Paroxetine versus other anti-depressive agents for depression

  • Review
  • Intervention

Authors


Abstract

Background

Paroxetine is the most potent inhibitor of the reuptake of serotonin of all selective serotonin reuptake inhibitors (SSRIs) and has been studied in many randomised controlled trials (RCTs). However, these comparative studies provided contrasting findings and systematic reviews of RCTs have always considered the SSRIs as a group, and evidence applicable to this group of drugs might not be applicable to paroxetine alone. The present systematic review assessed the efficacy and tolerability profile of paroxetine in comparison with tricyclics (TCAs), SSRIs and newer or non-conventional agents.

Objectives

1. To determine the efficacy of paroxetine in comparison with other anti-depressive agents in alleviating the acute symptoms of Major Depressive Disorder.

2. To review acceptability of treatment with paroxetine in comparison with other anti-depressive agents.

3. To investigate the adverse effects of paroxetine in comparison with other anti-depressive agents.

Search methods

We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialized Register (CCDANCTR, to 30 September 2012), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). Reference lists of relevant papers and previous systematic reviews were handsearched. Pharmaceutical companies marketing paroxetine and experts in this field were contacted for supplemental data.

Selection criteria

All randomised controlled trials allocating participants with major depression to paroxetine versus any other antidepressants (ADs), both conventional (such as TCAs, SSRIs) and newer or non-conventional (such as hypericum). For trials which had a cross-over design, only results from the first randomisation period were considered.

Data collection and analysis

Two review authors independently checked eligibility and extracted data using a standard form. Data were then entered in RevMan 5.2 with a double-entry procedure. Information extracted included study and participant characteristics, intervention details, settings and efficacy, acceptability and tolerability measures.

Main results

A total of 115 randomised controlled trials (26,134 participants) were included. In 54 studies paroxetine was compared with older ADs, in 21 studies with another SSRI, and in 40 studies with a newer or non-conventional antidepressant other than SSRIs. For the primary outcome (patients who responded to treatment), paroxetine was more effective than reboxetine at increasing patients who responded early to treatment (Odds Ratio (OR): 0.66, 95% Confidence Interval (CI) 0.50 to 0.87, number needed to treat to provide benefit (NNTb) = 16, 95% CI 10 to 50, at one to four weeks, 3 RCTs, 1375 participants, moderate quality of evidence), and less effective than mirtazapine (OR: 2.39, 95% CI 1.42 to 4.02, NNTb = 8, 95% CI 5 to 14, at one to four weeks, 3 RCTs, 726 participants, moderate quality of evidence). Paroxetine was less effective than citalopram in improving response to treatment (OR: 1.54, 95% CI 1.04 to 2.28, NNTb = 9, 95% CI 5 to 102, at six to 12 weeks, 1 RCT, 406 participants, moderate quality of evidence). We found no clear evidence that paroxetine was more or less effective compared with other antidepressants at increasing response to treatment at acute (six to 12 weeks), early (one to four weeks), or longer term follow-up (four to six months). Paroxetine was associated with a lower rate of adverse events than amitriptyline, imipramine and older ADs as a class, but was less well tolerated than agomelatine and hypericum. Included studies were generally at unclear or high risk of bias due to poor reporting of allocation concealment and blinding of outcome assessment, and incomplete reporting of outcomes.

Authors' conclusions

Some possibly clinically meaningful differences between paroxetine and other ADs exist, but no definitive conclusions can be drawn from these findings. In terms of response, there was a moderate quality of evidence that citalopram was better than paroxetine in the acute phase (six to 12 weeks), although only one study contributed data. In terms of early response to treatment (one to four weeks) there was moderate quality of evidence that mirtazapine was better than paroxetine and that paroxetine was better than reboxetine. However there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any time point. Even if some differences were identified, the findings from this review are better thought as hypothesis forming rather than hypothesis testing and it would be reassuring to see the conclusions replicated in future trials. Finally, most of included studies were at unclear or high risk of bias, and were sponsored by the drug industry. The potential for overestimation of treatment effect due to sponsorship bias should be borne in mind.

Résumé scientifique

La paroxétine par rapport aux autres agents antidépresseurs pour la dépression

Contexte

La paroxétine est le plus puissant de tous les inhibiteurs sélectifs de la recapture de la sérotonine (ISRS) et a été étudiée dans de nombreux essais contrôlés randomisés (ECR). Cependant, ces études comparatives fournissaient des résultats et les revues systématiques des ECR ont toujours considéré les ISRS en tant que groupe, de plus, les preuves applicables à ce groupe de médicaments pourraient ne pas être applicables à la paroxétine seule. La présente revue systématique a évalué l'efficacité et le profil de tolérabilité de la paroxétine en comparaison avec les antidépresseurs tricycliques (ATC), les ISRS et les agents nouveaux ou non conventionnels.

Objectifs

1. Déterminer l'efficacité de la paroxétine en comparaison avec d'autres agents antidépresseurs pour soulager les symptômes aigus du trouble dépressif majeur.

2. Examiner l'acceptabilité du traitement avec la paroxétine en comparaison avec d'autres agents antidépresseurs.

3. Examiner les effets indésirables de la paroxétine, en comparaison avec d'autres agents antidépresseurs.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur la dépression, l'anxiété et la névrose (CCDANCTR, jusqu'au 30 septembre 2012), qui inclut des essais contrôlés randomisés pertinents issus des bases de données bibliographiques suivantes : ( La Bibliothèque Cochrane (toutes les années), EMBASE (de 1974 à aujourd'hui), MEDLINE (de 1950 à aujourd'hui) et PsycINFO (de 1967 à aujourd'hui). Les références bibliographiques des articles pertinents et des revues systématiques précédentes ont été examinées manuellement. Des laboratoires pharmaceutiques commercialisant la paroxétine et des experts dans ce domaine ont été contactés pour obtenir des données supplémentaires.

