presented in a report by a 'design effect’ (Higgins 2011). This is calculated using the mean number of participants per cluster (m) and the intra-class correlation coefficient (ICC): design effect = 1 + (m-1) *ICC (Higgins 2011). If the ICC was not reported it was assumed to be 0.1. For continuous data only the sample size was reduced; means and standard deviations remained unchanged.

Studies with multiple treatment groups

Studies that compared more than two intervention groups were included in the meta-analysis by combining all relevant experimental intervention groups of the study into a single group, and all relevant control intervention groups into a single control group, as recommended in section 16.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

Dichotomous data

Responders and remitters to treatment were calculated on a strict intention-to-treat (ITT) basis: dropouts were included in this analysis. Where participants had been excluded from the trial before the endpoint, we assumed that they experienced a negative outcome by the end of the trial (for example failure to respond to treatment). We examined the validity of this decision in the sensitivity analyses by applying worst- and best-case scenarios.

When dichotomous outcomes were not reported but the baseline mean, endpoint mean and their SDs of the HRSD (or other depression scale) were provided, we converted continuous outcome data expressed as mean and SD into the number of responding and remitted patients, according to the validated imputation method (Furukawa 2006). We examined the validity of this imputation in the sensitivity analyses (Altman 1996; Furukawa 2006).

Continuous data

We applied the loose ITT analyses for continuous variables whereby all the patients with at least one post-baseline measurement were represented by their last observations carried forward (LOCF), with due consideration of the potential bias and uncertainty introduced. Data from trials not using a LOCF approach were extracted and analysed as reported by the authors. Where SDs were not reported, authors were asked to supply the data. When only the standard error (SE) or t-statistics or P values were reported, SDs were calculated according to Altman (Altman 1996). In the absence of data from the authors, we substituted SDs by those reported in other studies in the review (Furukawa 2006).

Assessment of heterogeneity

Heterogeneity between studies was investigated by visual inspection of the forest plots and using the I2 statistic (Higgins 2003). According to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the following thresholds for the interpretation of I2 were used: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; 75% to 100%, considerable heterogeneity. Moreover, we considered the sample size, and the magnitude and the direction of the treatment effects.

Assessment of reporting biases

Data from included studies were entered into a funnel plot (trial effect against trial variance) to investigate small-study effects (Sterne 2000). We used the tests for funnel plot asymmetry only when there were at least 10 studies included in the meta-analysis, and results were interpreted cautiously, with visual inspection of the funnel plots. We followed the Cochrane Handbook for Systematic Reviews of Interventions methodology (Higgins 2011). When evidence of small-study effects was identified, possible reasons for funnel plot asymmetry, including publication bias, were investigated.

Data synthesis

The primary analysis used a random-effects model (odds ratio (OR)), which had the highest generalisability in our empirical examination of summary effect measures for meta-analyses (Furukawa 2002). The robustness of this summary measure was routinely examined by checking the fixed-effect model OR and the random-effects model risk ratio (RR). Material differences between the models were reported. A P value of less than 0.05 and a 95% confidence interval (CI) not including 1 (for the dichotomous outcomes) were considered statistically significant.

Fixed-effect model analyses were performed routinely for the continuous outcomes as well, to investigate the effect of the choice of method on the estimates. Material differences between the models were reported.

Subgroup analysis and investigation of heterogeneity

We undertook a subgroup analysis for the duration of follow up. We considered the following categories: (1) less than 6 weeks, (2) 6 to 16 weeks, and (3) more than 16 weeks. Moreover, with the exception of the TCA group, stratification by each control agent was performed to ascertain whether there were treatment differences between fluoxetine and AD drugs belonging to the same pharmacological class. 

Sensitivity analysis

Sensitivity analyses (worst-case scenario; best-case scenario; excluding ORs imputed based on continuous data; fixed-effect rather than random-effects models; RR rather than OR; excluding trials using LOCF; excluding trials with substituted SD) were not performed in this version of the review. However, we will conduct these analyses in the next update. If cluster-randomised or cross-over trials are included in the next update, we will undertake a sensitivy analysis excluding studies with these study designs.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification

Results of the search

The original searches yielded 883 studies; after reading the abstracts, 364 papers were considered potentially relevant for this review. Of these, 219 were excluded because they were not randomised trials or for other reasons. The remaining 145 were retrieved for more detailed evaluation and 132 RCTs meeting the inclusion criteria were included in the 2005 version (see Figure 1).

Figure 1.

Study flow diagram, 2005 version.

In July 2012 a new search was conducted to update the review. This new search yielded 524 new records of RCTs published between 2005 and 2012, 12 unpublished RCTs, 10 RCTs defined as 'awaiting assessment' in the previous 2005 version, and five studies still ongoing at the time of inclusion. Of these, 536 were considered potentially relevant for this review. After reading the abstracts, 99 references were considered eligible for possible inclusion and the corresponding full papers were retrieved for a detailed evaluation; 55 trials were excluded or are awaiting assessment for wrong study design (not RCT) or other reasons and five are still ongoing. We included a total of 39 RCTs in the qualitative synthesis and 33 RCTs in the quantitative synthesis (meta-analysis) (see Figure 2).

Figure 2.

Study flow diagram, 2012 version.

Included studies

See: Characteristics of included studies

Overall, a total of 171 studies were included in the present systematic review (24,868 participants). Attempts to contact authors for additional information were unsuccessful in 22 cases and successful in two cases with additional data provided by the authors.

Design

The great majority of included studies were reported to be double-blind (161 out of 171 RCTs, that is 95%). The participants were followed up for six weeks (range four to 24 weeks) in a majority of the trials (80 trials).

Sample sizes

The mean number of participants per study was 135.2, with a minimum sample size of 16 (O'Keane 1992) and a maximum of 1096 (Keller 2007).

Setting

A total of 105 trials enrolled only outpatients, 14 trials enrolled only inpatients, and both inpatients and outpatients were enrolled in the remaining trials. Forty-one per cent of the included studies were undertaken in Europe, 20% in USA, 5% in Canada and in Central or South America, 4% of the trials were conducted in Iran and for the remaining 12% the geographic area was unclear. Three per cent of the included studies were multicentric international trials: 2% were conducted in Africa (South Africa and Zimbabwe); 2% in China, Australia and New Zealand; less than 1% in Israel and Turkey.

Participants

The majority of included trials (163 RCTs) enrolled patients with a diagnosis of major depression based on DSM-III (34 studies), DSM-III-R (64 studies), DSM-IV or ICD 10 criteria (67 studies). Seventy-eight trials excluded patients over 65 years, while 14 trials included only elderly patients. We also included a minority of studies in which up to 20% of patients presented with depressive episodes in bipolar disorder.

Intervention and comparators

In 74 studies fluoxetine was compared with TCAs (22 studies versus amitriptyline, 15 versus imipramine, 6 versus dothiepin or dosulepin, 5 versus maprotiline, 5 versus clomipramine, 6 versus nortriptyline, 4 versus desipramine, 4 versus doxepine, 3 versus mianserin, 2 versus trimipramine, 1 versus lofepramine, 1 versus nimofensine). Thirty RCTs compared fluoxetine with other SSRIs (13 versus paroxetine, 12 versus sertraline, 3 versus citalopram, 2 versus escitalopram), 20 versus SNRIs (15 versus venlafaxine, 3 versus milnacipran, 2 versus duloxetine), and 20 studies with MAOIs or newer agents (7 versus moclobemide, 4 versus reboxetine, 5 versus mirtazapine, 3 versus agomelatine, 1 versus phenelzine). Moreover, in 19 studies fluoxetine was compared with other conventional agents (4 versus trazodone, 4 versus nefazodone, 4 versus tianeptine, 2 versus amineptine, 2 versus bupropion, 1 versus pramipexole, 1 versus amisulpride, 1 versus ABT-200). Finally, eight studies compared fluoxetine with non-conventional agents (6 versus hypericum and 2 versus Crocus sativus). A fixed dose regimen for fluoxetine was employed in 72 studies.

Outcomes

At the end of the reviewing process, 165 RCTs were included in the meta-analysis. For efficacy outcomes, 121 RCTs provided continuous data and 91 dichotomous data. For acceptability outcomes, 139 RCTs provided data on total dropouts, 104 on dropouts due to inefficacy and 125 on dropouts due to side effects. In the majority of trials (130 out of 143, 90%) the 17- or 21- item HDRS was used for reporting outcomes.

Overall, 13,619 patients were included in the efficacy analysis dichotomous outcome (6441 participants randomised to fluoxetine and 7178 randomised to another antidepressant) and 15,870 were included in the efficacy analysis continuous outcome (7625 participants randomised to fluoxetine and 8245 randomised to another antidepressant). A total of 18,756 patients were included in the acceptability analysis (9009 partIcipants randomised to fluoxetine and 9747 randomised to another antidepressant).

Excluded studies

See: Characteristics of excluded studies; Characteristics of studies awaiting classification

Forty-four articles that were initially selected did not meet our inclusion criteria and were excluded because of one of the following reasons: wrong design (24 articles), review or pooled analysis (two articles), wrong comparison (nine articles), wrong intervention (one article) and wrong diagnosis or population (eight articles). A total of 34 records were classified as 'awaiting classification'. Of these, 28 were study reports written in Chinese.

Risk of bias in included studies

See: Included studies; Figure 3; Figure 4

Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 4.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Our judgement about the overall risk of bias in the individual studies is illustrated in Figure 3 and Figure 4. The methodological quality of many included studies was judged as poor, although judging articles from some time ago by today’s standard might be problematic (Begg 1996). Moreover, many articles failed to report methodologically relevant information on study procedure (in these cases the judgement was defined as 'unclear') and the overall reporting of studies was not good. This type of reporting has been associated with an overestimate of the estimate of effect (Schulz 1995) and it should be considered when interpreting the results. However, in general it is not possible to predict the direction or magnitude of bias associated with a lack of adequate sequence generation or adequate allocation concealment (Odgaard-Jensen 2011).

Allocation

Random sequence generation

The majority of studies (161) did not report the methods of generating random sequence, while eight studies (Akhondzadeh Basti 2007; Alves 1999; Byerley 1988; Harrer 1999; Hosak 2000; Noorbala 2005; Rudolph 1999; Sheehan 2009) specified this information and they were classified as 'low risk'.

Allocation concealment

All trials failed to report details on allocation concealment and were classified as 'unclear risk'.

Blinding

One hundred and sixty-three trials were undertaken on a double-blind basis, four trials employed a single-blind design and five an open design. None of the double-blind trials specified if blindness was maintained during the study. Nine studies were classified as 'high risk' of performance and detection bias while the remaining 163 were classified as 'unclear'. For the item on blinding of participants and personnel (performance bias), three RCTs were classified as 'low risk' of bias, nine RCTs as 'high risk' of bias and the remaining 160 as 'unclear'.

Incomplete outcome data

Only 11 trials (Alby 1993; Bennie 1995; Berlanga 1997; Chouinard 1999; Corrigan 2000; Dierick 1996; Fava 2005; Guelfi 1999; O'Keane 1992; Sheehan 2009; Suleman 1997) were rated as adequate in terms of addressing incomplete outcome data, while the majority (83 studies) were classified as 'unclear risk' and 77 as 'high risk'.

Selective reporting

The study protocol was not available for almost all studies so it was difficult to make a judgement on the possibility of outcome reporting bias. However, in six studies (Chouinard 1999; Fava 2005; Guelfi 1999; Hale 2010; O'Keane 1992; Wehmeier 2005) results were consistent with what was stated in the study protocols. Twenty-three studies were classified as 'high risk' of bias, five studies as 'low risk' of bias and the remaining 144 were classified as 'unclear'.

Other potential sources of bias

Most of the included studies (115 RCTs) were funded by pharmaceutical industry (and classified as 'high risk' of bias) and five studies were independent of industry (and classified as 'low risk' of bias). The remaining studies did not specify the source of funding and were defined as 'unclear'.

Effects of interventions

See: Summary of findings for the main comparison Fluoxetine compared to TCAs; Summary of findings 2 Fluoxetine compared to ABT-200; Summary of findings 3 Fluoxetine compared to agomelatine; Summary of findings 4 Fluoxetine compared to amineptine; Summary of findings 5 Fluoxetine compared to amisulpride; Summary of findings 6 Fluoxetine compared to bupropion; Summary of findings 7 Fluoxetine compared to citalopram; Summary of findings 8 Fluoxetine compared to Crocus sativus; Summary of findings 9 Fluoxetine compared to duloxetine; Summary of findings 10 Fluoxetine compared to escitalopram; Summary of findings 11 Fluoxetine compared to fluvoxamine; Summary of findings 12 Fluoxetine compared to hypericum; Summary of findings 13 Fluoxetine compared to maprotiline; Summary of findings 14 Fluoxetine compared to mianserin; Summary of findings 15 Fluoxetine compared to milnacipran; Summary of findings 16 Fluoxetine compared to mirtazapine; Summary of findings 17 Fluoxetine compared to moclobemide; Summary of findings 18 Fluoxetine compared to nefazodone; Summary of findings 19 Fluoxetine compared to paroxetine; Summary of findings 20 Fluoxetine compared to phenelzine; Summary of findings 21 Fluoxetine compared to pramipexole; Summary of findings 22 Fluoxetine compared to reboxetine; Summary of findings 23 Fluoxetine compared to sertraline; Summary of findings 24 Fluoxetine compared to tianeptine; Summary of findings 25 Fluoxetine compared to trazodone; Summary of findings 26 Fluoxetine compared to venlafaxine

Comparison 1: fluoxetine versus TCAs

Primary outcome: efficacy
1.1 Dichotomous outcome

Twenty-four studies contributed to this comparison including 2124 participants.

We found no difference in terms of efficacy between fluoxetine and TCAs as a class (OR 0.97, 95% CI 0.77 to 1.22, 24 RCTs, 2124 participants). In head-to-head comparisons, only dothiepin/dosulepin was found to be more effective than fluoxetine (OR 2.13, 95% CI 1.08 to 4.20; NNT = 6, 95% CI 3 to 50, 2 RCTs, 144 participants).

1.2 Continuous outcome

Fifty studies contributed to this comparison including 3393 participants.

On this outcome (measured with HDRS or MADRS), we found no differences between fluoxetine and TCAs as a class (SMD 0.03, 95% CI -0.07 to 0.14, 50 RCTs, 3393 participants) and between fluoxetine and individual TCAs.

Secondary outcome: acceptability
1.3 Failure to complete due to any cause

Forty-nine studies contributed to this comparison including 4194 participants.

In terms of participants who dropped out for any cause, fluoxetine was better tolerated than TCAs (OR 0.79, 95% CI 0.65 to 0.96; NNT = 20, 95% CI 13 to 48, 49 RCTs, 4194 participants), in particular amitriptyline (OR 0.62, 95% CI 0.46 to 0.85; NNT = 13, 95% CI 8 to 39, 18 RCTs, 1089 participants).

1.4 Failure to complete due to inefficacy

Thirty-three studies contributed to this comparison including 2911 participants.

We found no differences in terms of dropouts due to inefficacy (OR 1.29, 95% CI 0.96 to 1.72, 33 RCTs, 2911 participants).

1.5 Failure to complete due to side effects

Forty studies contributed to this comparison including 3647 participants.

The analysis of dropouts due to side effects revealed that amitriptyline (OR 0.41, 95% CI 0.23 to 0.71; NNT = 12, 95% CI 8 to 22, 16 RCTs, 1038 participants), clomipramine (OR 0.30, 95% CI 0.12 to 0.79; NNT = 11 , 95% CI 6 to 46, 2 RCTs, 163 participants), imipramine (OR 0.47, 95% CI 0.26 to 0.86; NNT= 8, 95% CI 6 to 12, 10 RCTs, 1093 participants) and overall TCAs (OR 0.55, 95% CI 0.40 to 0.75; NNT = 14, 95% CI 10 to 20, 40 RCTs, 3647 participants) were less well tolerated than fluoxetine.

Comparison 2: fluoxetine versus heterocyclics

Primary outcome: efficacy
2.1 Dichotomous outcome

Three studies contributed to this comparison including 216 participants.

In terms of dichotomous outcomes, we found no differences between fluoxetine and individual heterocyclics.

2.2 Continuous outcome

Eight studies contributed to this comparison including 561 participants.

In terms of continuous outcomes, we found no differences between fluoxetine and individual heterocyclics.

Secondary: acceptability
2.3 Failure to complete due to any cause

Six studies contributed to this comparison including 444 participants.

In terms of patients who dropped out during the trial for any reason, we found no differences between fluoxetine and individual heterocyclics.

2.4 Failure to complete due to inefficacy

Four studies contributed to this comparison including 262 participants overall.

We found no differences in terms of dropouts due to inefficacy.

2.5 Failure to complete due to side effects

Four studies contributed to this comparison including 262 participants overall.

Similarly, we found no differences in terms of dropouts due to side effects.

Comparison 3: fluoxetine versus other SSRIs

Primary outcome: efficacy
3.1 Dichotomous outcome

Eighteen studies contributed to this comparison including 3238 participants overall.

There was a difference in terms of efficacy in favour of sertraline over fluoxetine (OR 1.37, 95% CI 1.08 to 1.74; NNT = 13, 95% CI 7 to 58, 6 RCTs, 1188 participants).

3.2 Continuous outcome

Twenty-two studies contributed to this comparison including 4113 participants overall.

In terms of continuous outcomes (measured with HDRS or MADRS), there were inconclusive results.

Secondary outcome: acceptability
3.3 Failure to complete due to any cause

Twenty-six studies contributed to this comparison including 5033 participants.

In terms of patients who dropped out for any reason, we found a trend in favour of escitalopram over fluoxetine (OR 1.53, 95%, CI 1 to 2.37, 2 RCTs, 578 participants).

3.4 Failure to complete due to inefficacy

Fourteen studies contributed to this comparison including 3371 participants.

No difference was found between fluoxetine and other SSRIs in terms of discontinuation due to inefficacy.

3.5 Failure to complete due to side effects

Twenty-four studies contributed to this comparison including 4510 participants.

No difference was found between fluoxetine and other SSRIs in terms of discontinuation due to side effects.

Comparison 4: fluoxetine versus SNRIs

Primary outcome: efficacy
4.1 Dichotomous outcome

Fifteen studies contributed to this comparison including 3860 participants.

There was a difference in terms of efficacy in favour of venlafaxine over fluoxetine (OR 1.29, 95%, CI 1.10 to 1.51; NNT =11, 95% CI 8 to 16, 12 RCTs, 3387 participants). No difference was found between fluoxetine and other SNRIs (milnacipran and duloxetine).

4.2 Continuous outcome

Fifteen studies contributed to this comparison including 3310 participants.

There was a difference in terms of efficacy in favour of fluoxetine over milnacipran (measured with HDRS or Montgomery and Asberg Scale for Depression (MADRS)) (SMD -0.36, 95% CI -0.63 to -0.08, 2 RCTs, 213 participants) and a small difference in favour of venlafaxine over fluoxetine (SMD 0.10 95%, CI 0.00 to 0.19,13 RCTs, 3097 participants).

Secondary outcome: Acceptability
4.3 Failure to complete due to any cause

Nineteen studies contributed to this comparison including 3775 participants.

There was no evidence that fluoxetine was associated with a smaller or higher rate of dropout for any reason than the SNRIs.

4.4 Failure to complete due to inefficacy

Eighteen studies contributed to this comparison including 3632 participants.

There was no evidence that fluoxetine was associated with a smaller or higher rate of dropout for inefficacy than the SNRIs.

4.5 Failure to complete due to side effects

Eighteen studies contributed to this comparison including 3732 participants.

The analysis of dropouts due to side effects revealed that fluoxetine had an advantage over venlafaxine (OR 0.72, 95% CI 0.56-0.94; NNT = 36, 95% CI 20 to 202, 13 RCTs, 2640 participants).

Comparison 5: fluoxetine versus MAOIs or newer ADs

Primary outcome: efficacy
5.1 Dichotomous outcome

Sixteen studies contributed to this comparison including 2567 participants.

There was a difference in terms of efficacy in favour of mirtazapine over fluoxetine (OR 1.46, 95% CI 1.04 to 2.04; NNT = 12, 95% CI 6 to 134, 4 RCTs, 600 participants). No differences were found between fluoxetine and other newer ADs or MAOIs.

5.2 Continuous outcome

Thirteen studies contributed to this comparison including 2029 participants.

We found no differences in terms of efficacy between fluoxetine and MAOIs or newer ADs (measured with HDRS or MADRS).

Secondary outcome: acceptability
5.3 Failure to complete due to any reason

Seventeen studies contributed to this comparison including 2611 participants.

In terms of participants who dropped out during the trial for any reason, fluoxetine performed better in comparison with reboxetine only (OR 0.60, 95%, CI 0.44 to 0.82; NNT = 9, 95% CI 6 to 24, 4 RCTs, 764 participants).

5.4 Failure to complete due to inefficacy

Sixteen studies contributed to this comparison including 2568 participants.

No differences were found between fluoxetine and MAOIs or newer ADs in terms of dropout due to inefficacy.

5.5 Failure to complete due to side effects

Sixteen studies contributed to this comparison including 2157 participants.

No differences were found between fluoxetine and MAOIs or newer ADs in terms of dropout due to side effects. However, we found a trend in favour of fluoxetine over reboxetine (OR 0.41, 95% CI 0.15 to 1.09, 2 RCTs, 211 participants).

Comparison 6: fluoxetine versus other conventional psychotropic drugs

Primary outcome: efficacy
6.1 Dichotomous outcome

Eight studies contributed to this comparison including 1101 participants.

No differences between fluoxetine and any other conventional AD (amineptine, bupropion, pramipezole, tianeptine, trazodone) were found in terms of dichotomous outcome measures.

6.2 Continuous outcome

Thirteen studies contributed to this comparison including 1613 participants.

We found an advantage of fluoxetine over ABT-200 (SMD -1.85, 95% CI -2.25 to -1.45, 1 RCT, 141 participants) (measured with HDRS or MADRS). No differences in continuous outcome measures were found between fluoxetine and other conventional ADs.

Secondary outcome: acceptability
6.3 Failure to complete due to any cause

Seventeen studies contributed to this comparison including 2419 participants.

In terms of participants who dropped out for any reason, fluoxetine was better tolerated than ABT-200 (OR 0.18, 95% CI 0.08 to 0.39; NNT = 3, 95% CI 2 to 5, 1 RCT, 144 participants) and pramipexole (OR 0.12, 95% CI 0.03 to 0.42; NNT = 3, 95% CI 2 to 5, 1 RCT, 105 participants).

6.4 Failure to complete due to inefficacy

Fourteen studies contributed to this comparison including 2090 participants.

In terms of dropout due to inefficacy, we found no difference between fluoxetine and other conventional psychotropic drugs. However, due to the large confidence intervals, these results are inconclusive.

6.5 Failure to complete due to side effects

Seventeen studies contributed to this comparison including 2424 participants.

In terms of dropout due to side effects fluoxetine was better tolerated than ABT-200 (OR 0.08, 95% CI 0.02 to 0.27; NNT = 3, 95% CI 2 to 5, 1 RCT, 144 participants) and pramipexole (OR 0.06, 95% CI 0.01 to 0.50, NNT = 4, 95% CI 2 to 6, 1 RCT, 105 participants).

Comparison 7. fluoxetine versus other non-conventional AD agents

Primary outcome: efficacy
8.1 Dichotomous outcome

Seven studies contributed to this comparison including 757 participants overall.

No difference between fluoxetine and other non-conventional agents was found.

8.2 Continuous outcome

Five studies contributed to this outcome including 648 participants overall.

No difference was found on this outcome.

Secondary outcome: acceptability
8.3 Failure to complete due to any cause

Six studies contributed to this comparison including 719 participants overall.

In terms of patients who dropped out for any reason no differences were found between fluoxetine and other non-conventional ADs.

8.4 Failure to complete due to inefficacy

Two studies contributed to this comparison including 401 participants overall.

No difference was found on this outcome.

8.5 Failure to complete due to inefficacy

Five studies contributed to this comparison including 679 participants overall.

No difference was found on this outcome.

Subgroup analysis

The great majority of included studies had a follow-up period of between six and 16 weeks.

The subgroup analysis revealed a difference in favour of fluoxetine over nortriptyline, continuous outcome, follow-up > 16 weeks (SMD -0.86, 95% CI -1.27 to -0.44, 1 RCT, 97 participants), and a difference between fluoxetine and TCAs as a class, follow-up six to 16 weeks, dichotomous outcome (failure to complete - inefficacy) (OR 1.38, 95% CI 1.02 to 1.87, 28 RCTs, 1053 participants).

For the other comparisons we found no material difference between fluoxetine and other antidepressants both in terms of efficacy and acceptability.

Moreover, with the exception of the TCA group, stratification by each control agent was performed to ascertain whether there were treatment differences between fluoxetine and AD drugs belonging to the same pharmacological class (see results on efficacy and acceptability).

As reported in the methods, sensitivity analyses were not performed in this version of the review. However, we will conduct these analyses in the next update.

Assessment of heterogeneity

For the primary outcomes, I2 indicative of moderate heterogeneity was observed in the comparison between fluoxetine and TCA as a class, (I2 = 55%) and between fluoxetine and imipramine, continuous outcome analyses (I2 = 54%). Substantial heterogeneity was found in the comparison between fluoxetine and the following AD drugs: mianserin (I2 = 78%), paroxetine (I2 = 86%), agomelatine (I2 = 67%) and trazodone (I2 = 62%), desipramine, dothiepin or dosulepin (I2 = 67%), nortryptiline (I2 = 87%), and tianeptine (I2 = 63%). For dichotomous outcomes, moderate heterogeneity was observed in the comparison between fluoxetine and trazodone (I2 = 58%), while substantial heterogeneity was found in the comparison between fluoxetine versus hypericum (I2 = 68%) and versus imipramine (I2 = 68%).

Assessment of publication bias

Visual inspection of funnel plots did not reveal substantial asymmetry in any of the comparisons between fluoxetine and other conventional and unconventional ADs.

Discussion

Summary of main results

This systematic review detected differences between fluoxetine and some comparator ADs. On a dichotomous outcome, fluoxetine was less effective than dothiepin/dosulepin, sertraline, mirtazapine and venlafaxine. On a continuous outcome, fluoxetine was more effective than ABT-200 and milnacipran, and less effective than sertraline and venlafaxine, although these findings were of borderline statistical significance. However, it is uncertain how these differences translate into clinically meaningful measures. Despite the large number of comparative trials included in this systematic review, the total number of randomised patients was under 25,000. Studies were short, usually eight weeks or less, and the mean size of each trial was around 135 participants, indicating that they were generally underpowered for demonstrating clinically meaningful differences.

In terms of acceptability fluoxetine was better tolerated than TCA, reboxetine, ABT-200 and pramipexole (dropout due to any reasons). By contrast, escitalopram was better tolerated than fluoxetine, although the result was of borderline statistical significance. Moreover, considering dropout due to side effects, fluoxetine was better tolerated than amitriptyline, clomipramine, imipramine, ABT-200 and pramipexole. Fluoxetine was also better tolerated than venlafaxine (dropout due to side effects).

Overall completeness and applicability of evidence

Our review currently includes 171 randomised trials with 24,868 participants in total. All studies in the review involved participants with a formal diagnosis of depression on a standardised and validated scale according to DSM-III or DSM-IV criteria, and therefore there was considerable homogeneity in the study populations. However, studies were short in duration, for some comparisons the confidence intervals were large, and some analyses were unpowered to demonstrate clinically meaningful differences between treatments. Therefore, interpretation of treatment effects, either where there is a statistically different effect or no statistically different effect, should be made with caution There was also considerable variation in the type of control medication used in the trials. The majority used TCAs, SSRIs and SNRIs, with a minority of trials using other non-conventional ADs. Most trials provided useful data that were included in the analyses, but in some cases trials provided only efficacy or tolerability data thus limiting the overall completeness of evidence.

Although it has long been argued that placebo controlled trials are required to adequately demonstrate the efficacy of novel AD drugs (Cipriani 2009a), in the present review we focused only on the comparison between fluoxetine and other active treatments. The background logic that guided the development of the present review was based on the need to provide real-world evidence for patients in need of pharmacological treatment. We therefore made the choice of including only studies that compared fluoxetine with another active treatment, as we reasoned that clinicians need to know how fluoxetine, a reference AD agent, compares with a selection of possible comparator ADs.

Retrieved randomised evidence compared fluoxetine with a selection of possible comparator ADs but only few studies per comparison were found. This inevitably limited the applicability of the evidence pertaining to each pair wise comparison as often confidence intervals were quite wide around treatment estimates.

Although the search was thorough, it is still possible that some unpublished studies have not been identified. It is very difficult to make a fair judgement on this issue as the small number of trials identified per comparison might have hindered the detection of publication bias. However, although we did our very best to retrieve as much data as possible, through asking pharmaceutical companies and study authors to supply all available information, we can conservatively assume that some trial data are still lacking, most of which are likely to be studies with negative findings. We are also aware that other RCTs comparing fluoxetine with other AD drugs may be currently ongoing, and we aim to include these, as well as other unpublished data, in future updates of this review.

Quality of the evidence

The quality of evidence is a crucial issue in translating the results of research into clinical practice. Using high-quality research evidence is relevant to speedy translation of research in a way that really responds to clinically relevant questions. In the present review only randomised trials were included and the studies were all very similar in design and conduct. However, trial quality is not easy to assess. We note that the majority of included studies failed to report key methodological issues, for example information about randomisation and allocation concealment. Additionally, the reporting of outcome data was often unclear or incomplete and the figures used in the analyses were not immediately understandable. Clearly it is possible that the paucity of information about randomisation and allocation concealment may represent a problem of reporting and not a real defect in study design. However, sometimes discrepancies between published reports and unpublished data posted on drug companies' websites were highlighted, thus confirming that the average quality of clinical trials in the field of ADs is generally low, and that this may represent a potential serious risk of bias (Horder 2011).

Potential biases in the review process

The first limitation is that we made multiple comparisons. By making multiple comparisons we might have committed a type 1 error, that is, identifying and reporting a spurious association. As stated in the review protocol, we did not carry out a Bonferroni correction. As many statistical tests have been used in the review, the findings from this review are better thought of as hypothesis forming rather than hypothesis testing and it would be very reassuring to see the conclusions replicated in future trials and systematic reviews.

Another limitation is that for many of the comparisons, more trials were found presenting data on dropouts than on efficacy. This is because not all gave a 50% reduction in HDRS as their main outcome and therefore a lot of the data from our primary outcome was lost, which could have led to bias. Although this is a well-known limitation of secondary analyses of data extracted from RCTs, we attempted to control this potential source of bias by extracting continuous efficacy data according to each study’s definition of efficacy. This secondary analysis included many more participants than the primary analysis and the results did not differ substantially from the analysis of the primary outcomes. It is likely, therefore, that the overall comparison was not hampered by the exclusion of these trials.

Another compelling issue is that most of the included studies were sponsored by the drug industry, and data has shown that drug industry studies are more than four times more likely to demonstrate positive effects of the sponsors' drugs in comparison with independent studies (Lexchin 2003). For fluoxetine, it has been shown that the outcome of fluoxetine RCTs varies according to whether this drug was used as a new compound or a reference one, suggesting the presence of bias. This bias may work in favour of fluoxetine in trials where it was the experimental drug and in favour of comparators in trials where fluoxetine was the reference agent (Barbui 2004). A possible explanation for this finding is publication bias. Publication bias might have systematically excluded from publication RCTs failing to show a robust effect of the experimental agents in comparison with reference ones. Alternatively, the common belief that newer medicines are better than old ones, and pharmaceutical marketing pressures to show a positive effect of newer drugs, might have favoured fluoxetine when it was the experimental agent and comparators when fluoxetine was the reference drug.

In this review we decided to focus on treatment response because it is one of the main goals for the treatment of major depressive disorder. The term 'treatment response' describes a state of improvement in the patient’s condition of sufficient quality to result in the treating physician’s impression of at least a moderate degree of global improvement, conventionally defined as a reduction of at least 50% in depressive symptomatology. However, from a clinical point of view, the ultimate goal of the acute treatment phase of major depressive disorder may well be to achieve remission. Full remission from depression correlates with better longer-term functional recovery, lower risk of relapse and higher level of patients satisfaction than a partial response (without remission). Thus, one important limitation of the present review is that remission was not included as an outcome measure.

Another study limitation is that studies with different duration were lumped together, and this may limit the external validity of study findings. However, the subgroup analysis failed to show material differences, thus suggesting the robustness of the main findings.

From a clinical point of view the analysis of the safety profile of antidepressants remains of crucial importance. In this review, although we included total dropouts as a measure of treatment acceptability. and dropouts due to side effects as a measure of tolerability, individual side effects were not extracted. We acknowledge this limitation and we aim to include data on individual side effects in future updates of this systematic review.

Agreements and disagreements with other studies or reviews

Even though there is a heated debate in the scientific literature (Gartlehner 2010; Gartlehner 2011), there is now robust evidence that there are statistically and clinically significant differences among antidepressants (Cipriani 2009a). Results from this review are consistent with this interpretation and might contribute to the development of an evidence-based hierarchy of antidepressants to be used by clinicians (both specialists and general practitioners) (Barbui 2011a). Even though fluoxetine was not among the best treatments in terms of efficacy, it remains an important option for physicians when an AD is to be prescribed for moderate to severe major depression.

Authors' conclusions

Implications for practice

The main finding of the present study is that there are differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain and no definitive implications for clinical practice can be drawn. The better efficacy profile of sertraline and venlafaxine (and possibly other ADs) over fluoxetine may be clinically meaningful, as suggested by other reviews. In addition to efficacy data, treatment decisions should also be based on other considerations, for example, the fluoxetine long half-life, the fact that fluoxetine inhibits CYP-P450 isoenzymes more than some others (and this factor has to be considered particularly for people also taking other medications), the drug toxicity, the patient acceptability and the costs.

Implications for research

Results described in this systematic review come from a set of randomised studies that are in many cases financially supported by pharmaceutical industries. Industry-sponsored trials tend to follow a standard design which involves short-term, double-blind, parallel-group studies of patients with acute episodes or exacerbations of chronic illness. Moreover, it is known that economic support by drug manufacturers can strongly influence the progress of research and its results. Consequently, there is a risk that these studies do not provide adequate information to clinicians in real-world settings. Trials comparing two or more active treatments need to be much larger and of better quality than the studies that we identified for this review. More clinically meaningful outcome measures in trials of antidepressants, such as the ability to work or admission to hospital, are needed. Considering the methodological limitation of standard systematic reviews that rely only on evidence from direct comparisons, and given the wide spectrum of available comparisons for the treatment of major depression, the use of the methodology of multiple treatments meta-analysis (MTM) may provide a more informative and clinically useful summary of the results that can be used to guide treatment decisions. Moreover, an Individual Patient Data (IPD) meta-analysis would provide a more specific approach to those patients or illness characteristics related to clinically meaningful outcomes.

Acknowledgements

We would like to thank the CCDAN Editorial Team for their support, information and advice. We also would like to thank authors that provided additional data to be used in the present report (Professor Yusuf Moosa, Professor Homayoun Amini).

CRG funding acknowledgement

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Depression, Anxiety and Neurosis Group. 

Disclaimer

The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

Comparison 1. Fluoxetine versus TCAs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to respond - HDRS (-50%)242124Odds Ratio (M-H, Random, 95% CI)0.97 [0.77, 1.22]
1.1 Fluoxetine vs Amitriptyline11777Odds Ratio (M-H, Random, 95% CI)0.93 [0.68, 1.28]
1.2 Fluoxetine vs Clomipramine194Odds Ratio (M-H, Random, 95% CI)0.63 [0.27, 1.45]
1.3 Fluoxetine vs Desipramine284Odds Ratio (M-H, Random, 95% CI)1.70 [0.56, 5.15]
1.4 Fluoxetine vs Dothiepin/dosulepin2144Odds Ratio (M-H, Random, 95% CI)2.13 [1.08, 4.20]
1.5 Fluoxetine vs Doxepine140Odds Ratio (M-H, Random, 95% CI)1.0 [0.28, 3.54]
1.6 Fluoxetine vs Imipramine5761Odds Ratio (M-H, Random, 95% CI)0.74 [0.41, 1.35]
1.7 Fluoxetine vs Lofepramine1183Odds Ratio (M-H, Random, 95% CI)0.99 [0.55, 1.78]
1.8 Fluoxetine vs Trimipramine141Odds Ratio (M-H, Random, 95% CI)2.05 [0.56, 7.45]
2 End-point score on rating scale503393Std. Mean Difference (IV, Random, 95% CI)0.03 [-0.07, 0.14]
2.1 Fluoxetine vs Amiptriptyline191023Std. Mean Difference (IV, Random, 95% CI)0.10 [-0.09, 0.29]
2.2 Fluoxetine vs Clomipramine5372Std. Mean Difference (IV, Random, 95% CI)-0.10 [-0.31, 0.10]
2.3 Fluoxetine vs Desipramine4147Std. Mean Difference (IV, Random, 95% CI)0.27 [-0.32, 0.86]
2.4 Fluoxetine vs Dothiepin/dosulepin4266Std. Mean Difference (IV, Random, 95% CI)0.16 [-0.27, 0.59]
2.5 Fluoxetine vs Imipramine121063Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.21, 0.19]
2.6 Fluoxetine vs Lofepramine1183Std. Mean Difference (IV, Random, 95% CI)0.13 [-0.16, 0.42]
2.7 Fluoxetine vs Nomifensine128Std. Mean Difference (IV, Random, 95% CI)-0.37 [-1.12, 0.38]
2.8 Fluoxetine vs Nortriptyline2251Std. Mean Difference (IV, Random, 95% CI)-0.48 [-1.20, 0.24]
2.9 Fluoxetine vs Trimipramine260Std. Mean Difference (IV, Random, 95% CI)0.41 [-0.10, 0.92]
3 Failure to complete - Total494194Odds Ratio (M-H, Random, 95% CI)0.79 [0.65, 0.96]
3.1 Fluoxetine vs Amitriptyline181089Odds Ratio (M-H, Random, 95% CI)0.62 [0.46, 0.85]
3.2 Fluoxetine vs Clomipramine2263Odds Ratio (M-H, Random, 95% CI)0.65 [0.38, 1.14]
3.3 Fluoxetine vs Desipramine2104Odds Ratio (M-H, Random, 95% CI)0.44 [0.16, 1.24]
3.4 Fluoxetine vs Dothiepin/dosulepin5478Odds Ratio (M-H, Random, 95% CI)1.57 [0.92, 2.69]
3.5 Fluoxetine vs Doxepine4323Odds Ratio (M-H, Random, 95% CI)0.81 [0.49, 1.32]
3.6 Fluoxetine vs Imipramine121225Odds Ratio (M-H, Random, 95% CI)0.79 [0.51, 1.21]
3.7 Fluoxetine vs Lofepramine1183Odds Ratio (M-H, Random, 95% CI)0.50 [0.24, 1.04]
3.8 Fluoxetine vs Nomifensine140Odds Ratio (M-H, Random, 95% CI)6.33 [0.67, 60.16]
3.9 Fluoxetine vs Nortriptyline3448Odds Ratio (M-H, Random, 95% CI)0.73 [0.36, 1.47]
3.10 Fluoxetine vs Trimipramine141Odds Ratio (M-H, Random, 95% CI)2.0 [0.41, 9.78]
4 Failure to complete - Inefficacy332911Odds Ratio (M-H, Random, 95% CI)1.29 [0.96, 1.72]
4.1 Fluoxetine vs Amitriptyline13835Odds Ratio (M-H, Random, 95% CI)0.91 [0.44, 1.88]
4.2 Fluoxetine vs Clomipramine1120Odds Ratio (M-H, Random, 95% CI)7.37 [0.37, 145.75]
4.3 Fluoxetine vs Desipramine2104Odds Ratio (M-H, Random, 95% CI)1.03 [0.20, 5.35]
4.4 Fluoxetine vs Dothiepin/dosulepin3271Odds Ratio (M-H, Random, 95% CI)1.34 [0.49, 3.66]
4.5 Fluoxetine vs Doxepine3283Odds Ratio (M-H, Random, 95% CI)1.72 [0.60, 4.92]
4.6 Fluoxetine vs Imipramine101093Odds Ratio (M-H, Random, 95% CI)1.41 [0.97, 2.05]
4.7 Fluoxetine vs Nortriptyline1205Odds Ratio (M-H, Random, 95% CI)0.38 [0.07, 2.03]
5 Failure to complete - Side Effects403647Odds Ratio (M-H, Random, 95% CI)0.55 [0.40, 0.75]
5.1 Fluoxetine vs Amitriptyline161038Odds Ratio (M-H, Random, 95% CI)0.41 [0.23, 0.71]
5.2 Fluoxetine vs Clomipramine2263Odds Ratio (M-H, Random, 95% CI)0.30 [0.12, 0.79]
5.3 Fluoxetine vs Desipramine2104Odds Ratio (M-H, Random, 95% CI)0.27 [0.04, 1.68]
5.4 Fluoxetine vs Dothiepin/dosulepin5478Odds Ratio (M-H, Random, 95% CI)2.05 [0.59, 7.16]
5.5 Fluoxetine vs Doxepine3283Odds Ratio (M-H, Random, 95% CI)0.82 [0.44, 1.53]
5.6 Fluoxetine vs Imipramine101093Odds Ratio (M-H, Random, 95% CI)0.47 [0.26, 0.86]
5.7 Fluoxetine vs Lofepramine1183Odds Ratio (M-H, Random, 95% CI)0.16 [0.02, 1.38]
5.8 Fluoxetine vs Nortriptyline1205Odds Ratio (M-H, Random, 95% CI)0.86 [0.42, 1.77]
Analysis 1.1.