Critères de sélection

Tous les essais contrôlés randomisés administrant la paroxétine aux participants souffrant de dépression majeure par rapport à tous les autres antidépresseurs (AD) conventionnels (tels que les ATC, les ISRS) et nouveaux ou non conventionnels (tels que l'hypericum). Pour les essais avec un plan d'étude croisé, seuls les résultats de la première période de randomisation ont été pris en compte.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment vérifié l'éligibilité et extrait les données à l'aide d'un formulaire standard. Les données ont ensuite été saisies dans RevMan 5,2 avec une procédure à double entrée. Les informations extraites comprenaient les caractéristiques des études et des participants, les détails de l'intervention, les paramètres et l'efficacité, les mesures d'acceptabilité et de tolérance.

Résultats principaux

Un total de 115 essais contrôlés randomisés (26 134 participants) a été inclus. Dans 54 études, la paroxétine était comparée à des AD plus anciens, dans 21 études avec un autre ISRS et dans 40 études avec un antidépresseur plus récent ou non conventionnel autres que les ISRS. Pour le principal critère de jugement (patients qui répondaient au traitement), la paroxétine était plus efficace que la réboxétine pour augmenter le nombre de patients répondant précocement au traitement (rapport des cotes (RC) : 0,66, intervalles de confiance (IC) à 95 % de 0,50 à 0,87, nombre de sujets à traiter pour apporter un bénéfice (NNTB) = 16, IC à 95 % de 10 à 50, au bout d'une à quatre semaines, 3 ECR, 1 375 participants, preuves de qualité modérée), et moins efficace que la mirtazapine (rapport des cotes : 2,39, IC à 95 % de 1,42 à 4,02, NNTB = 8, IC à 95 % de 5 à 14, au bout d'une à quatre semaines, 3 ECR, 726 participants, preuves de qualité modérée). La paroxétine était moins efficace que le citalopram pour améliorer la réponse au traitement (rapport des cotes : 1,54, IC à 95 % de 1,04 à 2,28, NNTB = 9, IC à 95 % de 5 à 102, au bout de six à douze semaines, 1 ECR, 406 participants, preuves de qualité modérée). Aucune preuve précise ne montrait que la paroxétine était plus ou moins efficace par rapport à d'autres antidépresseurs pour augmenter la réponse au traitement lors de la phase aigüe du suivi (six à douze semaines), de la phase précoce du suivi (une à quatre semaines), ou du suivi à plus long terme (quatre à six mois). La paroxétine était associée à un faible taux d'effets indésirables comparée à l'amitriptyline, à l'imipramine et aux AD plus anciens en tant que classification, mais était moins bien tolérée que l'agomélatine et l'hypericum. Les études incluses étaient généralement à risque de biais incertain ou élevé en raison d'une notification inadéquate de l'assignation secrète et de l'assignation en aveugle pour l'évaluation des critères de jugements, ainsi que d'une documentation incomplète des critères de jugement.

Conclusions des auteurs

Certaines différences éventuellement cliniquement significatives entre la paroxétine et d'autres AD existent, mais aucune conclusion définitive ne peut être apportée à partir de ces résultats. En termes de réponse, des preuves de qualité modérée montraient que le citalopram était plus efficace que la paroxétine dans la phase aiguë (six à douze semaines), bien qu'une seule étude fournissait des données. En termes de réponse au traitement précoce (une à quatre semaines), des preuves de qualité modérée montraient que la mirtazapine était plus efficace que la paroxétine et que la paroxétine était plus efficace que la réboxétine. Cependant, aucune preuve claire ne montrait que la paroxétine était meilleure ou pire que d'autres antidépresseurs pour augmenter la réponse au traitement et ceci à toute période. Même si certaines différences ont été identifiées, les conclusions de cette revue sont considérées comme une formulation d'hypothèses plutôt qu'une vérification d'hypothèses et il serait rassurant de voir les conclusions reproduites dans de futurs essais. Enfin, la plupart des études incluses présentaient un risque de biais incertain ou élevé et étaient parrainées par l'industrie pharmaceutique. Le risque de surestimation de l'effet du traitement en raison d'un biais de parrainage devrait être pris en compte.

摘要

憂鬱症的paroxetinec和其他抗憂鬱劑治療

背景

paroxetine是所有選擇性血清素再吸收抑制劑 (selective serotonin reuptake inhibitor, SSRI) 中,效力最強的血清素再吸收抑制劑,且有許多隨機對照試驗 (randomized controlled trial, RCT) 針對paroxetine進行研究。不過這些比較性試驗的結果差別懸殊,而且RCT的系統性文獻回顧,總是將SSRI視為一種類別,但適用此類藥物的證據,未必適用於僅使用paroxetine的情況。此次系統性文獻回顧將相對於三環抗憂鬱劑 (tricyclic, TCA)、SSRI和新型或非傳統藥物,評估paroxetine的療效和耐受度 (tolerability) 特性。

目的

1. 相對於其他抗憂鬱劑,判定paroxetine減輕重鬱症 (Major Depressive Disorder) 急性症狀的療效。

2. 相對於其他抗憂鬱劑,檢視paroxetine治療的可接受度。

3. 相對於其他抗憂鬱劑,探討paroxetine的不良作用。

搜尋策略

我們搜尋考科藍憂鬱症、焦慮與精神官能症文獻回顧群組專業註冊 (Cochrane Depression, Anxiety and Neurosis Review Group's Specialized Register, CCDANCTR) (截至2012年9月30日為止),CCDANCTR納入下列書目資料庫的相關隨機對照試驗:考科藍圖書館 (所有年份)、EMBASE (1974年至今)、MEDLINE (1950年至今) 和PsycINFO (1967年至今)。以人工方式搜尋相關論文和先前系統性文獻回顧的參考文獻清單,此外我們也聯絡銷售paroxetine的製藥公司和此領域的專家,收集補充資料。

選擇標準

本次文獻回顧收錄所有將重鬱症患者分配至paroxetine治療組和任何其他抗憂鬱劑 (AD) 治療組、傳統治療 (例如TCA、SSRI) 及新型或非傳統治療組 (例如hypericum),並進行比較的隨機對照試驗。至於採交叉設計的試驗,則僅納入最初隨機分配期的結果。

資料收集與分析

由2位文獻回顧作者獨立確認試驗是否符合納入條件,並使用標準格式萃取資料。然後以雙重輸入 (double-entry) 的程序,將資料輸入 RevMan 5.2。所萃取的資訊包括試驗和受試者特性、詳細的介入資料、環境和療效、可接受度和耐受度測量結果。

主要結果

本次文獻回顧共計納入115篇隨機對照試驗 (26,134名受試者)。有54篇試驗比較paroxetine和舊型的AD;有21篇試驗比較paroxetine和其他SSRI;有40篇試驗比較paroxetine和新型或除SSRI外的非傳統抗憂鬱劑。關於主要結果 (對治療有反應的患者),paroxetine的療效優於reboxetine,因於治療早期即產生療效的患者人數增多 (勝算比 [OR] 為0.66,95%信賴區間 [CI] 為0.50至0.87,療效益一需治數 [NNTb] 為16.95%,95% CI為10至50,於1至4週,3項RCT,1375名受試者,證據品質中等);但劣於mirtazapine (OR為2.39,95% CI為1.42至4.02,NNTb為8,95% CI為5至14,於第1週至第4週,3篇RCT,726名受試者,證據品質中等)。至於對治療反應的改善,paroxetine的療效劣於citalopram (OR為1.54,95% CI為1.04至2.28,NNTb為9,95% CI為5至102,於第6至12週,1篇RCT,406名受試者,證據品質中等)。我們並未發現明確證據,可證實對於提高急性期 (6至12週)、早期 (1至4週) 或長期追蹤 (4至6個月) 的治療反應,paroxetine的療效優於或劣於其他抗憂鬱劑。paroxetine的不良事件發生率低於amitriptyline、imipramine和舊型AD類藥物,但耐受度則低於agomelatine和 hypericum。所納入試驗的偏差風險通常不明或偏高,因為分組隱匿 (allocation concealment) 的報告和結果評估的盲性處理不充分,以及結果報告不完整。

作者結論

paroxetine和其他AD間可能存在具臨床意義的差異,不過無法依據上述結果得出明確結論。雖然只有1項試驗提供資料,但citalopram在急性期 (6至12週) 的治療反應優於paroxetine (證據品質中等)。至於對治療的早期反應 (1至4週),mirtazapine優於paroxetine,而paroxetine則優於reboxetine (證據品質中等)。無論如何,並無明確證據顯示,於任一時間點,paroxetine提高治療反應的效果,優於或劣於其他抗憂鬱劑。即使發現有些差異,但本次文獻回顧所得結果應視為形成假設,而非驗證假設的過程,還須觀察日後進行的試驗,是否能複製所得結論,才能確認結果確實可靠。最後,大部分納入試驗的偏差風險不明或偏高,並由藥廠委託進行。應切記這些試驗可能具有資助偏差 (sponsorship bias),以致高估治療效果。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Plain language summary

Paroxetine versus other anti-depressive agents for depression

Major depression is a severe mental illness characterised by a persistent and unreactive low mood and loss of all interest and pleasure, usually accompanied by a range of symptoms such as appetite change, sleep disturbance, fatigue, loss of energy, poor concentration, inappropriate guilt and morbid thoughts of death. Although medication and psychological treatments are both effective for major depression, antidepressant drugs remain the mainstay of treatment in moderate to severe major depression. However, head-to-head comparisons of such drugs provide contrasting findings as to whether they are effective.

This review of the research on the effect of an antidepressant drug called paroxetine was conducted to shed light on the field of drug treatment for depression. In September 2012 we searched, in a wide ranging way, for all the useful studies (randomised controlled trials) which had been completed which compared paroxetine with any other antidepressant in treating people with depression. One hundred and fifteen studies were included in this review, with a total of 26,134 people. We grouped the studies according to the types of drug they compared paroxetine against; we then analysed the combined findings of these groups of studies.

For the primary outcome (number of people who responded to treatment) paroxetine was more effective than reboxetine, but less effective than mirtazapine (in the early phase: one to four weeks follow-up) and probably citalopram (at endpoint: six weeks follow-up). There was some evidence that paroxetine is less well tolerated than agomelatine and St John's Wort, as more patients allocated to paroxetine experienced at least some side effects (though this finding for St John's Wort was only based on one study).

In conclusion, some possibly meaningful differences between paroxetine and other antidepressants exist, but no definitive concluions can be drawn due to the limited number of studies per comparison. In addition, most of included studies were sponsored by the drug industry, which means they might potentially have overestimated the effect of paroxetine. Therefore, the results of this review should be interpreted with caution.

Résumé simplifié

La paroxétine par rapport aux autres agents antidépresseurs pour la dépression

La dépression majeure est une maladie mentale grave qui se caractérise par une humeur morose persistante et non réactive et une perte de tout intérêt et de tout plaisir, le plus souvent accompagnée d'un éventail de symptômes, tels qu'un changement d'appétit, des troubles du sommeil, de la fatigue, une perte d'énergie, un manque de concentration, une culpabilité inappropriée et des pensées morbides. Bien que l'administration de médicaments et les traitements psychologiques soient tous deux efficaces pour la dépression majeure, les médicaments antidépresseurs demeurent la base du traitement de la dépression majeure modérée à sévère. Cependant, les comparaisons directes de ces médicaments fournissent des résultats contrastés pour déterminer s'ils sont efficaces.

Cette revue de la recherche sur l'effet d'un médicament antidépresseur appelé paroxétine a été réalisée afin de clarifier les traitements médicamenteux pour la dépression. En septembre 2012, nous avons effectué de vastes recherches pour identifier toutes les études utiles (essais contrôlés randomisés) comparant la paroxétine à n'importe quel autre antidépresseur dans le traitement de patients souffrant de dépression. Cent quinze études ont été incluses dans cette revue, avec un total de 26 134 patients. Nous avons regroupé les études selon le type de médicament qui était comparé à la paroxétine; nous avons ensuite analysé les résultats combinés de ces groupes d'études.

Pour le critère de jugement principal (nombre de patients ayant répondu au traitement), la paroxétine était plus efficace que la réboxétine, mais moins efficace que la mirtazapine (dans la phase initiale : une à quatre semaines de suivi) et probablement le citalopram (à la fin : six semaines). Certaines preuves montraient que la paroxétine était moins bien tolérée que l'agomélatine et le millepertuis, car plus de patients assignés à la paroxétine ressentaient au moins certains effets secondaires (bien que le résultat pour le millepertuis était basé uniquement sur une étude).