Comparison 1 Fluoxetine versus TCAs, Outcome 1 Failure to respond - HDRS (-50%).

Analysis 1.2.

Comparison 1 Fluoxetine versus TCAs, Outcome 2 End-point score on rating scale.

Analysis 1.3.

Comparison 1 Fluoxetine versus TCAs, Outcome 3 Failure to complete - Total.

Analysis 1.4.

Comparison 1 Fluoxetine versus TCAs, Outcome 4 Failure to complete - Inefficacy.

Analysis 1.5.

Comparison 1 Fluoxetine versus TCAs, Outcome 5 Failure to complete - Side Effects.

Comparison 2. Fluoxetine versus heterocyclics
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to respond - HDRS (-50%)3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Maprotiline2163Odds Ratio (M-H, Random, 95% CI)1.95 [0.91, 4.18]
1.2 Fluoxetine vs Mianserin153Odds Ratio (M-H, Random, 95% CI)0.80 [0.27, 2.38]
2 End-point score on rating scale8 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Maprotiline5433Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.15, 0.23]
2.2 Fluoxetine vs Mianserin3128Std. Mean Difference (IV, Random, 95% CI)0.43 [-0.38, 1.23]
3 Failure to complete - Total6 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Maprotiline4351Odds Ratio (M-H, Random, 95% CI)1.75 [0.90, 3.41]
3.2 Fluoxetine vs Mianserin293Odds Ratio (M-H, Random, 95% CI)0.63 [0.18, 2.25]
4 Failure to complete - Inefficacy4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Fluoxetine vs Maprotiline3209Odds Ratio (M-H, Random, 95% CI)2.54 [0.33, 19.19]
4.2 Fluoxetine vs Mianserin153Odds Ratio (M-H, Random, 95% CI)2.27 [0.38, 13.63]
5 Failure to complete - Side Effects4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Fluoxetine vs Maprotiline3209Odds Ratio (M-H, Random, 95% CI)0.53 [0.15, 1.93]
5.2 Fluoxetine vs Mianserin153Odds Ratio (M-H, Random, 95% CI)1.05 [0.23, 4.70]
Analysis 2.1.

Comparison 2 Fluoxetine versus heterocyclics, Outcome 1 Failure to respond - HDRS (-50%).

Analysis 2.2.

Comparison 2 Fluoxetine versus heterocyclics, Outcome 2 End-point score on rating scale.

Analysis 2.3.

Comparison 2 Fluoxetine versus heterocyclics, Outcome 3 Failure to complete - Total.

Analysis 2.4.

Comparison 2 Fluoxetine versus heterocyclics, Outcome 4 Failure to complete - Inefficacy.

Analysis 2.5.

Comparison 2 Fluoxetine versus heterocyclics, Outcome 5 Failure to complete - Side Effects.

Comparison 3. Fluoxetine versus other SSRIs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to respond - HDRS (-50%)17 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Citalopram159Odds Ratio (M-H, Random, 95% CI)0.60 [0.20, 1.79]
1.2 Fluoxetine vs Escitalopram1240Odds Ratio (M-H, Random, 95% CI)1.02 [0.56, 1.85]
1.3 Fluoxetine vs Fluvoxamine1177Odds Ratio (M-H, Random, 95% CI)0.95 [0.52, 1.74]
1.4 Fluoxetine vs Paroxetine91574Odds Ratio (M-H, Random, 95% CI)1.23 [0.93, 1.65]
1.5 Fluoxetine vs Sertraline61188Odds Ratio (M-H, Random, 95% CI)1.37 [1.08, 1.74]
2 End-point score on rating scales21 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Citalopram3661Std. Mean Difference (IV, Random, 95% CI)0.06 [-0.10, 0.21]
2.2 Fluoxetine vs Escitalopram1231Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.19, 0.33]
2.3 Fluoxetine vs Paroxetine112061Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.26, 0.24]
2.4 Fluoxetine vs Sertraline71160Std. Mean Difference (IV, Random, 95% CI)0.09 [-0.03, 0.20]
3 Failure to complete - Total25 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Citalopram3732Odds Ratio (M-H, Random, 95% CI)0.87 [0.60, 1.27]
3.2 Fluoxetine vs Escitalopram2578Odds Ratio (M-H, Random, 95% CI)1.53 [1.00, 2.37]
3.3 Fluoxetine vs Fluvoxamine2284Odds Ratio (M-H, Random, 95% CI)0.71 [0.36, 1.37]
3.4 Fluoxetine vs Paroxetine101848Odds Ratio (M-H, Random, 95% CI)0.98 [0.81, 1.20]
3.5 Fluoxetine vs Sertraline91591Odds Ratio (M-H, Random, 95% CI)1.17 [0.93, 1.49]
4 Failure to complete - Inefficacy13 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Fluoxetine vs Citalopram3732Odds Ratio (M-H, Random, 95% CI)0.87 [0.48, 1.56]
4.2 Fluoxetine vs Escitalopram2578Odds Ratio (M-H, Random, 95% CI)1.74 [0.46, 6.53]
4.3 Fluoxetine vs Paroxetine41005Odds Ratio (M-H, Random, 95% CI)0.75 [0.41, 1.39]
4.4 Fluoxetine vs Sertraline51056Odds Ratio (M-H, Random, 95% CI)1.09 [0.68, 1.77]
5 Failure to complete - Side Effects23 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Fluoxetine vs Citalopram3732Odds Ratio (M-H, Random, 95% CI)0.64 [0.34, 1.20]
5.2 Fluoxetine vs Escitalopram2578Odds Ratio (M-H, Random, 95% CI)1.17 [0.64, 2.12]
5.3 Fluoxetine vs Fluvoxamine1100Odds Ratio (M-H, Random, 95% CI)1.04 [0.14, 7.71]
5.4 Fluoxetine vs Paroxetine91509Odds Ratio (M-H, Random, 95% CI)0.85 [0.62, 1.16]
5.5 Fluoxetine vs Sertraline91591Odds Ratio (M-H, Random, 95% CI)1.25 [0.92, 1.70]
Analysis 3.1.

Comparison 3 Fluoxetine versus other SSRIs, Outcome 1 Failure to respond - HDRS (-50%).

Analysis 3.2.

Comparison 3 Fluoxetine versus other SSRIs, Outcome 2 End-point score on rating scales.

Analysis 3.3.

Comparison 3 Fluoxetine versus other SSRIs, Outcome 3 Failure to complete - Total.

Analysis 3.4.

Comparison 3 Fluoxetine versus other SSRIs, Outcome 4 Failure to complete - Inefficacy.

Analysis 3.5.

Comparison 3 Fluoxetine versus other SSRIs, Outcome 5 Failure to complete - Side Effects.

Comparison 4. Fluoxetine versus SNRIs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to respond - HDRS (-50%)15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Duloxetine1103Odds Ratio (M-H, Random, 95% CI)1.41 [0.61, 3.25]
1.2 Fluoxetine vs Milnacipran2370Odds Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.84]
1.3 Fluoxetine vs Venlafaxine123387Odds Ratio (M-H, Random, 95% CI)1.29 [1.10, 1.51]
2 End-point score on rating scale15 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Milnacipran2213Std. Mean Difference (IV, Random, 95% CI)-0.36 [-0.63, -0.08]
2.2 Fluoxetine vs Venlafaxine133097Std. Mean Difference (IV, Random, 95% CI)0.10 [0.00, 0.19]
3 Failure to complete - Total19 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Duloxetine2532Odds Ratio (M-H, Random, 95% CI)0.90 [0.53, 1.52]
3.2 Fluoxetine vs Milnacipran3560Odds Ratio (M-H, Random, 95% CI)0.98 [0.68, 1.42]
3.3 Fluoxetine vs Venlafaxine142683Odds Ratio (M-H, Random, 95% CI)0.89 [0.74, 1.06]
4 Failure to complete - Inefficacy18 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Fluoxetine vs Duloxetine2432Odds Ratio (M-H, Random, 95% CI)3.33 [0.92, 12.11]
4.2 Fluoxetine vs Milnacipran3560Odds Ratio (M-H, Random, 95% CI)1.25 [0.68, 2.30]
4.3 Fluoxetine vs Venlafaxine132640Odds Ratio (M-H, Random, 95% CI)1.31 [0.91, 1.89]
5 Failure to complete - Side Effects18 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Fluoxetine vs Duloxetine2532Odds Ratio (M-H, Random, 95% CI)0.28 [0.07, 1.23]
5.2 Fluoxetine vs Milnacipran3560Odds Ratio (M-H, Random, 95% CI)1.50 [0.81, 2.76]
5.3 Fluoxetine vs Venlafaxine132640Odds Ratio (M-H, Random, 95% CI)0.72 [0.56, 0.94]
Analysis 4.1.

Comparison 4 Fluoxetine versus SNRIs, Outcome 1 Failure to respond - HDRS (-50%).

Analysis 4.2.

Comparison 4 Fluoxetine versus SNRIs, Outcome 2 End-point score on rating scale.

Analysis 4.3.

Comparison 4 Fluoxetine versus SNRIs, Outcome 3 Failure to complete - Total.

Analysis 4.4.

Comparison 4 Fluoxetine versus SNRIs, Outcome 4 Failure to complete - Inefficacy.

Analysis 4.5.

Comparison 4 Fluoxetine versus SNRIs, Outcome 5 Failure to complete - Side Effects.

Comparison 5. Fluoxetine versus MAOIs or newer ADs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to respond - HDRS (-50%)16 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Agomelatine1515Odds Ratio (M-H, Random, 95% CI)1.44 [0.99, 2.09]
1.2 Fluoxetine vs Mirtazapine4600Odds Ratio (M-H, Random, 95% CI)1.46 [1.04, 2.04]
1.3 Fluoxetine vs Moclobemide7721Odds Ratio (M-H, Random, 95% CI)1.27 [0.92, 1.75]
1.4 Fluoxetine vs Phenelzine140Odds Ratio (M-H, Random, 95% CI)1.42 [0.27, 7.34]
1.5 Fluoxetine vs Reboxetine3721Odds Ratio (M-H, Random, 95% CI)0.77 [0.55, 1.10]
2 End-point score on rating scales13 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Agomelatine31213Std. Mean Difference (IV, Random, 95% CI)0.02 [-0.18, 0.23]
2.2 Fluoxetine vs Mirtazapine131Std. Mean Difference (IV, Random, 95% CI)0.57 [-0.15, 1.29]
2.3 Fluoxetine vs Moclobemide6540Std. Mean Difference (IV, Random, 95% CI)0.13 [-0.04, 0.30]
2.4 Fluoxetine vs Phenelzine140Std. Mean Difference (IV, Random, 95% CI)-0.05 [-0.67, 0.57]
2.5 Fluoxetine vs Reboxetine2205Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.31, 0.40]
3 Failure to complete - Total17 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Agomelatine2785Odds Ratio (M-H, Random, 95% CI)1.22 [0.59, 2.49]
3.2 Fluoxetine vs Mirtazapine3301Odds Ratio (M-H, Random, 95% CI)0.92 [0.51, 1.68]
3.3 Fluoxetine vs Moclobemide7721Odds Ratio (M-H, Random, 95% CI)1.01 [0.70, 1.47]
3.4 Fluoxetine vs Phenelzine140Odds Ratio (M-H, Random, 95% CI)0.18 [0.01, 4.01]
3.5 Fluoxetine vs Reboxetine4764Odds Ratio (M-H, Random, 95% CI)0.60 [0.44, 0.83]
4 Failure to complete - Inefficacy16 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Fluoxetine vs Agomelatine2785Odds Ratio (M-H, Random, 95% CI)1.08 [0.41, 2.88]
4.2 Fluoxetine vs Mirtazapine4600Odds Ratio (M-H, Random, 95% CI)1.45 [0.71, 2.96]
4.3 Fluoxetine vs Moclobemide6679Odds Ratio (M-H, Random, 95% CI)0.70 [0.32, 1.56]
4.4 Fluoxetine vs Phenelzine140Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.5 Fluoxetine vs Reboxetine3464Odds Ratio (M-H, Random, 95% CI)0.92 [0.47, 1.77]
5 Failure to complete - Side Effects16 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Fluoxetine vs Agomelatine2785Odds Ratio (M-H, Random, 95% CI)1.50 [0.73, 3.08]
5.2 Fluoxetine vs Mirtazapine4600Odds Ratio (M-H, Random, 95% CI)0.95 [0.54, 1.66]
5.3 Fluoxetine vs Moclobemide7721Odds Ratio (M-H, Random, 95% CI)1.04 [0.54, 2.01]
5.4 Fluoxetine vs Phenelzine140Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]
5.5 Fluoxetine vs Reboxetine2211Odds Ratio (M-H, Random, 95% CI)0.40 [0.10, 1.61]
Analysis 5.1.

Comparison 5 Fluoxetine versus MAOIs or newer ADs, Outcome 1 Failure to respond - HDRS (-50%).

Analysis 5.2.

Comparison 5 Fluoxetine versus MAOIs or newer ADs, Outcome 2 End-point score on rating scales.

Analysis 5.3.

Comparison 5 Fluoxetine versus MAOIs or newer ADs, Outcome 3 Failure to complete - Total.

Analysis 5.4.

Comparison 5 Fluoxetine versus MAOIs or newer ADs, Outcome 4 Failure to complete - Inefficacy.

Analysis 5.5.

Comparison 5 Fluoxetine versus MAOIs or newer ADs, Outcome 5 Failure to complete - Side Effects.

Comparison 6. Fluoxetine versus other conventional psychotropic drugs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to respond - HDRS (-50%)8 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Amineptine163Odds Ratio (M-H, Random, 95% CI)0.37 [0.13, 1.04]
1.2 Fluoxetine vs Bupropion2436Odds Ratio (M-H, Random, 95% CI)0.83 [0.48, 1.43]
1.3 Fluoxetine vs Pramipexole1105Odds Ratio (M-H, Random, 95% CI)0.55 [0.24, 1.26]
1.4 Fluoxetine vs Tianeptine1387Odds Ratio (M-H, Random, 95% CI)1.12 [0.75, 1.67]
1.5 Fluoxetine vs Trazodone3110Odds Ratio (M-H, Random, 95% CI)0.49 [0.13, 1.86]
2 End-point score on rating scales13 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs ABT-2001141Std. Mean Difference (IV, Random, 95% CI)-1.85 [-2.25, -1.45]
2.2 Fluoxetine vs Amisulpride1268Std. Mean Difference (IV, Random, 95% CI)0.17 [-0.07, 0.41]
2.3 Fluoxetine vs Nefazodone4271Std. Mean Difference (IV, Random, 95% CI)-0.06 [-0.30, 0.18]
2.4 Fluoxetine vs Tianeptine3730Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.40, 0.10]
2.5 Fluoxetine vs Trazodone4203Std. Mean Difference (IV, Random, 95% CI)-0.25 [-0.76, 0.26]
3 Failure to complete - Total17 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs ABT-2001144Odds Ratio (M-H, Random, 95% CI)0.18 [0.08, 0.39]
3.2 Fluoxetine vs Amineptine2232Odds Ratio (M-H, Random, 95% CI)0.61 [0.17, 2.21]
3.3 Fluoxetine vs Amisulpride1281Odds Ratio (M-H, Random, 95% CI)1.39 [0.81, 2.38]
3.4 Fluoxetine vs Bupropion2436Odds Ratio (M-H, Random, 95% CI)1.00 [0.67, 1.48]
3.5 Fluoxetine vs Nefazodone3161Odds Ratio (M-H, Random, 95% CI)0.54 [0.22, 1.31]
3.6 Fluoxetine vs Pramipexole1105Odds Ratio (M-H, Random, 95% CI)0.12 [0.03, 0.42]
3.7 Fluoxetine vs Tianeptine3830Odds Ratio (M-H, Random, 95% CI)0.96 [0.69, 1.33]
3.8 Fluoxetine vs Trazodone4230Odds Ratio (M-H, Random, 95% CI)0.51 [0.23, 1.13]
4 Failure to complete - Inefficacy14 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Fluoxetine vs ABT-2001144Odds Ratio (M-H, Random, 95% CI)0.24 [0.03, 2.20]
4.2 Fluoxetine vs Amineptine163Odds Ratio (M-H, Random, 95% CI)1.04 [0.19, 5.57]
4.3 Fluoxetine vs Amisulpride1281Odds Ratio (M-H, Random, 95% CI)1.16 [0.43, 3.10]
4.4 Fluoxetine vs Bupropion2436Odds Ratio (M-H, Random, 95% CI)1.16 [0.33, 4.10]
4.5 Fluoxetine vs Nefazodone3161Odds Ratio (M-H, Random, 95% CI)0.71 [0.05, 10.71]
4.6 Fluoxetine vs Pramipexole1105Odds Ratio (M-H, Random, 95% CI)0.49 [0.05, 4.51]
4.7 Fluoxetine vs Tianeptine3830Odds Ratio (M-H, Random, 95% CI)0.82 [0.27, 2.53]
4.8 Fluoxetine vs Trazodone270Odds Ratio (M-H, Random, 95% CI)0.23 [0.04, 1.51]
5 Failure to complete - Side Effects17 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Fluoxetine vs ABT-2001144Odds Ratio (M-H, Random, 95% CI)0.08 [0.02, 0.27]
5.2 Fluoxetine vs Amineptine2232Odds Ratio (M-H, Random, 95% CI)0.52 [0.03, 7.82]
5.3 Fluoxetine vs Amisulpride1281Odds Ratio (M-H, Random, 95% CI)0.77 [0.33, 1.82]
5.4 Fluoxetine vs Bupropion2436Odds Ratio (M-H, Random, 95% CI)1.01 [0.45, 2.25]
5.5 Fluoxetine vs Nefazodone4286Odds Ratio (M-H, Random, 95% CI)0.76 [0.32, 1.81]
5.6 Fluoxetine vs Pramipexole1105Odds Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.50]
5.7 Fluoxetine vs Tianeptine3830Odds Ratio (M-H, Random, 95% CI)1.13 [0.71, 1.80]
5.8 Fluoxetine vs Trazodone3110Odds Ratio (M-H, Random, 95% CI)0.66 [0.20, 2.19]
Analysis 6.1.