En conclusion, certaines différences éventuellement significatives entre la paroxétine et d'autres antidépresseurs, mais aucune conclusion définitive ne peut être apportée en raison du nombre limité d'études par comparaison. De plus, la plupart des études incluses ont été parrainées par l'industrie pharmaceutique, ce qui signifie qu'elles pourraient potentiellement avoir surestimé l'effet de la paroxétine. Par conséquent, les résultats de cette revue doivent être interprétés avec prudence.

Notes de traduction

Traduit par: French Cochrane Centre 6th August, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

淺顯易懂的口語結論

憂鬱症的paroxetinec和其他抗憂鬱劑治療

重鬱症 (major depression) 是一種嚴重的精神疾病,特徵為持續和無反應 (unreactive) 的情緒低落,以及喪失所有興趣和快樂的感覺,通常伴隨各種症狀,例如食慾改變、睡眠障礙、疲倦、缺乏精力、注意力不佳、不適當的內疚和對死亡的病態想法。雖然藥物和心理治療皆可有效治療重鬱症,但抗憂鬱劑仍是中度至重度重鬱症治療的中流砥柱。無論如何,直接比較這類藥物的療效,所得到的結果並不一致。

本次文獻回顧針對研究paroxetine這種抗憂鬱劑的試驗,希望能闡明憂鬱症的藥物治療領域。我們於2012年9月,大範圍搜尋所有有用的試驗 (隨機對照試驗),找尋已完成的研究,比較paroxetine和任何其他抗憂鬱劑的憂鬱症療效。本次文獻回顧納入115篇試驗,共計包含26,134名受試者。我們依據用來和paroxetine比較的藥物類型,將試驗歸類,然後分析各類試驗的綜合結果。

對於主要結果 (對治療有反應的患者人數),paroxetine的療效優於reboxetine,但劣於mirtazapine (於早期:追蹤1至4週) 和citalopram (可能) (於治療結束:追蹤6週)。有部分證據顯示,paroxetine的耐受度低於agomelatine和聖約翰草 (St. John’s Wort),因為paroxetine治療組中,有較多患者至少出現部分副作用 (雖然聖約翰草的結果僅依據1篇試驗)。

最後,paroxetine和其他抗憂鬱劑間的差異可能具有部分意義,但因各項比較的試驗數量有限,以致無法得出明確結論。此外,大部分納入試驗由藥廠委託進行,表示可能會高估paroxetine的療效。因此須謹慎解讀本次文獻回顧的結果。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Laički sažetak

Usporedba paroksetina i drugih antidepresiva u terapiji depresije

Veliki depresivni poremećaj ozbiljna je mentalna bolest obilježena trajnim i nereaktivnim lošim raspoloženjem i gubitkom svih interesa i užitaka, uobičajeno praćena rasponom simptoma poput promjena apetita, poremećaja spavanja, malaksalosti, gubitka energije, slabe koncentracije, neprimjerenog osjećaja krivnje i morbidnih misli o smrti. Iako su i lijekovi i psihološka terapija učinkoviti za depresiju, antidepresivi su i dalje glavna terapija umjerene do teške depresije. Međutim, izravna usporedba lijekova pruža različite podatke o njihovoj učinkovitosti.

Ovaj Cochrane sustavni pregled o učinku paroksetina je proveden kako bi se razjasnila uporaba lijekova u terapiji depresije. U rujnu 2012. provedeno je opsežno pretraživanje literature kako bi se pronašli dovršeni klinički pokusi (randomizirane kontrolirane studije) koji su uspoređivali paroksetin s bilo kojim drugim antidepresivom u terapiji depresije. U ovaj pregled je uključeno 115 studija, s ukupno 26.134 sudionika. Studije su podijeljene u skupine s obzirom na tip lijekova s kojima su uspoređivali paroksetin, potom su analizirani kombinirani rezultati tih grupa studija.

Za primarni odgovor (broj osoba koje su odgovorile na terapiju) paroksetin je bio učinkovitiji od reboksetina, malo manje učinkovit od mirtazapina (u ranoj fazi: kontrola nakon jednog do četiri tjedna) i vjerojatno citaloprama (u završnoj točki: kontrola nakon šest tjedana). Postoje neki dokazi da je paroksetin slabije podnošljiv od agomelatina i gospine trave, s obzirom da je više pacijenata koji su uzimali paroksetin iskusilo bar nekakvu nuspojavu (iako je taj zaključak za gospinu travu temeljen na samo jednoj studiji).

Zaključno, postoje neke moguće značajne razlike između paroksetina i ostalih antidepresiva, ali ne mogu se izvući konačni zaključci zbog ograničenog broja studija po usporedbi. Uz to, većinu uključenih studija financirala je industrija lijekova, što znači da je moguće da je blago precijenjen učinak paroksetina. S obzirom na to, rezultati ovog pregleda trebaju se tumačiti s oprezom.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Streszczenie prostym językiem

Paroksetyna w porównaniu z innymi lekami przeciwdepresyjnymi w terapii chorych na depresję

Duża depresja jest ciężką chorobą psychiczną, która charakteryzuje się stałym i niereaktywnym, obniżonym nastrojem, utratą wszelkich zainteresowań i zdolności do odczuwania przyjemności. Zwykle towarzyszy jej szereg objawów, takich jak zmiany łaknienia, zaburzenia snu, zmęczenie, utrata energii, zaburzenia koncentracji uwagi, poczucie winy i "chorobliwe" myśli o śmierci. Chociaż zarówno leki i terapie psychologiczne są skuteczne u osób z dużą depresją, to stosowanie leków przeciwdepresyjnych pozostaje podstawową metodą leczenia chorych z umiarkowanymi lub ciężkimi epizodami dużej depresji. Niemniej jednak bezpośrednie porównania efektywności tych leków prowadzą do sprzecznych wniosków.

Ten przegląd wyników badań na temat efektów stosowania leku przeciwdepresyjnego zwanego paroksetyną przeprowadzono, aby poszerzyć wiedzę na temat metod farmakoterapii chorych na depresję. We wrześniu 2012 r. autorzy tej pracy przeprowadzili wszechstronny przegląd wyników wszystkich przydatnych i ukończonych badań klinicznych (badań z randomizacją), w których porównywano (skuteczność i bezpieczeństwo stosowania – przyp. red.) paroksetyny lub dowolnego innego lekiem przeciwdepresyjnym u pacjentów z depresją. Ogółem, w tym przeglądzie uwzględniono wyniki 115 badań, w których uczestniczyły łącznie 26134 osoby. Autorzy pogrupowali badania na podstawie rodzaju leku porównywanego z paroksetyną; następnie przeprowadzili łączną analizę wyników badań przypisanych do poszczególnych grup.

W odniesieniu do głównego punktu końcowego (liczby osób, którzy uzyskali odpowiedź na leczenie) paroksetyna była bardziej efektywna niż reboksetyna, ale mniej efektywna niż mirtazapina (w początkowej fazie leczenia, trwającej przez 1–4 tygodni) i prawdopodobnie mniej skuteczna niż citalopram (co stwierdzono po zakończeniu 6-tygodniowego leczenia). Istnieją pewne przesłanki sugerujące, że paroksetyna jest gorzej tolerowana niż agomelatyna lub dziurawiec zwyczajny, a u większej liczby pacjentów z grupy paroksetyny wystąpiły przynajmniej niektóre działania niepożądane (choć to stwierdzenie na temat terapii z użyciem dziurawca zwyczajnego oparto na wynikach zaledwie jednego badania).

Podsumowując, istnieją potencjalnie znaczące różnice pomiędzy paroksetyną i innymi lekami przeciwdepresyjnymi, ale możliwości sformułowania ostatecznych wniosków były ograniczone z powodu niewielkiej liczby badań przypisanych do poszczególnych grup. Ponadto większość z zakwalifikowanych badań była sponsorowana przez przemysł farmaceutyczny, co oznacza, że ​​efekty stosowania paroksetyny mogły być przeszacowane. Dlatego też wyniki tego przeglądu należy interpretować z ostrożnością.

Uwagi do tłumaczenia

Tłumaczenie: Dawid Storman, redakcja" Rafał Jaeschke

Резюме на простом языке

Пароксетин в сравнении с другими антидепрессантами при депрессии

Большая депрессия - это тяжелое психическое заболевание, характеризующееся постоянным и инертным подавленным настроением, потерей всех интересов и удовольствий, как правило, сопровождается целым рядом симптомов, таких, как изменение аппетита, нарушение сна, усталость, снижение работоспособности, снижение концентрации внимания, неадекватное чувство вины и болезненные мысли о смерти. Хотя лекарства и психологические методы лечения являются эффективными при большой депрессии, антидепрессанты остаются основой лечения депрессий от умеренной до тяжелой степени. Однако, прямые сравнения таких лекарств обеспечивают противоречивые результаты относительно их эффективности.

Этот обзор исследований о влиянии антидепрессанта под названием пароксетин был проведен с целью пролить свет на область медикаментозного лечения депрессии. В сентябре 2012 года мы провели обширный поиск всех пригодных исследований (рандомизированных контролируемых испытаний), которые были завершенными, и сравнивали пароксетин с другими антидепрессантами для лечения людей, страдающих депрессией.В этот обзор было включено сто пятнадцать исследований, в общей сложности 26 134 человек. Мы сгруппировали исследования согласно классу препарата, с которыми они сравнили пароксетин; затем анализировали объединенные результаты этих групп исследований.

По первичному исходу (число людей, которые поддались лечению) пароксетин был более эффективен, чем ребоксетин, но менее эффективен, чем миртазапин (на ранней стадии: от одной до четырех недель наблюдения) и по всей вероятности, чем циталопрам (в конечной точке: последующие шесть недель). Существовали некоторые доказательства того, что пароксетин переносится хуже, чем агомелатин и зверобой, так как пациенты, принимавшие пароксетин, испытали, по меньшей мере, некоторые побочные эффекты (хотя этот вывод в отношении зверобоя был основан только на одном исследовании).

В заключение, существуют некоторые, возможно, значимые, различия между пароксетином и другими антидепрессантами, но не может быть сделано каких-либо определенных выводов в связи с ограниченным числом исследований в каждом сравнении. Кроме того, большинство из включенных исследований были спонсированы фармацевтической промышленностью, что означает, что они могли потенциально переоценить эффект пароксетина. Таким образом, результаты этого обзора необходимо интерпретировать с осторожностью.

Заметки по переводу

Перевод: Джумалиева Эльнура Муходиновна. Редактирование: Александрова Эльвира Григорьевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Paroxetine compared with older ADs for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.
    2 I squared 79%.

Paroxetine compared with older ADs for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
Comparison: older ADs
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Older ADs Paroxetine
Failure to respond at endpoint (6-12 weeks) 416 per 1000 426 per 1000
(396 to 455)
OR 1.04
(0.92 to 1.17)
4647
(34 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeks 670 per 1000 416 per 1000
(328 to 509)
OR 0.90
(0.61 to 1.33)
526
(4 studies)
⊕⊕⊝⊝
low 1
 
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 550 per 1000 365 per 1000
(180 to 601)
OR 1.23
(0.49 to 3.07)
401
(3 studies)
⊕⊕⊝⊝
low 1,2
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.01 standard deviations higher
(0.08 lower to 0.09 higher)
 4745
(35 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause - 312 per 1000 276 per 1000
(249 to 303)
OR 0.84
(0.73 to 0.96)
6810
(44 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 707 per 1000 606 per 1000
(565 to 650)
OR 0.64
(0.54 to 0.77)
6132
(42 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; SMD: standardized mean difference; 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 Paroxetine compared with agomelatine for depression