Comparison 6 Fluoxetine versus other conventional psychotropic drugs, Outcome 1 Failure to respond - HDRS (-50%).

Analysis 6.2.

Comparison 6 Fluoxetine versus other conventional psychotropic drugs, Outcome 2 End-point score on rating scales.

Analysis 6.3.

Comparison 6 Fluoxetine versus other conventional psychotropic drugs, Outcome 3 Failure to complete - Total.

Analysis 6.4.

Comparison 6 Fluoxetine versus other conventional psychotropic drugs, Outcome 4 Failure to complete - Inefficacy.

Analysis 6.5.

Comparison 6 Fluoxetine versus other conventional psychotropic drugs, Outcome 5 Failure to complete - Side Effects.

Comparison 7. Fluoxetine versus other non-conventional AD agents
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to respond - HDRS (-50%)7 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Crocus Sativus140Odds Ratio (M-H, Random, 95% CI)0.53 [0.11, 2.60]
1.2 Fluoxetine vs Hypericum6717Odds Ratio (M-H, Random, 95% CI)0.98 [0.55, 1.73]
2 End-point score on rating scales5 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Hypericum5648Std. Mean Difference (IV, Random, 95% CI)0.13 [-0.02, 0.29]
3 Failure to complete - Total6 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Crocus Sativus140Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 17.18]
3.2 Fluoxetine vs Hypericum5679Odds Ratio (M-H, Random, 95% CI)1.04 [0.58, 1.85]
4 Failure to complete - Inefficacy2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Fluoxetine vs Hypericum2401Odds Ratio (M-H, Random, 95% CI)4.70 [0.22, 99.39]
5 Failure to complete - Side Effects5 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Fluoxetine vs Hypericum5679Odds Ratio (M-H, Random, 95% CI)1.21 [0.56, 2.64]
Analysis 7.1.

Comparison 7 Fluoxetine versus other non-conventional AD agents, Outcome 1 Failure to respond - HDRS (-50%).

Analysis 7.2.

Comparison 7 Fluoxetine versus other non-conventional AD agents, Outcome 2 End-point score on rating scales.

Analysis 7.3.

Comparison 7 Fluoxetine versus other non-conventional AD agents, Outcome 3 Failure to complete - Total.

Analysis 7.4.

Comparison 7 Fluoxetine versus other non-conventional AD agents, Outcome 4 Failure to complete - Inefficacy.

Analysis 7.5.

Comparison 7 Fluoxetine versus other non-conventional AD agents, Outcome 5 Failure to complete - Side Effects.

Comparison 8. Subgroup analysis for fluoxetine versus TCAs: failure to respond
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks5341Odds Ratio (M-H, Random, 95% CI)0.67 [0.35, 1.27]
1.1 Fluoxetine vs Amitriptyline3207Odds Ratio (M-H, Random, 95% CI)0.56 [0.19, 1.65]
1.2 Fluoxetine vs Clomipramine194Odds Ratio (M-H, Random, 95% CI)0.63 [0.27, 1.45]
1.3 Fluoxetine vs Imipramine140Odds Ratio (M-H, Random, 95% CI)1.42 [0.27, 7.34]
2 follow-up 6-16 weeks181742Odds Ratio (M-H, Random, 95% CI)1.02 [0.80, 1.31]
2.1 Fluoxetine vs Amitriptyline8570Odds Ratio (M-H, Random, 95% CI)1.06 [0.75, 1.50]
2.2 Fluoxetine vs Desipramine284Odds Ratio (M-H, Random, 95% CI)1.70 [0.56, 5.15]
2.3 Fluoxetine vs Dothiepin/dosulepin2144Odds Ratio (M-H, Random, 95% CI)2.13 [1.08, 4.20]
2.4 Fluoxetine vs Doxepine140Odds Ratio (M-H, Random, 95% CI)1.0 [0.28, 3.54]
2.5 Fluoxetine vs Imipramine4721Odds Ratio (M-H, Random, 95% CI)0.69 [0.36, 1.34]
2.6 Fluoxetine vs Lofepramine1183Odds Ratio (M-H, Random, 95% CI)0.99 [0.55, 1.78]
Analysis 8.1.

Comparison 8 Subgroup analysis for fluoxetine versus TCAs: failure to respond, Outcome 1 follow-up <6 weeks.

Analysis 8.2.

Comparison 8 Subgroup analysis for fluoxetine versus TCAs: failure to respond, Outcome 2 follow-up 6-16 weeks.

Comparison 9. Subgroup analysis for fluoxetine versus TCAs: endpoint score
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks12541Std. Mean Difference (IV, Random, 95% CI)0.18 [-0.15, 0.50]
1.1 Fluoxetine vs Amiptriptyline6290Std. Mean Difference (IV, Random, 95% CI)0.39 [-0.25, 1.02]
1.2 Fluoxetine vs Clomipramine2124Std. Mean Difference (IV, Random, 95% CI)-0.00 [-0.36, 0.35]
1.3 Fluoxetine vs Desipramine126Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.72, 0.82]
1.4 Fluoxetine vs Imipramine260Std. Mean Difference (IV, Random, 95% CI)-0.04 [-1.31, 1.22]
1.5 Fluoxetine vs Trimipramine141Std. Mean Difference (IV, Random, 95% CI)0.38 [-0.24, 1.00]
2 follow-up 6-16 weeks362727Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.06, 0.14]
2.1 Fluoxetine vs Amiptriptyline13733Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.07, 0.22]
2.2 Fluoxetine vs Clomipramine3248Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.40, 0.10]
2.3 Fluoxetine vs Desipramine3121Std. Mean Difference (IV, Random, 95% CI)0.33 [-0.47, 1.12]
2.4 Fluoxetine vs Dothiepin/dosulepin4266Std. Mean Difference (IV, Random, 95% CI)0.16 [-0.27, 0.59]
2.5 Fluoxetine vs Imipramine101003Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.21, 0.19]
2.6 Fluoxetine vs Lofepramine1183Std. Mean Difference (IV, Random, 95% CI)0.13 [-0.16, 0.42]
2.7 Fluoxetine vs Nortriptyline1154Std. Mean Difference (IV, Random, 95% CI)-0.12 [-0.44, 0.20]
2.8 Fluoxetine vs Trimipramine119Std. Mean Difference (IV, Random, 95% CI)0.47 [-0.44, 1.39]
3 follow-up >16 weeks197Std. Mean Difference (IV, Random, 95% CI)-0.86 [-1.27, -0.44]
3.1 Fluoxetine vs Nortriptyline197Std. Mean Difference (IV, Random, 95% CI)-0.86 [-1.27, -0.44]
Analysis 9.1.

Comparison 9 Subgroup analysis for fluoxetine versus TCAs: endpoint score, Outcome 1 follow-up <6 weeks.

Analysis 9.2.

Comparison 9 Subgroup analysis for fluoxetine versus TCAs: endpoint score, Outcome 2 follow-up 6-16 weeks.

Analysis 9.3.

Comparison 9 Subgroup analysis for fluoxetine versus TCAs: endpoint score, Outcome 3 follow-up >16 weeks.

Comparison 10. Subgroup analysis for fluoxetine versus TCAs: failure to complete - total
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks11663Odds Ratio (M-H, Random, 95% CI)0.70 [0.47, 1.05]
1.1 Fluoxetine vs Amitriptyline6309Odds Ratio (M-H, Random, 95% CI)0.57 [0.29, 1.13]
1.2 Fluoxetine vs Doxepine151Odds Ratio (M-H, Random, 95% CI)1.25 [0.29, 5.31]
1.3 Fluoxetine vs Imipramine398Odds Ratio (M-H, Random, 95% CI)0.56 [0.10, 3.13]
1.4 Fluoxetine vs Nortriptyline1205Odds Ratio (M-H, Random, 95% CI)0.77 [0.44, 1.35]
2 follow-up 6-16 weeks363450Odds Ratio (M-H, Random, 95% CI)0.79 [0.63, 0.98]
2.1 Fluoxetine vs Amitriptyline12780Odds Ratio (M-H, Random, 95% CI)0.63 [0.44, 0.90]
2.2 Fluoxetine vs Clomipramine2263Odds Ratio (M-H, Random, 95% CI)0.65 [0.38, 1.14]
2.3 Fluoxetine vs Desipramine2104Odds Ratio (M-H, Random, 95% CI)0.44 [0.16, 1.24]
2.4 Fluoxetine vs Dothiepin/dosulepin5478Odds Ratio (M-H, Random, 95% CI)1.57 [0.92, 2.69]
2.5 Fluoxetine vs Doxepine3272Odds Ratio (M-H, Random, 95% CI)0.78 [0.44, 1.40]
2.6 Fluoxetine vs Imipramine91127Odds Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.27]
2.7 Fluoxetine vs Lofepramine1183Odds Ratio (M-H, Random, 95% CI)0.50 [0.24, 1.04]
2.8 Fluoxetine vs Nortriptyline2243Odds Ratio (M-H, Random, 95% CI)0.82 [0.17, 3.93]
Analysis 10.1.

Comparison 10 Subgroup analysis for fluoxetine versus TCAs: failure to complete - total, Outcome 1 follow-up <6 weeks.

Analysis 10.2.

Comparison 10 Subgroup analysis for fluoxetine versus TCAs: failure to complete - total, Outcome 2 follow-up 6-16 weeks.

Comparison 11. Subgroup analysis for fluoxetine versus TCAs: failure to complete - inefficacy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks5401Odds Ratio (M-H, Random, 95% CI)0.49 [0.16, 1.50]
1.1 Fluoxetine vs Amitriptyline2105Odds Ratio (M-H, Random, 95% CI)0.38 [0.07, 2.09]
1.2 Fluoxetine vs Doxepine151Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Fluoxetine vs Imipramine140Odds Ratio (M-H, Random, 95% CI)3.15 [0.12, 82.16]
1.4 Fluoxetine vs Nortriptyiline1205Odds Ratio (M-H, Random, 95% CI)0.38 [0.07, 2.03]
2 follow-up 6-16 weeks282510Odds Ratio (M-H, Random, 95% CI)1.38 [1.02, 1.87]
2.1 Fluoxetine vs Amitriptyline11730Odds Ratio (M-H, Random, 95% CI)1.11 [0.50, 2.47]
2.2 Fluoxetine vs Clomipramine1120Odds Ratio (M-H, Random, 95% CI)7.37 [0.37, 145.75]
2.3 Fluoxetine vs Desipramine2104Odds Ratio (M-H, Random, 95% CI)1.03 [0.20, 5.35]
2.4 Fluoxetine vs Dothiepin/dosulepin3271Odds Ratio (M-H, Random, 95% CI)1.34 [0.49, 3.66]
2.5 Fluoxetine vs Doxepine2232Odds Ratio (M-H, Random, 95% CI)1.72 [0.60, 4.92]
2.6 Fluoxetine vs Imipramine91053Odds Ratio (M-H, Random, 95% CI)1.40 [0.96, 2.04]
Analysis 11.1.

Comparison 11 Subgroup analysis for fluoxetine versus TCAs: failure to complete - inefficacy, Outcome 1 follow-up <6 weeks.

Analysis 11.2.

Comparison 11 Subgroup analysis for fluoxetine versus TCAs: failure to complete - inefficacy, Outcome 2 follow-up 6-16 weeks.

Comparison 12. Subgroup analysis for fluoxetine versus TCAs: failure to complete - side effects
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks7554Odds Ratio (M-H, Random, 95% CI)0.81 [0.46, 1.43]
1.1 Fluoxetine vs Amitriptyline4258Odds Ratio (M-H, Random, 95% CI)0.62 [0.21, 1.82]
1.2 Fluoxetine vs Doxepine151Odds Ratio (M-H, Random, 95% CI)3.13 [0.30, 32.31]
1.3 Fluoxetine vs Imipramine140Odds Ratio (M-H, Random, 95% CI)0.63 [0.09, 4.24]
1.4 Fluoxetine vs Nortriptyline1205Odds Ratio (M-H, Random, 95% CI)0.86 [0.42, 1.77]
2 follow-up 6-16 weeks333093Odds Ratio (M-H, Random, 95% CI)0.51 [0.36, 0.72]
2.1 Fluoxetine vs Amitriptyline12780Odds Ratio (M-H, Random, 95% CI)0.33 [0.18, 0.61]
2.2 Fluoxetine vs Clomipramine2263Odds Ratio (M-H, Random, 95% CI)0.30 [0.12, 0.79]
2.3 Fluoxetine vs Desipramine2104Odds Ratio (M-H, Random, 95% CI)0.27 [0.04, 1.68]
2.4 Fluoxetine vs Dothiepin/dosulepin5478Odds Ratio (M-H, Random, 95% CI)2.05 [0.59, 7.16]
2.5 Fluoxetine vs Doxepine2232Odds Ratio (M-H, Random, 95% CI)0.73 [0.42, 1.28]
2.6 Fluoxetine vs Imipramine91053Odds Ratio (M-H, Random, 95% CI)0.47 [0.25, 0.87]
2.7 Fluoxetine vs Lofepramine1183Odds Ratio (M-H, Random, 95% CI)0.16 [0.02, 1.38]
Analysis 12.1.

Comparison 12 Subgroup analysis for fluoxetine versus TCAs: failure to complete - side effects, Outcome 1 follow-up <6 weeks.

Analysis 12.2.

Comparison 12 Subgroup analysis for fluoxetine versus TCAs: failure to complete - side effects, Outcome 2 follow-up 6-16 weeks.

Comparison 13. Subgroup analysis for fluoxetine versus heterocyclics: endpoint score
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks2 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Maprotiline2181Std. Mean Difference (IV, Random, 95% CI)0.06 [-0.34, 0.46]
2 follow-up 6-16 weeks6 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Maprotiline3252Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.20, 0.30]
2.2 Fluoxetine vs Mianserin3128Std. Mean Difference (IV, Random, 95% CI)0.43 [-0.38, 1.23]
Analysis 13.1.

Comparison 13 Subgroup analysis for fluoxetine versus heterocyclics: endpoint score, Outcome 1 follow-up <6 weeks.

Analysis 13.2.

Comparison 13 Subgroup analysis for fluoxetine versus heterocyclics: endpoint score, Outcome 2 follow-up 6-16 weeks.

Comparison 14. Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - total
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Maprotiline2188Odds Ratio (M-H, Random, 95% CI)1.54 [0.63, 3.75]
2 follow-up 6-16 weeks4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Maprotiline2163Odds Ratio (M-H, Random, 95% CI)2.06 [0.75, 5.63]
2.2 Fluoxetine vs Mianserin293Odds Ratio (M-H, Random, 95% CI)0.63 [0.18, 2.25]
Analysis 14.1.

Comparison 14 Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - total, Outcome 1 follow-up <6 weeks.

Analysis 14.2.

Comparison 14 Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - total, Outcome 2 follow-up 6-16 weeks.

Comparison 15. Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - inefficacy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Maprotiline146Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 follow-up 6-16 weeks3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Maprotiline2163Odds Ratio (M-H, Random, 95% CI)2.54 [0.33, 19.19]
2.2 Fluoxetine vs Mianserin153Odds Ratio (M-H, Random, 95% CI)2.27 [0.38, 13.63]
Analysis 15.1.

Comparison 15 Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - inefficacy, Outcome 1 follow-up <6 weeks.

Analysis 15.2.

Comparison 15 Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - inefficacy, Outcome 2 follow-up 6-16 weeks.

Comparison 16. Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - side effects
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Maprotiline146Odds Ratio (M-H, Random, 95% CI)0.41 [0.07, 2.49]
2 follow-up 6-16 weeks3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Maprotiline2163Odds Ratio (M-H, Random, 95% CI)0.69 [0.11, 4.38]
2.2 Fluoxetine vs Mianserin153Odds Ratio (M-H, Random, 95% CI)1.05 [0.23, 4.70]
Analysis 16.1.

Comparison 16 Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - side effects, Outcome 1 follow-up <6 weeks.

Analysis 16.2.

Comparison 16 Subgroup analysis for fluoxetine versus heterocyclics: failure to complete - side effects, Outcome 2 follow-up 6-16 weeks.

Comparison 17. Subgroup analysis for fluoxetine versus other SSRIs: failure to respond
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Citalopram159Odds Ratio (M-H, Random, 95% CI)0.60 [0.20, 1.79]
2 follow-up 6-16 weeks15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Fluvoxamine1177Odds Ratio (M-H, Random, 95% CI)0.95 [0.52, 1.74]
2.2 Fluoxetine vs Paroxetine91574Odds Ratio (M-H, Random, 95% CI)1.23 [0.93, 1.65]
2.3 Fluoxetine vs Sertraline5950Odds Ratio (M-H, Random, 95% CI)1.31 [1.00, 1.71]
2.4 Fluoxetine vs Escitalopram1240Odds Ratio (M-H, Random, 95% CI)1.02 [0.56, 1.85]
3 follow-up >16 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Sertraline1238Odds Ratio (M-H, Random, 95% CI)1.67 [0.97, 2.85]
Analysis 17.1.

Comparison 17 Subgroup analysis for fluoxetine versus other SSRIs: failure to respond, Outcome 1 follow-up <6 weeks.

Analysis 17.2.

Comparison 17 Subgroup analysis for fluoxetine versus other SSRIs: failure to respond, Outcome 2 follow-up 6-16 weeks.

Analysis 17.3.

Comparison 17 Subgroup analysis for fluoxetine versus other SSRIs: failure to respond, Outcome 3 follow-up >16 weeks.

Comparison 18. Subgroup analysis for fluoxetine versus other SSRIs: endpoint score
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Citalopram151Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.48, 0.61]
2 follow-up >16 weeks2 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Paroxetine1242Std. Mean Difference (IV, Random, 95% CI)0.24 [-0.01, 0.49]
2.2 Fluoxetine vs Sertraline1168Std. Mean Difference (IV, Random, 95% CI)0.22 [-0.08, 0.53]
3 follow-up 6-16 weeks18 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Citalopram2610Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.10, 0.21]
3.2 Fluoxetine vs Paroxetine101819Std. Mean Difference (IV, Random, 95% CI)-0.03 [-0.31, 0.24]
3.3 Fluoxetine vs Sertraline6992Std. Mean Difference (IV, Random, 95% CI)0.06 [-0.06, 0.19]
3.4 Fluoxetine vs Escitalopram1231Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.19, 0.33]
Analysis 18.1.

Comparison 18 Subgroup analysis for fluoxetine versus other SSRIs: endpoint score, Outcome 1 follow-up <6 weeks.

Analysis 18.2.

Comparison 18 Subgroup analysis for fluoxetine versus other SSRIs: endpoint score, Outcome 2 follow-up >16 weeks.

Analysis 18.3.

Comparison 18 Subgroup analysis for fluoxetine versus other SSRIs: endpoint score, Outcome 3 follow-up 6-16 weeks.