Summary of findings 2. Paroxetine compared with agomelatine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with agomelatine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks)
Follow-up: 6-12 weeks
394 per 1000 449 per 1000
(337 to 567)
OR 1.25
(0.78 to 2.01)
284
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint
HDRS
Follow-up: 6-12 weeks
701 per 1000 748 per 1000
(637 to 834)
OR 1.27
(0.75 to 2.14)
284
(1 study)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint
HDRS
Follow-up: 6-12 weeks
 The mean SMD at endpoint in the intervention groups was
0.18 standard deviations lower
(0.38 lower to 0.02 higher)
 1074
(4 studies)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause - 234 per 1000 232 per 1000
(148 to 343)
OR 0.99
(0.57 to 1.71)
284
(1 study)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 547 per 1000 659 per 1000
(545 to 758)
OR 1.60
(0.99 to 2.59)
284
(1 study)
⊕⊕⊕⊝
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; SMD: standardized mean difference; 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 Paroxetine compared with amisulpride for depression

Summary of findings 3. Paroxetine compared with amisulpride for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with amisulpride for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 254 per 1000 181 per 1000
(109 to 281)
OR 0.65
(0.36 to 1.15)
277
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 268 per 1000 237 per 1000
(152 to 348)
OR 0.85
(0.49 to 1.46)
277
(1 study)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.13 standard deviations lower
(0.37 lower to 0.10 higher)
 272
(1 study)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause -See commentSee commentNot estimable

0

(0)

See commentNo trial reported this outcome.
Participants with at least some Side Effects Study population OR 1.49
(0.89 to 2.50)
277
(1 study)
⊕⊕⊕⊝
moderate 1
 
261 per 1000 345 per 1000
(239 to 469)
Moderate
  
*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; SMD: standardized mean difference; 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 Paroxetine compared with aprepitant for depression

Summary of findings 4. Paroxetine compared with aprepitant for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

paroxetine compared with aprepitant for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
Comparison: aprepitant
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Aprepitant Paroxetine
Failure to respond at endpoint (6-12 weeks)See commentSee commentSee comment0 (0)See commentNo trial reported this outcome.
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 444 per 1000 557 per 1000
(464 to 647)
OR 1.57
(1.08 to 2.29)
807
(4 studies)
⊕⊕⊕⊕
high
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.00 standard deviations higher
(0.39 lower to 0.39 higher)
 102
(1 study)
⊕⊕⊕⊕
high
This correspond to no treatment effect.
Failure to complete - any cause - 282 per 1000 375 per 1000
(230 to 548)
OR 1.53
(0.76 to 3.09)
143
(1 study)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side EffectsSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
*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; SMD: standardized mean difference; 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 Paroxetine compared with bupropion for depression

Summary of findings 5. Paroxetine compared with bupropion for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with bupropion for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 292 per 1000 231 per 1000
(110 to 424)
OR 0.73
(0.3 to 1.79)
100
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpointSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.04 standard deviations lower
(0.38 lower to 0.3 higher)
 132
(1 study)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause - 188 per 1000 212 per 1000
(126 to 338)
OR 1.16
(0.62 to 2.2)
240
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 913 per 1000 944 per 1000
(819 to 984)
OR 1.60
(0.43 to 5.92)
140
(1 study)
⊕⊕⊕⊝
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; SMD: standardized mean difference; 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 Paroxetine compared with citalopram for depression

Summary of findings 6. Paroxetine compared with citalopram for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with citalopram for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 507 per 1000 613 per 1000
(517 to 701)
OR 1.54
(1.04 to 2.28)
406
(1 study)
⊕⊕⊕⊝
moderate
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpointSee commentSee commentNot estimable See commentNo trial reported this outcome.
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.16 standard deviations lower
(0.44 lower to 0.11 higher)
 201
(1 study)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause - 208 per 1000 206 per 1000
(138 to 296)
OR 0.99
(0.61 to 1.6)
406
(1 study)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects Study population OR 0.74
(0.46 to 1.21)
406
(1 study)
⊕⊕⊕⊝
moderate 1
 
821 per 1000 773 per 1000
(679 to 848)
Moderate
  
*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; SMD: standardized mean difference; 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 Paroxetine compared with duloxetine for depression

Summary of findings 7. Paroxetine compared with duloxetine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with duloxetine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
Comparison: duloxetine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Duloxetine Paroxetine
Failure to respond at endpoint (6-12 weeks) 459 per 1000 431 per 1000
(373 to 492)
OR 0.89
(0.70 to 1.14)
1821
(6 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 592 per 1000 587 per 1000
(537 to 633)
OR 0.98
(0.80 to 1.19)
1821
(6 studies)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.04 standard deviations higher
(0.06 lower to 0.15 higher)
 1481
(6 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause - 237 per 1000 232 per 1000
(193 to 277)
OR 0.97
(0.77 to 1.23)
1821
(6 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 700 per 1000 654 per 1000
(599 to 702)
OR 0.81
(0.64 to 1.01)
1870
(6 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; SMD: standardized mean difference; 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 Paroxetine compared with escitalopram for depression

Summary of findings 8. Paroxetine compared with escitalopram for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.
    2 I squared 81%
    3 I squared 78%

Paroxetine compared with escitalopram for depression
Patient or population: depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 312 per 1000 336 per 1000
(256 to 427)
OR 1.12
(0.76 to 1.65)
784
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
 No trial reported this outcome.
Failure to respond at 16-24 weeks Study population OR 1.36
(0.87 to 2.12)
459
(1 study)
⊕⊕⊕⊝
moderate 1
 
194 per 1000 247 per 1000
(173 to 338)
Moderate
  
Failure to remit at endpoint 407 per 1000 441 per 1000
(292 to 604)
OR 1.15
(0.6 to 2.22)
784
(2 studies)
⊕⊕⊝⊝
low 1,2
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.05 standard deviations higher
(0.26 lower to 0.36 higher)
 772
(2 studies)
⊕⊕⊝⊝
low 1,3
This effect approaches zero.
Failure to complete - any cause - 156 per 1000 213 per 1000
(124 to 340)
OR 1.47
(0.77 to 2.79)
784
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects Study population OR 1.28
(0.86 to 1.91)
454
(1 study)
⊕⊕⊕⊝
moderate 1
 
668 per 1000 720 per 1000
(634 to 794)
Moderate
  
*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; SMD: standardized mean difference; 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 Paroxetine compared with fluoxetine for depression

Summary of findings 9. Paroxetine compared with fluoxetine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with fluoxetine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
Comparison: fluoxetine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Fluoxetine Paroxetine
Failure to respond at endpoint (6-12 weeks) 386 per 1000 555 per 1000
(332 to 436)
OR 1.98
(0.79 to 1.23)
2418
(11 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpointSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.04 standard deviations higher
(0.05 lower to 0.12 higher)
 2109
(9 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause -
total drop out rate
325 per 1000 336 per 1000
(300 to 372)
OR 1.05
(0.89 to 1.23)
2798
(13 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 774 per 1000 763 per 1000
(703 to 814)
OR 0.94
(0.69 to 1.28)
2255
(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; SMD: standardized mean difference; 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 Paroxetine compared with fluvoxamine for depression

Summary of findings 10. Paroxetine compared with fluvoxamine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with fluvoxamine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 466 per 1000 510 per 1000
(386 to 629)
OR 1.19
(0.72 to 1.94)
261
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeks Study population OR 0.71
(0.41 to 1.24)
281
(3 studies)
⊕⊕⊕⊝
moderate 1
 
769 per 1000 703 per 1000
(577 to 805)
Moderate
  
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
 No trial reported this outcome.
Failure to remit at endpoint 752 per 1000 703 per 1000
(571 to 807)
OR 0.78
(0.44 to 1.38)
261
(3 studies)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.09 standard deviations higher
(0.43 lower to 0.6 higher)
 58
(1 study)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause - 293 per 1000 285 per 1000
(183 to 416)
OR 0.96
(0.54 to 1.72)
261
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 609 per 1000 636 per 1000
(395 to 822)
OR 1.12
(0.42 to 2.97)
261
(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; SMD: standardized mean difference; 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 Paroxetine compared with hypericum for depression

Summary of findings 11. Paroxetine compared with hypericum for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with hypericum for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 312 per 1000 420 per 1000
(301 to 550)
OR 1.60
(0.95 to 2.69)
251
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 512 per 1000 659 per 1000
(538 to 762)
OR 1.84
(1.11 to 3.06)
251
(1 study)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.35 standard deviations higher
(0.09 to 0.6 higher)
 244
(1 study)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause - 136 per 1000 230 per 1000
(134 to 366)
OR 1.90
(0.98 to 3.67)
251
(1 study)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 552 per 1000 762 per 1000
(650 to 846)
OR 2.60
(1.51 to 4.46)
251
(1 study)
⊕⊕⊕⊝
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; SMD: standardized mean difference; 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 Paroxetine compared with milnacipran for depression

Summary of findings 12. Paroxetine compared with milnacipran for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with milnacipran for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 423 per 1000 405 per 1000
(302 to 519)
OR 0.93
(0.59 to 1.47)
302
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint Study population OR 0.92
(0.57 to 1.49)
302
(1 study)
⊕⊕⊕⊝
moderate 1
 
671 per 1000 652 per 1000
(538 to 753)
Moderate
  
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.05 standard deviations lower
(0.28 lower to 0.18 higher)
 299
(1 study)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause - 172 per 1000 195 per 1000
(122 to 323)
OR 1.17
(0.67 to 2.3)
343
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 772 per 1000 700 per 1000
(581 to 795)
OR 0.69
(0.41 to 1.15)
302
(1 study)
⊕⊕⊕⊝
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; SMD: standardized mean difference; 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 Paroxetine compared with mirtazapine for depression

Summary of findings 13. Paroxetine compared with mirtazapine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with mirtazapine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 509 per 1000 554 per 1000
(483 to 625)
OR 1.20
(0.90 to 1.61)
766
(4 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeks 735 per 1000 869 per 1000
(797 to 918)
OR 2.39
(1.42 to 4.02)
726
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 16-24 weeks Study population OR 1.41
(0.81 to 2.48)
726
(3 studies)
⊕⊕⊕⊝
moderate 1
 
735 per 1000 869 per 1000
(797 to 918)
Moderate
  
Failure to remit at endpoint 597 per 1000 692 per 1000
(626 to 753)
OR 1.52
(1.13 to 2.06)
766
(4 studies)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.33 standard deviations higher
(0.08 to 0.58 higher)
 246
(1 study)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause - 306 per 1000 357 per 1000
(286 to 434)
OR 1.26
(0.91 to 1.74)
726
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 743 per 1000 756 per 1000
(687 to 813)
OR 1.07
(0.76 to 1.50)
726
(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; SMD: standardized mean difference; 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 Paroxetine compared with nefazodone for depression

Summary of findings 14. Paroxetine compared with nefazodone for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with nefazodone for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 450 per 1000 202 per 1000
(54 to 506)
OR 0.31
(0.07 to 1.25)
40
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeks Study population OR 0.64
(0.17 to 2.38)
40
(1 study)
⊕⊕⊕⊝
moderate 1
 
400 per 1000 299 per 1000
(102 to 613)
Moderate
  
Failure to remit at endpoint  Not estimable0
(0)
  
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.12 standard deviations lower
(0.37 lower to 0.14 higher)
 235
(2 studies)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause - 250 per 1000 150 per 1000
(35 to 464)
OR 0.53
(0.11 to 2.60)
40
(1 study)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 838 per 1000 781 per 1000
(638 to 879)
OR 0.69
(0.34 to 1.40)
206
(1 study)
⊕⊕⊕⊝
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; SMD: standardized mean difference; 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 Paroxetine compared with reboxetine for depression

Summary of findings 15. Paroxetine compared with reboxetine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with reboxetine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 500 per 1000 451 per 1000
(398 to 505)
OR 0.82
(0.66 to 1.02)
1369
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeks 846 per 1000 784 per 1000
(733 to 827)
OR 0.66
(0.5 to 0.87)
1375
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpointSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.10 standard deviations lower
(0.21 lower to 0 higher)
 1291
(3 studies)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause - 277 per 1000 230 per 1000
(164 to 313)
OR 0.78
(0.51 to 1.19)
1375
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 849 per 1000 859 per 1000
(806 to 899)
OR 1.08
(0.74 to 1.58)
1375
(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; SMD: standardized mean difference; 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 Paroxetine compared with sertraline for depression