Comparison 19. Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - total
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Citalopram159Odds Ratio (M-H, Random, 95% CI)0.96 [0.22, 4.27]
2 follow-up 6-16 weeks21 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Citalopram2673Odds Ratio (M-H, Random, 95% CI)0.87 [0.59, 1.27]
2.2 Fluoxetine vs Fluvoxamine2284Odds Ratio (M-H, Random, 95% CI)0.71 [0.36, 1.37]
2.3 Fluoxetine vs Paroxetine91606Odds Ratio (M-H, Random, 95% CI)1.00 [0.81, 1.25]
2.4 Fluoxetine vs Sertraline71111Odds Ratio (M-H, Random, 95% CI)1.12 [0.85, 1.48]
2.5 Fluoxetine vs Escitalopram2578Odds Ratio (M-H, Random, 95% CI)1.53 [1.00, 2.37]
3 follow-up >16 weeks3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Paroxetine1242Odds Ratio (M-H, Random, 95% CI)0.89 [0.53, 1.49]
3.2 Fluoxetine vs Sertraline2480Odds Ratio (M-H, Random, 95% CI)1.33 [0.84, 2.09]
Analysis 19.1.

Comparison 19 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - total, Outcome 1 follow-up <6 weeks.

Analysis 19.2.

Comparison 19 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - total, Outcome 2 follow-up 6-16 weeks.

Analysis 19.3.

Comparison 19 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - total, Outcome 3 follow-up >16 weeks.

Comparison 20. Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - inefficacy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Citalopram159Odds Ratio (M-H, Random, 95% CI)0.47 [0.04, 5.43]
2 follow-up >16 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Sertraline1238Odds Ratio (M-H, Random, 95% CI)0.98 [0.47, 2.07]
3 follow-up 6-16 weeks11 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Citalopram2673Odds Ratio (M-H, Random, 95% CI)0.90 [0.49, 1.65]
3.2 Fluoxetine vs Paroxetine41005Odds Ratio (M-H, Random, 95% CI)0.75 [0.41, 1.39]
3.3 Fluoxetine vs Sertraline4818Odds Ratio (M-H, Random, 95% CI)1.18 [0.61, 2.29]
3.4 Fluoxetine vs Escitalopram2578Odds Ratio (M-H, Random, 95% CI)1.74 [0.46, 6.53]
Analysis 20.1.

Comparison 20 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - inefficacy, Outcome 1 follow-up <6 weeks.

Analysis 20.2.

Comparison 20 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - inefficacy, Outcome 2 follow-up >16 weeks.

Analysis 20.3.

Comparison 20 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - inefficacy, Outcome 3 follow-up 6-16 weeks.

Comparison 21. Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - side effects
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Citalopram159Odds Ratio (M-H, Random, 95% CI)1.5 [0.23, 9.70]
2 follow-up 6-16 weeks20 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Citalopram2673Odds Ratio (M-H, Random, 95% CI)0.57 [0.29, 1.12]
2.2 Fluoxetine vs Fluvoxamine1100Odds Ratio (M-H, Random, 95% CI)1.04 [0.14, 7.71]
2.3 Fluoxetine vs Paroxetine91509Odds Ratio (M-H, Random, 95% CI)0.85 [0.62, 1.16]
2.4 Fluoxetine vs Sertraline71111Odds Ratio (M-H, Random, 95% CI)1.21 [0.85, 1.71]
2.5 Fluoxetina vs Escitalopram2578Odds Ratio (M-H, Random, 95% CI)1.17 [0.64, 2.12]
3 follow-up >16 weeks2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Fluoxetine vs Sertraline2480Odds Ratio (M-H, Random, 95% CI)1.41 [0.72, 2.76]
Analysis 21.1.

Comparison 21 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - side effects, Outcome 1 follow-up <6 weeks.

Analysis 21.2.

Comparison 21 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - side effects, Outcome 2 follow-up 6-16 weeks.

Analysis 21.3.

Comparison 21 Subgroup analysis for fluoxetine versus other SSRIs: failure to complete - side effects, Outcome 3 follow-up >16 weeks.

Comparison 22. Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to respond
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Moclobemide170Odds Ratio (M-H, Random, 95% CI)1.01 [0.39, 2.60]
2 follow-up 6-16 weeks15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Agomelatine1515Odds Ratio (M-H, Random, 95% CI)1.44 [0.99, 2.09]
2.2 Fluoxetine vs Mirtazapine4600Odds Ratio (M-H, Random, 95% CI)1.46 [1.04, 2.04]
2.3 Fluoxetine vs Moclobemide6651Odds Ratio (M-H, Random, 95% CI)1.31 [0.90, 1.89]
2.4 Fluoxetine vs Phenelzine140Odds Ratio (M-H, Random, 95% CI)1.42 [0.27, 7.34]
2.5 Fluoxetine vs Reboxetine3721Odds Ratio (M-H, Random, 95% CI)0.77 [0.55, 1.10]
Analysis 22.1.

Comparison 22 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to respond, Outcome 1 follow-up <6 weeks.

Analysis 22.2.

Comparison 22 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to respond, Outcome 2 follow-up 6-16 weeks.

Comparison 23. Subgroup analysis for fluoxetine versus MAOIs or newer ADs: endpoint score
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Moclobemide153Std. Mean Difference (IV, Random, 95% CI)-0.12 [-0.66, 0.42]
2 follow-up 6-16 weeks12 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Agomelatine31213Std. Mean Difference (IV, Random, 95% CI)0.02 [-0.18, 0.23]
2.2 Fluoxetine vs Mirtazapine131Std. Mean Difference (IV, Random, 95% CI)0.57 [-0.15, 1.29]
2.3 Fluoxetine vs Moclobemide5487Std. Mean Difference (IV, Random, 95% CI)0.16 [-0.02, 0.33]
2.4 Fluoxetine vs Phenelzine140Std. Mean Difference (IV, Random, 95% CI)-0.05 [-0.67, 0.57]
2.5 Fluoxetine vs Reboxetine2205Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.31, 0.40]
Analysis 23.1.

Comparison 23 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: endpoint score, Outcome 1 follow-up <6 weeks.

Analysis 23.2.

Comparison 23 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: endpoint score, Outcome 2 follow-up 6-16 weeks.

Comparison 24. Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - total
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Moclobemide170Odds Ratio (M-H, Random, 95% CI)0.92 [0.31, 2.76]
2 follow-up 6-16 weeks15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetina vs Agomelatine2785Odds Ratio (M-H, Random, 95% CI)1.22 [0.59, 2.49]
2.2 Fluoxetine vs Mirtazapine3301Odds Ratio (M-H, Random, 95% CI)0.92 [0.51, 1.68]
2.3 Fluoxetine vs Moclobemide6651Odds Ratio (M-H, Random, 95% CI)1.02 [0.68, 1.53]
2.4 Fluoxetine vs Reboxetine4764Odds Ratio (M-H, Random, 95% CI)0.60 [0.44, 0.83]
Analysis 24.1.

Comparison 24 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - total, Outcome 1 follow-up <6 weeks.

Analysis 24.2.

Comparison 24 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - total, Outcome 2 follow-up 6-16 weeks.

Comparison 25. Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - inefficacy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Moclobemide170Odds Ratio (M-H, Random, 95% CI)1.06 [0.20, 5.68]
2 follow-up 6-16 weeks15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Agomelatine2785Odds Ratio (M-H, Random, 95% CI)1.08 [0.41, 2.88]
2.2 Fluoxetine vs Mirtazapine4600Odds Ratio (M-H, Random, 95% CI)1.45 [0.71, 2.96]
2.3 Fluoxetine vs Moclobemide5609Odds Ratio (M-H, Random, 95% CI)0.61 [0.23, 1.65]
2.4 Fluoxetine vs Phenelzine140Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.5 Fluoxetine vs Reboxetine3464Odds Ratio (M-H, Random, 95% CI)0.92 [0.47, 1.77]
Analysis 25.1.

Comparison 25 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - inefficacy, Outcome 1 follow-up <6 weeks.

Analysis 25.2.

Comparison 25 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - inefficacy, Outcome 2 follow-up 6-16 weeks.

Comparison 26. Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - side effects
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 follow-up <6 weeks1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Fluoxetine vs Moclobemide170Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 follow-up 6-16 weeks15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Fluoxetine vs Agomelatine2785Odds Ratio (M-H, Random, 95% CI)1.50 [0.73, 3.08]
2.2 Fluoxetine vs Mirtazapine4600Odds Ratio (M-H, Random, 95% CI)0.95 [0.54, 1.66]
2.3 Fluoxetine vs Moclobemide6651Odds Ratio (M-H, Random, 95% CI)1.04 [0.54, 2.01]
2.4 Fluoxetine vs Phenelzine140Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]
2.5 Fluoxetine vs Reboxetine2211Odds Ratio (M-H, Random, 95% CI)0.40 [0.10, 1.61]
Analysis 26.1.

Comparison 26 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - side effects, Outcome 1 follow-up <6 weeks.

Analysis 26.2.

Comparison 26 Subgroup analysis for fluoxetine versus MAOIs or newer ADs: failure to complete - side effects, Outcome 2 follow-up 6-16 weeks.

What's new

DateEventDescription
16 July 2013New search has been performedStudies published between 2005 and 2012 added.
16 July 2013New citation required but conclusions have not changedMajor update of methods and new studies, conclusions not changed.

History

Protocol first published: Issue 2, 2003
Review first published: Issue 4, 2005

DateEventDescription
1 November 2008AmendedConverted to new review format.
23 August 2005New citation required and conclusions have changedSubstantive amendment

Contributions of authors

LRM, CG, MP collected the data; LRM, MP, AC and CB ran the analysis; LRM, CG, MP, DP, TAF, AC and CB drafted and critically revised the manuscript.

Declarations of interest

LRM, CG, MP, DP, AC, CB: none declared.
TAF has received honoraria for speaking at continuing medical education (CME) meetings sponsored by Asahi Kasei, Eli Lilly, GlaxoSmithKline, Mochida, MSD, Otsuka, Pfizer, Shionogi and Tanabe-Mitsubishi. He is a diplomate of the Academy of Cognitive Therapy. He has received royalties from Igaku-Shoin, Seiwa-Shoten and Nihon Bunka Kagakusha. He is on the advisory board for Sekisui Chemicals and Takeda Science Foundation. The Japanese Ministry of Education, Science, and Technology; the Japanese Ministry of Health, Labor and Welfare; and the Japan Foundation for Neuroscience and Mental Health have funded his research projects.

Sources of support

Internal sources

  • Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy.

  • Department of Psychiatry, University of Oxford, UK.

External sources

  • No sources of support supplied

Differences between protocol and review

In this update of the review we applied the risk of bias tool to assess the quality of all included studies. However, a formal comparison of intervention effects according to risk of bias was not performed as for most studies the risk of bias was rated as unclear.

A dosage subgroup analysis was not performed as this can be more appropriately examined in a MTM meta-analysis (see discussion).

Summary of findings tables using the GRADE methodology were added.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aguglia 1993

MethodsEight-week double-blind, multicentre study
ParticipantsOutpatients suffering from a major depressive episode according to DSM-III-R, with a baseline score on Hamilton Rating Scale for Depression-17 Item (HDRS-17) of at least 18, recruited from nine separated psychiatric clinics.
Age: 18 years or more
Exclusion criteria: depression secondary to other conditions, concomitant illness of renal, cardiac or hepatic origin; hypersensitivity to other antidepressants, likelihood of poor compliance, risk of suicide, peptic ulcer history, an improvement of greater than 25% in the HDRS score during a pre-treatment placebo washout period.
InterventionsFluoxetine: 56 participants
Sertraline: 52 participants
Fluoxetine dose range: 20-60 mg/day
Sertraline dose range: 50-150 mg/day
Benzodiazepines were allowed for hypnotic use and as maintenance treatment for pre-existing anxiety
OutcomesHDRS-17 and Hamilton Rating Scale for Anxiety (HAM-A), Montgomery and Asberg Scale for Depression (MADRS), Zung Self-Rating Scale for Anxiety, Leeds Sleep Evaluation Questionnaire, Clinical Global Impression Scale, including severity (CGI-S) and improvement (CGI-I)
NotesSeventy-five per cent of the patients were women. Higher percentage of patients with a family history of psychiatric illness in the fluoxetine group. Higher percentage of patients with severe depression in the fluoxetine group (30.4%) than in the sertraline group (13.7%).
Funding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information about randomisation procedure
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double-blind". No further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double-blind". No further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIncoherence between denominators
Selective reporting (reporting bias)High riskNo follow-up scores reported
Other biasUnclear riskFunding: unclear information

Akhondzadeh 2003

MethodsSix-week double-blind, randomised study
ParticipantsOutpatients meeting DSM-IV diagnostic criteria for major depression, with a minimum baseline score of 20 on the Hamilton Rating Scale for Depression-17 Item (HDRS-17).
Age range: 19-54 years
Exclusion criteria: any other psychiatric primary disease, current or past history of bipolar disorder, use of anxiolytic or MAOI or tryptophan, organic mental disorder, epilepsy, suicidal tendencies, any severe general disease, pregnancy, lactation.
InterventionsFluoxetine: 24 participants
Nortriptyline: 24 participants
Fluoxetine dose: 60 mg/day
Nortriptyline dose: 150 mg/day
OutcomesPrimary outcome: HDRS-17
NotesFunding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "patients were randomly assigned". No further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind". No further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "were put in capsules to provide similar appearance with fluoxetine". No further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if raters were independent
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber and reasons for discontinuation reported, but not included in the analysis
Selective reporting (reporting bias)Unclear riskMean endpoint scores and standard deviation reported only in figure. Side effects reported
Other biasUnclear riskInsufficient information

Akhondzadeh Basti 2007

MethodsEight-week double-blind, randomised trial
ParticipantsOutpatients meeting DSM-IV diagnostic criteria for major depression, with a minimum baseline score of 18 and not superior to 25 on the Hamilton Rating Scale for Depression-17 Item (HDRS-17).
Age range: 19-55 years
Exclusion criteria: patients posed a significant risk of suicide at any time during participation, persons who scored greater than 2 on the suicide item of the HDRS, any clinical significant deterioration during the trial, pregnancy and women not using medically accepted means of birth control.
InterventionsFluoxetine: 20 participants
Petal of Crocus sativus: 20 participants
Fluoxetine dose: 10 mg/day
Petal of Crocus sativus dose: 15 mg/day
OutcomesPrimary outcome: HDRS-17, remission was defined as an endpoint score of 7 or less
NotesFunding: independent study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "patients were randomised to receive capsule of petal of Crocus or fluoxetine in a 1:1 ratio using computer code", no further information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "capsules (...) did not have any different taste compared to fluoxetine", "the person who administered the medication, raters and patients were blind to assignment", not clear if blindness was successful
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "the person who administered the medication, raters and patients were blind to assignment", not clear if blindness was successful
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of responders reported with denominator. Reasons for dropout not reported
Selective reporting (reporting bias)Unclear riskMean endpoint scores and standard deviation reported only in figures. Side effects reported
Other biasLow riskFunding: independent study

Alby 1993

MethodsTwelve-week double-blind study
ParticipantsOutpatients suffering from a major depressive episode, recurrent depression or disthymia according to DSM-III-R, with a score of at least 25 on the HARD Humeur, Agoisse, Ralentissement, Danger (HARD), Ferreri anxiety rating diagram (FARD), Hopkins Symptom check-list (HSCL).
Age range: 25-65 years
Exclusion criteria: not reported
InterventionsFluoxetine: 104 participants
Tianeptine: 102 participants
Fluoxetine dose: 20 mg/day
Tianeptine dose: 37.5 mg/day
Benzodiazepines allowed for severe anxiety or sleep disorders
OutcomesHARD and on the FARD scales
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Low riskDropout rate reported with reasons. Scores at endpoint are reported with denominator
Selective reporting (reporting bias)Unclear riskFull side effects reported. Other outcomes not clearly stated
Other biasHigh riskLast author's affiliation was IRIS and this company produces tianeptine

Altamura 1989

MethodsFive-week double-blind randomised study
ParticipantsInpatients fulfilling DSM-III criteria for major depressive episode and scoring at least 18 on Hamilton Rating Scale for Depression-17 item (HDRS-17).
Age: over 65 years
Exclusion criteria: not reported
InterventionsFluoxetine: 13 participants
Amitriptyline: 15 participants
Fluoxetine dose: 20 mg/day
Amitriptyline dose: 75 mg/day
OutcomesHDRS-17 score
NotesElderly patients only
Funding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomised". No other information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind". No further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double blind". No further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "double blind". No further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Number of dropouts reported, but reasons not specified

Scores reported without denominator

Selective reporting (reporting bias)Unclear riskEndpoint scores reported only in figure. Only most common side effects reported
Other biasUnclear riskFunding: unclear

Alves 1999

MethodsTwelve-week double-blind randomised multicentre study
ParticipantsOutpatients meeting DSM-IV diagnostic criteria for major depression, with a minimum baseline score of 20 on the Hamilton Rating Scale for Depression-21 item (HDRS-21), recruited from three clinical sites.
Age range: 18-65 years
Exclusion criteria: known sensitivity to venlafaxine or fluoxetine, a history of any clinically significant cardiac, hepatic or renal disease or abnormalities on a screening physical examination, ECG or laboratory tests, with any mental or neurologic disorder and breast-feeding women; used of any investigational drug, antipsychotic drug, electroconvulsive therapy or sumatriptan within 30 days of baseline, fluoxetine within 21 days and MAOIs within 14 days.
InterventionsFluoxetine: 47 participants
Venlafaxine: 40 participants
Fluoxetine dose range: 20-40 mg/day
Venlafaxine dose range: 75-150 mg/day
OutcomesHDRS-21, Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression (CGI)
NotesPatients in the fluoxetine group had more chronic histories of depression at baseline. Predominance of females in the whole study.
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were allocated to treatments groups using a balanced randomisation from randomly permuted blocks"
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "the investigators were provided individual sealed envelopes"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote: "Efficacy analysis were performed on ITT basis using a last observation carried forward method (LOCF)", but scores reported without denominator. Reasons and number of dropouts reported
Selective reporting (reporting bias)Unclear riskOnly most common side effects reported (at last 7% incidence). Mean endpoint scores and standard deviation reported
Other biasHigh riskFirst author's affiliation was Wyeth-Lederle, Portugal, and this company produces venlafaxine

Amini 2005

MethodsSix-week double-blind randomised trial
ParticipantsIn and outpatients meeting DSM-IV diagnostic criteria for major depression, with a minimum baseline score of 18 on the Hamilton Rating Scale for Depression-17 item (HDRS-17).
Age range: 18-60 years
Exclusion criteria: history of recent suicidal attempt (1 month or less before the study) or actual ideation; pregnancy or lactation; history or current diagnosis (DSM-IV) of dysthymic disorder, bipolar disorder, any psychotic disorder, eating disorders, personality disorders and mental retardation; current diagnosis (DSM-IV) of anxiety disorders (except for specific phobia), mental disorder due to general medical condition, substance or alcohol abuse or dependency (except for nicotine and caffeine) and postpartum depression; current diagnosis of any serious systemic medical illnesses; treatment with any antidepressant drugs within 1 week, or with MAOIs within 5 weeks, or electroconvulsive therapy within 3 months ago; BMI more than 30 and white blood count more than 4000/mm or neutrophil more than 1500/mm.
Interventions

Fluoxetine: 18 participants
Mirtazapine: 18 participants
Fluoxetine dose: 20 mg/day

Mirtazapine dose: 30 mg/day

OutcomesMean decrease in HDRS-17 score from baseline
NotesFunding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised trial, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double blind", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Double blind", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Double blind", no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote: "A observed cases analysis over the 6 weeks was the primary efficacy analysis (...) an intention to treat analysis with LOCF was also performed...all discussion of result is based on observed cases (OC) analysis". Number of randomised, and number of lost during the follow-up reported. Number of responders reported without denominator
Selective reporting (reporting bias)Unclear risk

Side-effects are reported. Vital signs and body weight not reported

Mean endpoint scores (HDRS) reported in figures and without standard deviations

Other biasUnclear riskFunding: unclear

Andreoli 2002

MethodsEight-week double-blind, randomised multicentre study
ParticipantsIn and outpatients meeting DSM-III-R diagnostic criteria for major depression, with a minimum baseline score of 22 on the Hamilton Rating Scale for Depression-21 item (HDRS-21), recruited from 33 clinical sites.
Age range: 18-65 years
Exclusion criteria: history of unresponsiveness to antidepressant treatment, association with endocrine disorders, substance abuse, drug hypersensitivity, chronic respiratory insufficiency, or gastro-intestinal, hepatic or renal disease, ECT within 6 months of baseline, high risk of suicide, pregnancy or absence of adequate contraception measures.
InterventionsFluoxetine: 127 participants
Reboxetine: 126 participants
Placebo: 128 participants
Fluoxetine dose range: 20-40 mg/day
Reboxetine dose range: 8-10 mg/day
Chloral hydrate (0.5-1 g) was allowed as hypnotic
OutcomesPrimary outcome: absolute change in the HDRS-21 total score
Secondary outcomes: Clinical Global Impression Scale (CGI) Severity and Improvement, Montgomery and Asberg Scale for Depression (MADRS), Quality of Sleep Questionnaire
NotesResponse: decrease of at least 50% in the HDRS total score
Remission: total score less than 10
Funding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised trial, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double blind", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Double blind", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Double blind", no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Number of randomised and number of lost during follow-up reported, but the reasons for dropout were not clear. Only most common side effects were reported

Quote: "Statistical analysis was carried out on the intent to treat population"

Selective reporting (reporting bias)Unclear risk

Only most common side effects were reported

Mean endpoint scores and standard deviation reported

Other biasUnclear riskFunding: unclear

Ansseau 1994

MethodsSix-week double-blind, randomised multicentre study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depressive episode, with a score of at least 25 on Montgomery and Asberg Scale for Depression (MADRS) and of at least 4 on Clinical Global Impression Scale (CGI).
Age range: 19-68 years
Exclusion criteria: serious or uncontrolled medical illness, major anxiety, agitation, suicide risk, resistance during the current episode to at least two antidepressants, substance abuse or dependence, concomitant therapy with lithium, MAOIs, long-acting neuroleptic.
InterventionsFluoxetine: 93 participants
Milnacipram: 97 participants
Fluoxetine dose: 20 mg/day
Milnacipram dose: 100 mg/day
OutcomesHamilton Rating Scale for Depression-24 item (HDRS-24), MADRS, CGI
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned". No further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double blind", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "double blind", no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber and reasons for drop-out reported. Rating scale scores reported without denominator
Selective reporting (reporting bias)High riskEndpoint scores reported only in figures. Side effects reported
Other biasHigh riskLast author's affiliation was Laboratories Pierre Fabre Medicament, and this company produces milnacipran

Armitage 1997

MethodsEight-week double-blind, randomised trial
Participants

Patients meeting DSM-III-R diagnostic criteria for non psychotic, moderate to severe major depression disorder and a minimum score of 18 on the Hamilton Rating Scale for Depression-17 item (HDRS-17). All patients were required to have subjective sleep disturbance (score of 1 or 2 on at least one of the sleep items of the HDRS-17).

Age range: 18-55 years
Exclusion criteria: patients with current general medical condition, history of head trauma or current DSM-III-R axis I disorder in the categories of organic mental syndromes or disorders, bipolar disorder, schizophrenia, delusional disorder, or psychotic disorder NOS. Shift workers, or those with any evidence of independence sleep disorder (such as narcolepsy, bruxism, sleep apnoea) were ineligible. Patients with a history of psychoactive substance abuse, to be pregnant, lactating, or sexual active without an adequate method of contraception, previous participation in a nefazodone trial, significant suicide risk, or known hypersensitivity to trazodone, etoperidone, fluoxetine or metachlorophenylpiperazine were other exclusion criteria.

InterventionsFluoxetine: 22 participants
Nefazodone: 12 participants
Fluoxetine dose range: 20-40 mg/day
Nefazodone dose range: 400-500 mg/day
OutcomesHDRS-17 total score and sleep parameters
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised trial, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "double dummy capsule-dosing scheme"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMean baseline and endpoint scores reported without standard deviations. Number and reasons for dropout specified
Selective reporting (reporting bias)Unclear riskSide effects not reported
Other biasHigh riskThis study was supported in part by Bristol-Myers Squibbs. This company produces nefazodone

Bakish 1997

MethodsTwelve-week double-blind, randomised study
Participants

Patients meeting DSM-III-R diagnostic criteria for major affective disorder, unipolar and had met the diagnostic criteria for major depressive disorder episode for at least one month before entering the study, with a minimum baseline score of 18 on the Hamilton Rating Scale for Depression-17 item (HDRS-17), with a score of two or more on item one.

Age range: 23-54 years
Exclusion criteria: concurrent DSM-III-R Axis I diagnosis or unstable medical condition, suicidal patients or having receiving fluoxetine within 36 days preceding enrolment.

InterventionsFluoxetine: 9 participants
Paroxetine: 12 participants
Fluoxetine dose range: 20-80 mg/day
Paroxetine dose range: 20-50 mg/day
OutcomesResponse: decrease of at least 50% in the HDRS-17 total score
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised trial, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
High riskBaseline and endpoint scores for each arm not reported. Number and reasons for dropout not specified
Selective reporting (reporting bias)High riskSide effects not reported. Mean baseline and endpoint score reported only in the whole sample
Other biasHigh riskQuote: "this study was supported by grants from SmithKline Beecham", and this company produces paroxetine

Basterzi 2009

MethodsSix-week double-blind randomised trial
ParticipantsPatients diagnosed with major depression (MD) or MD-recurrent according to DSM-IV diagnostic criteria.
Exclusion criteria: any additional axis I or axis II DSM-IV diagnosis, current pregnancy, acute or chronic infections within the past month, autoimmune, allergic, neoplastic, or endocrine disease and other acute physical disorders, including surgery or infarction of the hearth or brain within the past 6 months, patients exposed to any drug including antidepressants, non-steroidal anti-inflammatory drugs and oral contraceptives in the past 4 weeks.
Interventions

Fluoxetine: 21 participants
Venlafaxine: 22 participants

Placebo: 21 participants
Fluoxetine dose range: 20-40 mg/day

Venlafaxine dose range: 75-150 mg/day

OutcomesResponse was defined as a 50% reduction in the index total Hamilton Rating Scale for Depression (HDRS) score
NotesFunding: by academy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "consequently randomised", no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if raters were independent and unclear if blinding was successful
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber and reason for dropout not clearly reported. Scores reported without denominator
Selective reporting (reporting bias)High riskAdverse effects not reported. Number of responders only reported for the whole sample (not for each study arm)
Other biasLow riskFunding: by academy

Beasley 1993a

MethodsSix-week double-blind, randomised study
ParticipantsInpatients fulfilling DSM-III-R criteria for major depressive episode, with a score of at least 20 on the Hamilton Rating Scale for Depression-21 item (HDRS-21).
Age range: 18-70 years
Exclusion criteria: psychosis, organic mental disorder, substance abuse active within 1 year
InterventionsFluoxetine: 56 participants
Imipramine: 62 participants
Fluoxetine dose range: 40-80 mg/day
Imipramine dose range: 150-300 mg/day
Chloral hydrate (max 1g) and flurazepam (max 30 mg) were allowed as hypnotic
OutcomesHDRS-21, Raskin, Covi, Clinical Global Impression Severity and Improvement Scales (CGI)
NotesResponse: decrease of at least 50% in the total score
Remission: total score less than 7
One patient on fluoxetine committed suicide
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote: "efficacy data were analysed in accordance with ITT principle", but scores reported without denominator.

Study completion rates and reasons for study discontinuations reported

Selective reporting (reporting bias)Unclear riskOnly side-effect over 5% reported. Vital signs reported
Other biasHigh riskAuthors' affiliation was Psychopharmacology Division, Lilly Reasearch Laboratories, Eli Lilly and Company, Indianapolis. This company produces fluoxetine

Behnke 2002

MethodsSix-week double-blind, randomised multicentre study
ParticipantsPatients with ICD-10 depression, with a score between 16 and 24 points on Hamilton Rating Scale for Depression (HDRS-17).
Age range: 18-73 years
Exclusion criteria: participation in a clinical study less than 4 weeks, pregnancy and lactation, insufficient contraception, suicide risk, dementia, or other severe intellectual impairment, chronic alcohol or drug abuse or dependence, severe cardiac, liver, kidney or respiratory insufficiency, neoplasia, Parkinson's or Alzheimer's disease, hypersensitivity to an ingredient of the Hypericum perforatum, febrile illness, anaemia, thyroid or parathyroid disease, pituitary insufficiency.
InterventionsFluoxetine: 35 participants
Hypericum: 35 participants
Fluoxetine dose: 40 mg/day
Hypericum dose: 300 mg/day
OutcomesHDRS-17, von Zerssen Depression Scale (VZD), Clinical Global Impression (CGI) Scale
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no other information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of dropouts reported, but reasons not specified. Endpoint scores reported without denominator
Selective reporting (reporting bias)Unclear riskSide effects not reported. Mean endpoint scores and standard deviation reported
Other biasHigh riskLast author's affiliation was PhytoPharm Consulting, Istitute for Phytopharmaceuticals, Berlin; probably this company produces Hypericum perforatum

Bennie 1995

MethodsSix-week double-blind, randomised multicentre study
ParticipantsOutpatients with a diagnosis of major depression or bipolar disorder, depressed, according to DSM-III-R, scoring at least 18 on the Hamilton Rating Scale for Depression-17 item (HDRS-17), and with a higher on the Raskin Depression Scale than on the Covi Anxiety Scale.
Age: over 18 years
Exclusion criteria: pregnant or lactating women, women of childbearing potential not practicing a reliable method of contraception, patients with previous treatment with sertraline or fluoxetine, treated with MAOI within two weeks or other antidepressants medication within one week of double-blind therapy, treated with reserpine or methyl-dopa, likely to require additional treatments with psychoactive medication, ECT or intensive psychotherapy during the study; failure to respond to previous antidepressant therapy at clinically appropriate dosages, use of ECT to treat a previous episode of depression, a history of severe allergies or multiple adverse events associated with pharmacotherapy, the presence of significant medical disease; psychiatric history including another Axis I disorder and significant suicide risk.
InterventionsFluoxetine: 144 participants
Sertraline: 142 participants
Fluoxetine dose range: 20-40 mg/day
Sertraline dose range: 50-100 mg/day
Chloral hydrate (max 1 g) and temazepam (max 20 mg) were allowed as hypnotic
OutcomesPrimary outcome: HDRS-17, Clinical Global Impression Severity and Improvement Scales (CGI S-I)
Secondary outcomes: Hamilton Rating Scale for Anxiety, the Raskin Depression Scale and Covi Anxiety Scale, self-rated Leeds Sleep Questionnaire
Notes

Patients with concomitant medical conditions were allowed to participate in the study provided that the conditions were clearly not associated with the illness of the study and that any required medications were not psychoactive agents.

One patient attempted suicide in the fluoxetine group.
Funding: by industry

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned, in equal proportion", no other information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber and reasons for dropout reported. Scores reported with denominator
Selective reporting (reporting bias)Unclear riskScores reported without standard deviations. Only adverse events occurring at least in 3% of the sample reported
Other biasHigh riskQuote: "supported by a research grant from international Pharmaceuticals group, Pfizer, Inc, New York". This company produces sertraline

Berlanga 1997

MethodsEight-week double-blind, randomised two-centre study
ParticipantsOutpatients with a diagnosis of moderate to severe major depressive episode without psychotic features or bipolar disorder of the depressed type according to DSM-III-R, with a total score of least 18 points on Hamilton Rating Scale for Depression-17 item (HDRS-17) at baseline.
Age: over 18 years
Exclusion criteria: concomitant organic mental disorder, psychoactive substance abuse disorder, schizophrenia or other psychotic disorder or any medical condition that contraindicated treatment with antidepressants; pregnancy or lactating; women of childbearing potential not practicing a reliable method of contraception.
InterventionsFluoxetine: 37 participants
Nefazodone: 37 participants
Fluoxetine dose range: 20-40 mg/day
Nefazodone: 400-500 mg/day
Concomitant psychotropic medication was prohibited, but occasionally use of benzodiazepines for severe anxiety or insomnia was allowed
OutcomesHDRS-17, Hamilton Rating Scale for Anxiety, Clinical Global Impression, Patient Global Assessment
NotesOne patient attempted suicide in the fluoxetine group.
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomised". No other information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "this was a double-blind trial", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double-dummy", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "this was a double-blind trial", no further information
Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber of dropouts reported. Scores at rating scales were reported with denominator
Selective reporting (reporting bias)Unclear riskScores reported without standard deviations. Only adverse effect occurred in at least 10% of the sample were reported
Other biasHigh riskQuote: "supported by Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT". This company produces nefazodone

Besancon 1993

MethodsEight-week double-blind, randomised study
Participants

Outpatients with a diagnosis of depressive episode less than 2 months duration, according to DSM-III criteria, with a minimum score of 25 on the Montgomery and Asberg Scale for Depression (MADRS).

Age range: 18-65 years
Exclusion criteria: absence of resistance to mianserin or fluoxetine, absence of associated psychotropic treatment, with the exception of prazepam (40 mg/day).

InterventionsFluoxetine: 33 participants
Mianserin: 32 participants
Fluoxetine dose range: 20-40 mg/day
Mianserin dose range: 60-90 mg/day
OutcomesHamilton Rating Scale for Depression (HDRS), Hamilton Rating Scale for Anxiety (HAM-A), MADRS
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "the patients were allocated at random", no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of dropouts reported. Mean endpoint scores not clearly reported. No further information
Selective reporting (reporting bias)Unclear riskSIde effects not clearly reported. No further information
Other biasHigh riskLast author's affiliation was Organon, and this company produces mianserin

Bhurgri 2011

MethodsTwelve-week randomised study
Participants

Patients with a diagnosis of major depressive episode, single episode or recurrent, according to DSM-IV criteria, with a minimum score of 18 on the Hamilton Rating Scale for Depression-24 item (HDRS-24).

Age range: 30-50 years

Exclusion criteria: DSM-IV diagnosis of acute or chronic mental disorder, a Mini Mental State Examination score less than 23, concomitant use of any psychotropic drugs (except intermittent use of chloral Hydate or diazepam specifically for sleep), presence of another axis I psychiatric disorder, or any unstable medical condition that might interfere with safety or the interpretation of results.

InterventionsFluoxetine: 96 participants
Nortriptyline: 96 participants
Fluoxetine dose range: 20-80 mg/day
Nortriptyline dose range: 25-100 mg/day
OutcomesHDRS-24 and Clinical Global Impression (CGI)
NotesFunding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "patients were randomly assigned". No other information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "a double dummy-procedure was used to preserve the blind". No further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "a double dummy-procedure was used to preserve the blind". No further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "a double dummy-procedure was used to preserve the blind". No further information
Incomplete outcome data (attrition bias)
All outcomes
High riskMean endpoint score not reported. Number and reasons for drop-out not reported
Selective reporting (reporting bias)High riskMean score reported at sixth week and without number of patients. Side effects reported
Other biasUnclear riskFunding: unclear

Bjerkenstedt 2005

MethodsSix-week double-blind randomised trial
ParticipantsOutpatients meeting the DSM-IV criteria for an acute, recurrent episode of Major Depressive Disorder (MDD) with mild or moderate intensity, aged 18-70 years, a minimum total score of 21 on the Hamilton Rating Scale for Depression-21 item (HDRS-21), history of at least two episodes of non-psychotic MDD, capacity and willingness to give informed consent and to comply with study procedures.
Exclusion criteria: a diagnosis of psychotic mental disorder, other disorders requiring concomitant psychoactive medication; MAOI treatment within 14 days prior to entry; history of treatment resistant MDD (at least two different antidepressants over 6 weeks at sufficient doses) from at least two previous depressive episodes, risk of suicide; history of seizure disorder, alcohol or substance abuse; other serious unstable acute or chronic medical illness; severely impaired hepatic or renal function, pregnancy, breast feeding, or use of inadequate contraceptives in fertile women; known intolerance or hypersensibility to study medications, substantial placebo response at the end of placebo run-in phase; treatment with any investigation drug during 3 months prior to inclusion; participation in another clinical trial within 30 days before the start of the study.
Interventions

Fluoxetine: 57 participants

Hypericum: 59 participants

Placebo: 58 participants
Fluoxetine dose: 20 mg/day

Hypericum dose: 900 mg/day

Outcomes

Primary outcome: change in HDRS-21 total score

Secondary endpoint: change in total Montgomery and Asberg Scale for Depression (MADRS) score and Clinical Global Impression (CGI) score

Response was defined as a 50% reduction in the HDRS-21 total score

NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "a double dummy technique with matching placebos for each active treatment was applied. Thus, both placebos were identical in shape, weight, colour, smell and taste to their corresponding verum formulations", no other information
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "all investigators and personnel, actively involved in the trial, were blinded to group assignment until the database was closed", no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskReasons for and number of dropouts reported. Number of responders in the text is different from number reported in the table. The so called "ITT population" in this study was different from the randomised sample
Selective reporting (reporting bias)Unclear riskThe duration of the study was not clearly reported. Adverse experiences reported
Other biasHigh riskQuote: "the study was funded by a grant from Lichtwer Pharma GmbH, Berlin, Germany", and this company produces hypericum extract LI 160

Bougerol 1997a

MethodsEight-week double-blind, multicentre study
ParticipantsIn- and outpatients fulfilling DSM-III-R criteria for a major depressive disorder or bipolar disorder. The severity of depression should be 25 or more on the Montgomery and Asberg Scale for Depression (MADRS).
Age range: 18-65 years
Exclusion criteria: pregnancy, lactation, failure to use a safe contraceptive method, alcohol or drug abuse within the last year, patients with severe somatic, neurological or psychiatric disease, treatment with MAOI within 2 weeks prior to entry the trial, hypersensitivity to study drugs, suicide risk.
InterventionsFluoxetine: 158 participants
Citalopram: 158 participants
Fluoxetine dose: 20 mg/day
Citalopram dose range: 20-40 mg/day
Concomitant psychotropic medication was prohibited, but use of benzodiazepines for insomnia was allowed
OutcomesPrimary outcome: MADRS score
Secondary outcomes: Hamilton Rating Scale for Depression -17 item (HDRS-17), Clinical Global Impression (CGI) scores
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble dummy" no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "all efficacy analyses were made on the basis of the efficacy group, whereas the tolerability analyses were made on the basis of the ITT population"
Selective reporting (reporting bias)Unclear riskSide effects reported only when recorded in at least 5 patients
Other biasHigh riskQuote: "sponsored by Lundbeck, Copenaghen. This company also delivered the citalopram tablets and bought (in bulk) the fluoxetine capsules (active and placebo) from Eli LIlly, England, and packed them"

Bougerol 1997b

MethodsEight-week double-blind, multicentre study
ParticipantsOutpatients (primary care) fulfilling DSM-III-R criteria for a major depressive disorder. The severity of depression should be 22 or more on the Montgomery and Asberg Scale for Depression (MADRS) score.
Age range: 18-70 years
Exclusion criteria: pregnancy, lactation, failure to use a safe contraceptive method, alcohol or drug abuse within the last year, patients with severe somatic, neurological or psychiatric disease, treatment with MAOI within 2 weeks prior to entry the trial, hypersensitivity to study drugs, suicide risk.
InterventionsFluoxetine: 184 participants
Citalopram: 173 participants
Fluoxetine dose: 20 mg/day
Citalopram dose: 20 mg/day
Concomitant psychotropic medication was prohibited, but use of benzodiazepines for insomnia
OutcomesPrimary outcome: MADRS score
Secondary outcomes: Hamilton Rating Scale for Depression-17 item (HDRS-17), Clinical Global Impression (CGI) scores
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "all efficacy analyses were made on the basis of the efficacy group, whereas the tolerability analyses were made on the basis of the ITT population"
Selective reporting (reporting bias)Unclear riskSide effects reported only when recorder in at least 5 patients
Other biasHigh riskQuote: "sponsored by Lundbeck, Copenaghen. This company also delivered the citalopram tablets and bought (in bulk) the fluoxetine capsules (active and placebo) from Eli LIlly, England, and packed them"

Bowden 1993

MethodsSix-week double-blind, randomised, multicentre study
ParticipantsIn- and outpatients fulfilling DSM-III-R criteria for major depressive disorder, with a total score of at least 20 on Hamilton Rating Scale for Depression-21 item (HDRS-21).
Age range: 18-60 years
Exclusion criteria: use of heterocyclics antidepressant drugs within 7 days or MAOI within 14 days of starting active treatment; patients with other significant medical disorders.
InterventionsFluoxetine: 28 participants
Desipramine: 30 participants
Fluoxetine dose range: 20-60 mg/day
Desipramine dose range: 150-250 mg/day
OutcomesHDRS-21, Clinical Global Impression (CGI), Patient self-rated Global Improvement (PGI)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no other information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "all medication were prepared in identical capsules and administered by use of the double dummy technique", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskRating scale reported without denominator. Number and reasons for dropout reported
Selective reporting (reporting bias)Unclear riskNo standard deviations reported. No endpoint scores. Vital signs measures not reported
Other biasHigh riskQuote: "this research was supported in part by a grant from Eli Lilly and Company", this company produces fluoxetine

Boyer 1998

MethodsTwenty-six-week double-blind, randomised, multicentre study
ParticipantsOutpatients (primary care) fulfilling DSM-IV criteria for major depressive disorder, with a score of at least 20 at Montgomery and Asberg Scale for Depression (MADRS).
Age range: 18-65 years
Exclusion criteria: pregnancy, lactation, failure to use a safe contraceptive method; concurrent major psychiatric disorders, such as anxiety disorder, dementia, somatoform disorders, agoraphobia, social phobia, any history of schizophrenia, psychosis or personality disorder; severe concurrent medical illness; alcohol or drug dependence; serious adverse reactions related to medicines; previous treatment with antidepressant for less than 3 week; major suicide risk.
InterventionsFluoxetine: 120 participants
Sertraline: 122 participants
Fluoxetine dose range: 20-60 mg/day
Sertraline dose range: 50-150 mg/day
OutcomesMADRS and Clinical Global Impression (CGI)
NotesResponse: decrease of at least 50% in the MADRS total score
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskCriteria and number of drop-out reported. Rating scale reported without denominator
Selective reporting (reporting bias)Unclear riskScores at rating scales were reported without standard deviations. Side effects reported
Other biasHigh riskLast author's affiliation was Pfizer France, Orsay. This company produces sertraline

Bremner 1984

MethodsFive-week double-blind, randomised study
ParticipantsOutpatients fulfilling Research Diagnostic Criteria (RDC) criteria for major depressive disorder, with a score of at least 20 on Hamilton Rating Scale for Depression (HDRS), of 8 on Raskin Depression Scale (RDS).
Age range: 23-69 years
Exclusion criteria: suicide risk, history of schizophrenia or other psychotic state likely to be aggravated by imipramine, organic brain disease, history of seizures; glaucoma, chronic urinary retention or serious cardiovascular disease; history of multiple adverse reaction to drugs, drug or alcohol abuse, pregnancy.
InterventionsFluoxetine: 20 participants
Imipramine: 20 participants
Fluoxetine dose range: 60-80 mg/day
Imipramine dose range: 125-300 mg/day
OutcomesHDRS, RDS, Covi Anxiety scale (CAS), Clinical Global Impressions (CGI)
NotesPatients over 65 years in the imipramine group only
Funding: by academy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "the study drugs and placebo were supplied as identical capsules". No other information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if raters were independent and unclear if blinding was successful
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskCriteria and number of dropouts reported, but not included in the analysis
Selective reporting (reporting bias)Unclear riskScores at rating scales were reported without standard deviations
Other biasLow riskFunding: by academy

Bressa 1989

MethodsFive-week, double-blind, randomised study
Participants

Outpatients fulfilling DSM-III criteria for major depression, with a score of at least 20 on Hamilton Rating Scale for Depression (HDRS).

Age: not stated
Exclusion criteria: suicidal ideas, psychosis, seizure disorders, serious cardiac, renal or hepatic disease, alcoholism or drug abuse, use of antidepressant drug with the preceding 14 days, concurrent medication potentially interacting.

Interventions

Fluoxetine: 18 participants

Imipramine: 12 participants
Fluoxetine dose range: 20-60 mg/day
imipramine dose range: 75-175 mg/day

OutcomesHDRS, Clinical Global Impression (CGI) scores
NotesFunding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomised schedule". No other information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnclear if raters were independent and unclear if blinding was successful
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of drop-out reported, but unclear reasons for dropout. Rating scale scores reported without denominators. Vital signs and side effects not reported
Selective reporting (reporting bias)Unclear riskNo secondary endpoint scores. No standard deviations reported for HDRS score
Other biasUnclear riskFunding: unclear

Byerley 1988

MethodsSix-week double-blind, randomised, multicentre study
ParticipantsOutpatients fulfilling DSM-III criteria for major depression (duration of at least 1 month) with a score of at least 20 on Hamilton Rating Scale for Depression-21 item (HDRS-21).
Age: not stated
Exclusion criteria: psychotic symptoms bipolar illness, schizophrenia, active drug or alcohol abuse, significant medical illness
InterventionsFluoxetine: 32 participants
Imipramine: 34 participants
Placebo: 29 participants
Fluoxetine dose range: 40-80 mg/day
Imipramine dose range: 150-300 mg/day
Intermittent administration of flurazepam for insomnia (15-30 mg)
OutcomesHDRS-21, Clinical Global Impression (CGI) scores
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "randomisation was carried out by using a table of random numbers"
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind". No further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "capsules looked identical", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber and reason for dropout during the study were reported. Withdrawals were not included in the analysis
Selective reporting (reporting bias)Unclear riskNo detailed endpoint scores at CGI. Side effects reported only with percentage, without denominator
Other biasHigh riskThe study was supported, in part, by Eli Lilly. This company produces fluoxetine

Cassano 2002

MethodsFifty-two week double-blind, randomised, multicentre study
ParticipantsOutpatients fulfilling ICD-10 criteria for major depression, with a Mini Mental State Examination (MMSE) score of at least 22 and a Hamilton Rating Scale for Depression (HDRS-21) score of at least 18.
Age: over 65 years
Exclusion criteria: concurrent major medical disorders, dementia, any history of schizophrenia, psychosis; alcohol or drug dependence; major suicide risk; use of long-acting neuroleptic drugs within 6 months or oral neuroleptics within 2 weeks before the study entry; ECT; daily use of benzodiazepines within 8 weeks or SSRI within 4 weeks, MAOI within 3 weeks, TCA within 1 week before the study entry.
InterventionsFluoxetine: 119 participants
Paroxetine: 123 participants
Fluoxetine dose range: 20-60 mg/day
Paroxetine dose range: 20-40 mg/day
OutcomesHDRS-21, Clinical Anxiety Scale, Buschke Selective Reminding Test (BSRT), Blessed Information and Memory Test (BIMT), Clifton Assessment Scale (CLAS), Cancellation Task Test (CTT), Wechsler Paried Word Test (WPW), Mini Mental Sate Evaluation (MMSE) and Clinical Global Impression (CGI)
NotesDepression response: total score less than 10 on the HDRS-21
Anxiety response: total score less than 8 on the Covi Anxiety scale (CAS)
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnclear if raters were independent and unclear if blinding was successful
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
High riskRating scale scores reported without denominator
Selective reporting (reporting bias)High riskStandard deviations not reported (HDRS). No endpoint scores (CGI, CAS)
Other biasHigh riskThe study was supported by SmithKline. This company produces paroxetine

Chouinard 1985

MethodsFive-week double-blind, randomised study
Participants

Outpatients fulfilling Research Diagnostic Criteria (RDC) criteria for major depressive disorder, with a score of at least 21 on Hamilton Rating Scale for Depression (HDRS-17) and of at least 8 on the Raskin Depression Scale (RAS).

Age range: 21-70 years
Exclusion criteria: physical illness, schizophrenia, schizoaffective illness, chronic or acute organic brain syndrome, mental deficiency, alcoholism, epilepsy, drug addiction.

InterventionsFluoxetine: 23 participants
Amitriptyline: 28 participants
Fluoxetine dose range: 40-80 mg/day
Amitriptyline dose range: 100-300 mg/day
Benzodiazepines were allowed for agitation and insomnia
Outcomes

Primary outcome: HDRS-17, Clinical Global Impression (CGI), Efficacy Index-Side Effects rating (EISE)

Secondary outcomes: Hamilton Rating Scale for Anxiety (HAM-A) and Zung Depression Scale (SDS)

NotesOne patient attempted suicide in the fluoxetine group
Funding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned. Assigment was stratified to ensure balanced distribution of male and female patients to each of the two study drug regimen". No other information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double blind conditions in identical capsules", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
High riskScores reported without standard deviations. Reasons for withdrawal reported, but withdrawals not included in analysis
Selective reporting (reporting bias)Unclear riskSide effects reported only with an incidence over 10%
Other biasUnclear riskFunding: unclear

Chouinard 1999

MethodsTwelve-week double-blind, randomised, multicentre study
Participants

Patients fulfilling DSM-III criteria for major depressive disorder, with a score of at least 20 on Hamilton Rating Scale for Depression (HDRS-21).

Age: not stated
Exclusion criteria: significant concurrent illness including renal, hepatic, cardiovascular or neurological disease, non-stabilised diabetes, other current Axis I psychiatric diagnosis; organic brain syndrome, past or present abuse of alcohol or drugs; pregnancy or lactating; ECT; continuous lithium therapy in preceding 2 months, use of important psychotropic drug, current therapy with an anticoagulant or type 1 antiarrhythmic.

InterventionsFluoxetine: 101 participants
Paroxetine: 102 participants
Fluoxetine dose range: 20-80 mg/day
Paroxetine dose range: 20-50 mg/day
Chloral hydrate was allowed just during the first two weeks of the study
OutcomesPrimary outcomes: HDRS-21, Clinical Global Impression
Secondary outcomes: HDRS-21 anxiety and somatization scores
NotesResponse: decrease of at least 50% in the HDRS-21 total score and/or a total score less than 10
Two participants dropped out (1 in the fluoxetine and 1 in the paroxetine group) due to attempted suicide
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "the efficacy analysis included all randomised patients who underwent at least one on-therapy efficacy evaluation". Number of patients responding to treatment reported with denominator. Reason for withdrawal reported
Selective reporting (reporting bias)Low riskEffect side reported only with an incidence over 10%
Other biasHigh riskFunding by SmithKline, and this company produces paroxetine

CL3-022

MethodsSix-week double-blind, randomised study
Participants

In- and outpatients fulfilling DSM-IV criteria for single or recurrent episode of Major Depressive Disorder (MDD), with or without melancholic features, without atypical features, without psychotic features and a score of at least 22 on Hamilton Rating Scale for Depression (HDRS). Morover decrease in HDRS total score should not be more than 20% between start of run-in and inclusion visit and a severity of illness of at least 4 on CGI.

Age range: 18-59 years
Exclusion criteria: not specified

InterventionsFluoxetine: 137 participants
Agomelatine: 133 participants
Fluoxetine dose: 20 mg/day
Agomelatine dose: 25 mg/day
OutcomesPrimary outcome: HDRS score
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information
Selective reporting (reporting bias)Unclear riskInsufficient information
Other biasHigh riskFunding: by industry

CL3-024

MethodsSix-week double-blind, randomised, multicentre study
Participants

In- and outpatients fulfilling DSM-IV criteria for single or recurrent episode of Major Depressive Disorder (MDD), with or without melancholic features, without atypical features, without psychotic features and a score of at least 22 on Hamilton Rating Scale for Depression (HDRS).

Age range: 18-59 years
Exclusion criteria: not specified

Interventions

Fluoxetine: 148 participants
Agomelatine 25mg: 150 participants

Agomelatine 50mg: 151 participants
Fluoxetine dose: 20 mg/day
Agomelatine dose range: 25-50 mg/day

OutcomesPrimary outcome: HDRS score
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information
Selective reporting (reporting bias)Unclear riskInsufficient information
Other biasHigh riskFunding: by industry

Clayton 2003

MethodsEight-week double-blind, randomised study
ParticipantsOutpatients fulfilling DSM-IV criteria for major depressive disorder, with a score of at least 22 on the Hamilton Rating Scale for Depression (HDRS).
Age range: 18-65 years
Exclusion criteria: other psychiatric diagnoses, have received Tricyclics (TCAs) within the previous 14 days and fluoxetine within 14 days or 28 days when resistant to treatment, uncontrolled medical or metabolic illness, use of illicit drugs, history of DSM-IV substance abuse in the previous 12 months.
InterventionsFluoxetine: 150 participants
Reboxetine: 150 participants
Fluoxetine dose: 20-40 mg/day
Reboxetine dose: 8-10 mg/day
Outcomes

Primary outcome: HDRS score

Response: decrease of at least 50% in the HDRS score

NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of withdrawals reported, but reasons not clearly described. Mean scores reported only at the baseline and not at the endpoint
Selective reporting (reporting bias)Unclear riskSide effects reported partially. Baseline mean scores reported without standard deviations
Other biasHigh riskFunding by Pharmacia Corporation

Clerc 1994

MethodsSix-week double-blind, randomised, multicentre study
ParticipantsInpatients fulfilling DSM-III-R criteria for major depressive disorder, with melancholia, with a score of at least 25 on the Montgomery and Asberg Scale for Depression (MADRS).
Age: over 18 years
Exclusion criteria: medical illness, psychotherapy or ECT during the study duration
InterventionsFluoxetine: 34 participants
Venlafaxine: 34 participants
Fluoxetine dose: 40 mg/day
Venlafaxine dose: 200 mg/day
OutcomesPrimary outcome: Hamilton Rating Scale for Depression (HDRS-21), MADRS, Clinical Global Impression Scale (CGI)
NotesResponse: decrease of at least 50% in the HDRS or in the MADRS total scores, or a CGI score of 1 or 2
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned"
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind medication, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind medication, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind medication, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote: "analysis are on the ITT patients and use the last observation carried forward (LOCF) method"
Selective reporting (reporting bias)Unclear riskTreatment-emergent study events reported only if it was reported by three or more patients
Other biasHigh riskQuote: "this work was supported by a grant from Wyeth-Ayerst Research, Paris, France", this company produces venlafaxine

Cohn 1985

MethodsSix-week double-blind, randomised study
ParticipantsOutpatients fulfilling DSM-III criteria for major depressive illness, with a score of at least 20 on the Hamilton Rating Scale for Depression (HDRS).
Age range: 20-64 years
Exclusion criteria: concomitant physical condition or history of conditions that could interfere with therapy
InterventionsFluoxetine: 54 participants
Imipramine: 54 participants
Placebo: 57 participants
Fluoxetine dose range: 20-80 mg/day
Imipramine dose range: 75-300 mg/day
OutcomesHDRS, Raskin Depression Scale (RDS), Covi Anxiety Scale (CAS), Clinical Global Impression (CGI) Severity and Improvement
NotesOne patient attempted suicide in the fluoxetine group
Funding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no other information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double blind study. Placebo and the study drugs were supplied as identical capsules", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
High riskScores reported without standard deviations. Reasons for dropout not clear. Scores reported without denominator
Selective reporting (reporting bias)Unclear riskSide effects reported only over 10%
Other biasUnclear riskFunding: unclear

Corne 1989

MethodsSix-week double-blind, randomised study
ParticipantsOutpatients (general practice) fulfilling Research Diagnostic Criteria (RDC) criteria for primary unipolar major depressive disorder, with a score of at least 17 on the Hamilton Rating Scale for Depression (HDRS-17).
Age range: 18-70 years
Exclusion criteria: physical illness, use of other antidepressant medication, pregnancy, potential childbearing, lactation
InterventionsFluoxetine: 49 participants
Dothiepin: 51 participants
Fluoxetine dose range: 20-60 mg/day
Dothiepine dose range: 50-100 mg/day
OutcomesHDRS-17 score
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomly assigned, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "a double dummy technique was employed", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
High riskScores reported without denominator. Effect side reported. Number of patients randomised and number lost during follow-up not clear
Selective reporting (reporting bias)High riskMeans and standard deviations reported only in figures
Other biasHigh riskSecond author had affiliation in Eli Lilly, this company produces fluoxetine

Corrigan 2000

MethodsEight-week double-blind, randomised study
ParticipantsPatients fulfilling DSM-III-R criteria for major depression (single or recurrent episode, with or without melancholia and without psychotic features).
Age range: 18-65 years
Exclusion criteria: clinically relevant disease, clinically significant changes on the ECG, lifetime history of hypomania/mania, psychotic disorder, dementia, borderline or antisocial personality disorders, history of a serious suicidal attempting the past 12 months, pregnancy or lactation, non-responders to at least two trials of antidepressant treatment in the past, use of fluoxetine in the past 6 months or use of another investigational drug within one month prior to the baseline visit.
InterventionsFluoxetine: 35 participants
Pramipexole 1 mg: 35 participants
Pramipexole 5 mg: 33 participants
Placebo: 35 participants
Fluoxetine dose: 20 mg/day
OutcomesPrimary outcomes: Hamilton Rating Scale for Depression (HDRS-17), Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression (CGI) Severity
Secondary outcomes: Beck Depression Inventory, CGI Improvement
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: “randomised clinical trial”, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no other information
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "results are reported for the observed-case analysis, for which no missing data were replaced". Number randomised, and number lost during follow-up reported
Selective reporting (reporting bias)Unclear riskScores reported without standard deviations. Adverse events were reported with a frequency of at least 10%
Other biasHigh riskAuthors' affiliation was in Pharmacia&Upjohn Inc, and this company produces pramipexole

Costa e Silva 1998

MethodsEight-week double-blind, randomised, multicentre study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 20 on the Hamilton Rating Scale for Depression-21 item (HDRS-21) and depressive symptoms for at least 1 month before study entry.
Age range: 18-60 years
Exclusion criteria: pregnancy, absence of methods of contraception, known sensitivity to fluoxetine or venlafaxine, history of significant cardiac, renal or hepatic disease, clinically significant abnormalities on a screening examination, ECG, laboratory tests, acute suicide tendency, seizures, history or presence of any psychotic disorder not associated with depression, drug or alcohol dependence within the past year, psychotherapy, use of fluoxetine, antipsychotic drugs, ECT, MAOI within the past 14 days, any other antidepressant, anxiolitics, sedative-hypnotic drugs (but zopiclone) within 7 days before baseline.
InterventionsFluoxetine: 186 participants
Venlafaxine: 196 participants
Fluoxetine dose range: 20-40 mg/day
Venlafaxine dose range: 75-125 mg/day
OutcomesPrimary outcomes: HDRS-21, Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression (CGI) Severity and Improvement
NotesResponse: decrease of at least 50% in the HDRS or in the MADRS; or a CGI-I score of 1 or 2
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no other information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if raters were independent and unclear if blinding was successful
Incomplete outcome data (attrition bias)
All outcomes
High riskRating scale scores reported without denominator
Selective reporting (reporting bias)Unclear riskMean scores reported without standard deviations. Side effects reported only if they occurred at least in 5% of the patients
Other biasHigh riskQuote: "supported by a grant from Wyeth-AYerst International". This company produces venlafaxine

Dalery 1997

MethodsTwelve-week double-blind, randomised, multicentre study
ParticipantsPatients fulfilling DSM-III-R criteria for major depression (single or recurrent), with a score of at least 20 on the Montgomery and Asberg Scale for Depression (MADRS).
Age range: 18-70 years
Exclusion criteria: not stated
InterventionsFluoxetine: 82 participants
Amineptine: 87 participants
Fluoxetine dose: 20 mg/day
Amineptine dose: 200 mg/day
Anxiolitics and non-barbiturate hypnotics were allowed
OutcomesMADRS, Clinical Global Impression (CGI), Mood Anxiety Retardation and Danger (MARD)
NotesFunding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "random allocation". No further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber and reasons of attrition not clear. Ratings scores reported without denominator
Selective reporting (reporting bias)Unclear riskData at follow-up not reported. Adverse effects not reported
Other biasUnclear riskFunding: unclear

Dalery 2003

MethodsSix-week double-blind, randomised study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 17 on the Hamilton Rating Scale for Depression-17 item (HDRS-17).
Age range: 18-70 years
Exclusion criteria: acute suicidal ideation, dementia, history of epilepsy, alcoholism in the previous 6 months, other psychoactive substance, pregnancy, lactation, absence of contraception, hepatic, renal, pulmonary, endocrine, cardiac disease, previous failure with SSRI therapy, concomitant use of lithium, warfarin, carbamazepine, theophyline, insulin, hypoglycaemic agents, MAOI or ECT in the previous 2 weeks.
InterventionsFluoxetine: 94 participants
Fluvoxamine: 90 participants
Fluoxetine dose: 20 mg/day
Fluvoxamine dose: 100 mg/day
OutcomesPrimary outcome: area under the curve of the change in HDRS-17 total score from baseline
Secondary outcomes: numbers of HDRS-17 responders, Clinical Global Impression (CGI) Severity and Improvement, Clinical Anxiety Scale (CAS), Irritability Depression and Anxiety Scale (IDAS) total score and sub-scores, Beck Scale for Suicide Ideation (SSI), Sleep Evaluation and the HDRS-17 total and subtotal scores
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskReasons and number of dropouts were not clear. Rating scale scores reported without denominators
Selective reporting (reporting bias)Unclear riskScores reported without standard deviations
Other biasHigh riskQuote: "the study was supported by a grant from Solvay Pharmaceuticals". This company produces maprotiline

De Jonghe 1991

MethodsSix-week double-blind, randomised, two-site study
ParticipantsInpatients fulfilling DSM-III-R criteria for major depressive disorder without psychotic features, with a score of at least 18 on the Hamilton Rating Scale for Depression-17 item (HDRS-17).
Age range: 18-70 years
Exclusion criteria: high suicide risk, other psychiatric diagnosis, somatic disease which could contraindicate treatment with fluoxetine or maprotiline, history of hypersensitivity, severe allergies, multiple severe reactions to drugs, lactation, pregnancy or pregnancy wish, MAOI use within 2 weeks before starting the trial.
InterventionsFluoxetine: 30 participants
Maprotiline: 35 participants
Fluoxetine dose range: 40-80 mg/day
Maprotiline dose range: 50-150 mg/day
Only oxazepam was allowed as hypnotic or anxiolytic, if absolutely required
OutcomesHDRS-17, Raskin Depression Scale (RDS), Covi Anxiety Scale (CAS), Clinical Global Impression (CGI) Severity and Improvement
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskRating scale scores reported without denominator. Number and reasons of dropouts reported
Selective reporting (reporting bias)Unclear riskVital signs not reported
Other biasHigh riskQuote: "the study was supported by Eli Lilly Nederlands". This company produces fluoxetine

De Nayer 2002

MethodsTwelve-week double-blind, randomised, multicentre study
ParticipantsOutpatients with a score between 18 and 25 on the Hamilton Rating Scale for Depression-21 item (HDRS-21) and minimum baseline of 8 on the Covi Anxiety Scale (CAS), and considered by the investigator to be moderately depressed.
Age range: 18-70 years
Exclusion criteria: pregnancy, childbearing potential, absence of contraceptive method, psychiatric disease or personality disorder, known clinically significant laboratory abnormalities, use of antipsychotic drug or ECT within 30 days of baseline, use of fluoxetine within 21 and MAOI within 14 days before baseline; patients who previously failed to respond to venlafaxine or fluoxetine, high suicide risk.
InterventionsFluoxetine: 73 participants
Venlafaxine: 73 participants
Fluoxetine dose range: 20-40 mg/day
Venlafaxine dose range: 75-150 mg/day
Lormetazepam was allowed (2 mg) as hypnotic
OutcomesPrimary outcomes: HDRS-21, Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression (CGI) Severity
Secondary outcome: CAS
NotesResponse: decrease of at least 50% in the HDRS-21 or in the MADRS total score
Remission: total score less than 8 on the HDRS-21
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnclear if blinding was successful
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskRating scale scores reported without denominator. Number and reason for discontinuation reported
Selective reporting (reporting bias)Unclear riskMean scores reported without standard deviation
Other biasHigh riskFunding by Wyeth, and this company produces venlafaxine

De Ronchi 1998

MethodsTen-week double-blind, randomised, multicentre study
ParticipantsIn- and outpatients fulfilling DSM-III-R criteria for major depressive disorder, with a score of at least 16 on the Hamilton Rating Scale for Depression-17 item (HDRS-17).
Age: over 60 years
Exclusion criteria: mental organic disorder, Mini Mental State Examination (MMSE) less than 24, high suicide risk, history of alcohol or drug abuse, severe physical illness, epilepsy, schizophrenia.
InterventionsFluoxetine: 32 participants
Amitriptyline: 33 participants
Fluoxetine dose: 20 mg/day
Amitriptyline dose range: 50-100 mg/day
Patients taking lorazepam 5 mg/day for at least 6 months before enrolment were allowed to continue; triazolam was allowed (0.25 mg/day) during the first 2 weeks for insomnia
OutcomesHDRS-17, Montgomery and Asberg Scale for Depression (MADRS), Covi Anxiety Scale (CAS), Clinical Global Impression (CGI) Severity and Improvement
NotesResponse: decrease of at least 50% in the HDRS-17 total score or a total score less than 10
Funding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomised trial", no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskInsufficient information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "all ratings were conducted under double blind condition", no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskRating scale scores reported without denominators. Number and reasons for discontinuation not clear
Selective reporting (reporting bias)Unclear riskIncidence of adverse effects not clear
Other biasUnclear riskFunding: unclear

De Wilde 1993

MethodsSix-week double-blind, randomised study
ParticipantsPatients fulfilling DSM-III criteria for major depression, with a score of at least 18 on the Hamilton Rating Scale for Depression-21 item (HDRS-21).
Age range: 18-65 years
Exclusion criteria: pregnancy, lactation, severe concomitant disease, schizophrenia, abuse of alcohol or drugs, severe risk of suicide, ECT in the previous 3 months, MAOI or oral neuroleptics in the previous 14 days, depot neuroleptics in the previous 4 weeks, patients receiving lithium.
InterventionsFluoxetine: 41 participants
Paroxetine: 37 participants
Fluoxetine dose range: 20-60 mg/day
Paroxetine dose range: 20-40 mg/day
Temazepam or other short-acting benzodiazepines were permitted as hypnotic
OutcomesHDRS-21, Montgomery and Asberg Scale for Depression (MADRS), Hopkins Symptoms Check List (HSLC), Clinical Global Impression (CGI)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "the Last Observation Carried Forward (LOCF) data set was used". Scores in follow-up were reported without denominator. Reasons for withdrawal not clear
Selective reporting (reporting bias)High riskNo follow-up scores (MADRS, HDRS, HSLC)
Other biasHigh riskFunding by Smithkline, and this company produces paroxetine

Debus 1988

MethodsSix-week double-blind, randomised study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 20 on the Hamilton Rating Scale for Depression-21 item (HDRS-21).
Age: over 18 years
Exclusion criteria: pregnancy, lactation, absence of contraception, history of glaucoma, suicidal risk, history serious medical conditions, seizures, history of severe allergies, multiple adverse medication reactions or known allergy, other DSM-III diagnosis including substance abuse, bipolar disorder, schizophrenia, schizoaffective disorder, paranoid disorder, organic mental disorder, other psychotropic medications, with the exception of some hypnotics, use of fluoxetine or MAOI within the past 4 weeks.
InterventionsFluoxetine: 22 participants
Trazodone: 21 participants
Fluoxetine dose range: 20-60 mg/day
Trazodone dose range: 50-400 mg/day
OutcomesHDRS-21, Inventory for Depressive Symptomatology - Clinician Version (IDS-C)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskRating scale scores reported with denominator, but withdrawal not included in analysis. Side effects reported
Selective reporting (reporting bias)Unclear riskNo endpoint scores (IDS-C). Scores without standard deviation (HDRS)
Other biasHigh riskQuote: "supported in part by Ely Lilly". This company produces fluoxetine

Demyttenaere 1998

MethodsNine-week double-blind study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 15 on the Hamilton Rating Scale for Depression (HDRS-21).
Age range: 18-60 years
Exclusion criteria: not stated
InterventionsFluoxetine: 35 participants
Amitriptyline: 31 participants
Fluoxetine dose: 20 mg/day
Amitriptyline dose: 150 mg/day
OutcomesHDRS-21, Clinical Global Impression (CGI)
NotesResponse: decrease of at least 50% in the HDRS-21 total score
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskInsufficient information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind design", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double blind design", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "double blind design", no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskRating scale scores reported without denominator. Reasons for dropouts not clear
Selective reporting (reporting bias)Unclear riskNo endpoint scores (CGI). Adverse events not reported
Other biasHigh riskQuote: "we are indebted to Eli Lilly Belgium for financial support for the present study", and this company produces fluoxetine

Demyttenaere 2004

MethodsTwenty-two-week double-blind randomised study
ParticipantsOutpatients fulfilling DSM-IV criteria for major depression disorder.
Age range: 22-63 years
Exclusion criteria: other DSM-IV Axis I disorders
InterventionsFluoxetine: 42 participants
Paroxetine: 43 participants
Fluoxetine dose: 20 mg/day
Paroxetine dose: 20 mg/day
OutcomesHamilton Rating Scale for Depression (HDRS-17)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised trial, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind trial", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double blind trial", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "double blind trial", no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskMean scores at rating scales only referred to the whole sample (not to each arm). Number and reasons for dropouts not clear
Selective reporting (reporting bias)Unclear riskThe type of adverse events was not reported
Other biasHigh riskQuote: "Eli Lilly Benelux provided logistic and material support for this study", and this company produces fluoxetine

Diaz Martinez 1998

MethodsEight-week randomised, multicentre study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 20 on the Hamilton Rating Scale for Depression-21 item (HDRS-21).
Age range: 18-55 years
Exclusion criteria: lactation, childbearing potential, previous treatment with venlafaxine or fluoxetine, history of clinically significant medical disease, abnormalities on ECG or laboratory tests, acute suicidal tendencies, history of seizure disorder, organic mental disorder, bipolar disorder, history of any psychotic disorder not associated with depression, current use of investigational drugs, antipsychotic drugs, ECT within the previous 30 days or MAOI or paroxetine within the previous 14 days, use of antidepressant or hypnotic drugs, but zopiclone (7.5 mg), history of drug or alcohol abuse.
InterventionsFluoxetine: 75 participants
Venlafaxine: 70 participants
Fluoxetine dose range: 20-40 mg/day
Venlafaxine dose range: 75-150 mg/day
Only zopiclone was allowed for insomnia
OutcomesHDRS-21, Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression, Symptom Checklist 61 Item (SCL-61)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "Open-label"
Blinding of participants and personnel (performance bias)
All outcomes
High riskQuote: "Open-label"
Blinding of outcome assessment (detection bias)
All outcomes
High riskQuote: "Open-label"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskRating scale scores reported without denominator. Number and reasons for withdrawal reported
Selective reporting (reporting bias)Unclear riskMean scores reported without standard deviations. Adverse events reported over 5%
Other biasHigh riskQuote: "this study was supported by Wyeth-Ayerst International, Saint David's, Pennsylvania": Tihs company produces venlafaxine

Dierick 1996

MethodsEight-week randomised, double-blind, multicentre study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 20 on the Hamilton Rating Scale for Depression (HDRS-21).
Age range: 18-83 years
Exclusion criteria: history of clinically significant disease, abnormalities on ECG or laboratory tests, acute suicidal tendencies, history of seizure disorder, organic mental disorder, bipolar disorder or personality disorder, history of any psychotic disorder not associated with depression, venlafaxine or fluoxetine hypersensitivity or use within 2 months of baseline, current use of investigational drugs, antipsychotic drugs, ECT or MAOI within the previous 14 days, use of antidepressant drug within 7 days, use of any anxiolytic that could not be withdrawn at baseline, drug or alcohol abuse within 2 years of the start of the study.
InterventionsFluoxetine: 161 participants
Venlafaxine: 153 participants
Fluoxetine dose: 20 mg/day
Venlafaxine dose range: 75-150 mg/day
OutcomesHDRS-21, Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression (CGI) scales
NotesResponse: decrease of at least 50% in the HDRS or MADRS total score, or a score of 1 or 2 on the CGI
Funding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blind, no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble-blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
Low riskScores reported with denominator. Number and reasons for withdrawals reported
Selective reporting (reporting bias)Unclear riskNo CGI endpoint scores reported. Only most common (over 5%) side effects reported
Other biasHigh riskQuote: "this study was supported by Wyeth-Ayerst Research" and this company produces venlafaxine

Dowling 1990

MethodsSix-week double-blind, randomised study
ParticipantsOutpatients fulfilling DSM-III criteria for major depression (unipolar), with a score of at least 17 on the Hamilton Rating Scale for Depression (HDRS-17).
Age range: 18-75 years
Exclusion criteria: significant physical illness, lactation, pregnancy, history of schizophrenia or drug or alcohol abuse, current use of antidepressant.
InterventionsFluoxetine: 30 participants
Dothiepin: 30 participants
Fluoxetine dose range: 20-40 mg/day
Dothiepine dose range: 100-200 mg/day
Benzodiazepines were allowed for sedation at the discretion of the doctor
OutcomesHDRS, Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression (CGI) Severity and Improvement, Patient Global Impression (PGI)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "all patients took identical capsules", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber and reasons for dropouts were reported. Scores reported without denominators
Selective reporting (reporting bias)Unclear riskOnly most common side effects were reported. Mean scores were reported without standard deviations. No endpoint scores (MADRS, CGI)
Other biasHigh riskIn the aknowledgements authors thank Eli Lilly Company. This company produces fluoxetine and probably the study was supported by this industry

Duarte 1996

MethodsSix-week randomised, double-blind study
Participants

Outpatients fulfilling DSM-III-R criteria for double depression (dysthymia and major depression), with a score of at least 16 on the Hamilton Rating Scale for Depression (HDRS).

Age range: 18-65 years
Exclusion criteria: suicidal tendencies, delusional depression, severe organic disease, alcoholism, drug abuse, ongoing ECT or structured psychotherapy.

InterventionsFluoxetine: 21 participants
Moclobemide: 21 participants
Fluoxetine dose: 20 mg/day
Moclobemide dose: 300 mg/day
Use of single benzodiazepines was allowed at discretion of the doctor
OutcomesPrimary outcomes: percentage of responders defined as decrease of at least 50% in the HDRS
Secondary outcomes: endpoint score at HDRS, percentage of end of treatment Clinical Global Impression (CGI) very good and good responses
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blinding was achieved by appropriate drug packaging and formulation", no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double blinding was achieved by appropriate drug packaging and formulation", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "double blinding was achieved by appropriate drug packaging and formulation", no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskScores reported without denominators. Mean scores and standard deviations reported only in figure and they were not clear
Selective reporting (reporting bias)Unclear riskNo vital signs and side effects reported. Quote: "no clinically significant changes in vitals signs were recorded"
Other biasHigh riskThe last author's affiliation was Hoffmann–La Roche Ltd, and this company produces moclobemide

Fabre 1991

MethodsFive-week randomised, double-blind, multicentre study
ParticipantsOutpatients fulfilling DSM-III-R criteria for major depression (single episode or recurrent).
Age range: 18-65 years
Exclusion criteria: concurrent diagnosis of bipolar disorder or schizophrenia, hyperactivity or agitation, presence of hyper thyroidism or a clinically unstable medical condition, history of narrow angle glaucoma, urinary retention, seizures or substance abuse, MAOI use within 14 days of baseline, pregnancy, lactation, potential childbearing, history of allergy to the study drugs.
InterventionsFluoxetine: 103 participants
Nortriptyline: 102 participants
Fluoxetine dose range: 20-40 mg/day
Nortriptyline dose range: 50-100 mg/day
OutcomesHamilton Rating Scale for Depression (HDRS), Zung Depression Scale, Clinical Global Impression (CGI)
NotesFunding: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "patients received two bottles of identical capsules". No further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if blinding was successful
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber and reasons for withdrawal reported. No endpoint scores (CGI, Zung Depression Scale) reported
Selective reporting (reporting bias)Unclear riskScores reported without standard deviations. Only most common adverse events were reported
Other biasUnclear riskFunding: unclear

Fairweather 1999

MethodsSix-week randomised, double-blind study
Participants

Outpatients (general practice) fulfilling DSM-III-R criteria for major depression.

Age range: 18-70 years
Exclusion criteria: concurrent illness, concomitant use of psychotropic medication, long-term treatment with benzodiazepines

InterventionsFluoxetine: 42 participants
Dothiepin: 42 participants
Fluoxetine dose: 20 mg/day
Dothiepine dose range: 75-150 mg/day
OutcomesHamilton Rating Scale for Depression (HDRS), Leeds Sleep Evaluation Questionnaire (LSEQ)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "drugs and placebos were packaged in identical capsules", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble blind, no further information
Incomplete outcome data (attrition bias)
All outcomes
High riskScores reported without denominators. Number and reasons for dropouts not clear
Selective reporting (reporting bias)Unclear riskOnly most common adverse events were reported
Other biasHigh riskQuote: "the research grant provided by Lilly Industries", and Eli LIlly produces fluoxetine

Falk 1989

MethodsSix-week randomised, double-blind study
Participants

Outpatients fulfilling DSM-III criteria for unipolar major depression (single or recurrent), with the present episode lasting 4 weeks or more and with a score of at least 20 on the Hamilton Rating Scale for Depression-21 item (HDRS-21).

Age: over 62 years
Exclusion criteria: serious medical illness, unstable cardiac arrhythmia, seizure disorders, history of allergy to either drug, severe psychosis, suicidal symptoms or DSM-II diagnosis of schizophrenia, bipolar disorder, organic mental disorder, substance abuse disorder within the past year or paranoid disorders, use of either drugs within 1 month preceding study entry, MAOI in the prior 14 days or other antidepressants at the time of entry.

InterventionsFluoxetine: 14 participants
Trazodone: 13 participants
Fluoxetine dose range: 20-60 mg/day
Trazodone dose range: 50-400 mg/day
Only use of benzodiazepines and chloral hydrate for sleep were allowed
OutcomesHDRS-21, Clinical Global Impression (CGI), Treatment Emergent Symptom Scale (TESS)
NotesFunding: by industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, no further information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "all capsules were identical", no further information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskScores reported without denominators. Reasons and number of dropouts described
Selective reporting (reporting bias)Unclear riskSide effects reported. Scores reported for each follow-up with standard deviations
Other biasHigh riskQuote: "this research was supported by a grant from Eli Lilly and Company", and this company produces fluoxetine

Fava 1998

MethodsTwelve-week rand