Summary of findings 16. Paroxetine compared with sertraline for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with sertraline for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 292 per 1000 340 per 1000
(269 to 422)
OR 1.25
(0.89 to 1.77)
618
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 577 per 1000 562 per 1000
(478 to 647)
OR 0.94
(0.67 to 1.34)
545
(2 studies)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.13 standard deviations lower
(0.34 lower to 0.07 higher)
 353
(1 study)
⊕⊕⊕⊝
moderate 1
The point estimate of the effect size corresponds to a small effect according to Cohen 1992.
Failure to complete - any cause - 338 per 1000 411 per 1000
(210 to 648)
OR 1.37
(0.52 to 3.6)
426
(2 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side EffectsSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
*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; SMD: standardized mean difference; 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 Paroxetine compared with tianeptine for depression

Summary of findings 17. Paroxetine compared with tianeptine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with tianeptine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 370 per 1000 379 per 1000
(294 to 473)
OR 1.04
(0.71 to 1.53)
648
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 727 per 1000 638 per 1000
(324 to 863)
OR 0.66
(0.18 to 2.36)
44
(1 study)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.04 standard deviations higher
(0.12 lower to 0.2 higher)
 586
(3 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause - 174 per 1000 235 per 1000
(136 to 375)
OR 1.46
(0.75 to 2.85)
648
(3 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 427 per 1000 484 per 1000
(398 to 570)
OR 1.26
(0.89 to 1.78)
604
(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; SMD: standardized mean difference; 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 Paroxetine compared with trazodone for depression

Summary of findings 18. Paroxetine compared with trazodone for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.

Paroxetine compared with trazodone for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 127 per 1000 94 per 1000
(30 to 260)
OR 0.71
(0.21 to 2.41)
108
(1 study)
⊕⊕⊕⊝
moderate 1
 
Failure to respond at 1-4 weeks Study population OR 0.54
(0.25 to 1.19)
108
(1 study)
⊕⊕⊕⊝
moderate 1
 
691 per 1000 547 per 1000
(358 to 727)
Moderate
  
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 309 per 1000 322 per 1000
(174 to 516)
OR 1.06
(0.47 to 2.38)
108
(1 study)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.08 standard deviations lower
(0.46 to 0.30 lower)
 108
(1 study)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause -See commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Participants with at least some Side Effects 345 per 1000 264 per 1000
(137 to 450)
OR 0.68
(0.30 to 1.55)
108
(1 study)
⊕⊕⊕⊝
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; SMD: standardized mean difference; 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 Paroxetine compared with venlafaxine for depression

Summary of findings 19. Paroxetine compared with venlafaxine for depression
  1. 1 Blinding stated but not tested. No information on randomisation procedures and allocation concealment.
    2 I squared 76%

Paroxetine compared with venlafaxine for depression
Patient or population: patients with depression
Settings: in- and out-patients
Intervention: paroxetine
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 Paroxetine
Failure to respond at endpoint (6-12 weeks) 433 per 1000 457 per 1000
(307 to 617)
OR 1.10
(0.58 to 2.11)
747
(4 studies)
⊕⊕⊝⊝
low 1,2
 
Failure to respond at 1-4 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to respond at 16-24 weeksSee commentSee commentNot estimable0
(0)
See commentNo trial reported this outcome.
Failure to remit at endpoint 444 per 1000 557 per 1000
(464 to 647)
OR 1.57
(1.08 to 2.29)
807
(4 studies)
⊕⊕⊕⊝
moderate 1
 
SMD at endpoint The mean SMD at endpoint in the intervention groups was
0.07 standard deviations higher
(0.13 lower to 0.26 higher)
 411
(2 studies)
⊕⊕⊕⊝
moderate 1
This effect approaches zero.
Failure to complete - any cause - 250 per 1000 265 per 1000
(215 to 324)
OR 1.08
(0.82 to 1.44)
1079
(6 studies)
⊕⊕⊕⊝
moderate 1
 
Participants with at least some Side Effects 500 per 1000 502 per 1000
(342 to 661)
OR 1.01
(0.52 to 1.95)
200
(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; SMD: standardized mean difference; 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 a severe mental illness characterised by a persistent low mood and/or loss of interest and pleasure 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). 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 (NICE 2010). It was the third leading cause of burden among all diseases in the year 2002, and it is expected to show a rising trend during the coming 20 years (WHO 2006).

Description of the intervention

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 (APA 2000; Ellis 2004; NICE 2010 ). Paroxetine hydrochloride is a component of the class of AD known as selective serotonin reuptake inhibitors (SSRIs). In vitro studies suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. (Germann 2013).

How the intervention might work

Paroxetine is the most potent inhibitor of the reuptake of serotonin (Ki = 65 pmol/L) of all SSRIs and shows an intermediate affinity profile between the other SSRIs and tricyclic antidepressants (TCAs) with regards to the norepinephrine transporter (Ki = 45 nmol/L). At higher concentrations paroxetine loses its serotonin transporter (SERT) selectivity and may therefore act as a dual serotonin/norepinephrine uptake inhibitor (SNRI), nevertheless it is necessary to administer high doses of paroxetine (40 mg/day and higher) to determine a sufficient plasma level (higher than 100 ng/mL). (Gibiino 2012; Germann 2013).

Why it is important to do this review

Amongst ADs many different agents are available for the treatment of depression, including TCAs, monoamine oxidase inhibitors (MAOIs), SSRIs, SNRIs, and other newer agents (such as agomelatine, mirtazapine, reboxetine, bupropion). During the last 20 years, AD consumption has risen dramatically worldwide, mainly because of the increasing consumption of SSRIs and newer ADs, which have progressively become the most commonly prescribed ADs (Ciuna 2004). SSRIs are generally better tolerated than TCAs and there is evidence of similar efficacy (Anderson 2000). However, head-to-head comparison has provided contrasting findings. Amitriptyline, for example, may have the edge over SSRIs in terms of efficacy, and individual SSRIs and SNRIs may differ in terms of efficacy and tolerability (Hansen 2005; Cipriani 2009). 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 to inform clinical practice and mental health policies. We have up to now completed some individual reviews (about fluoxetine (Magni 2013), duloxetine (Cipriani 2012a), citalopram (Cipriani 2012b), sertraline (Cipriani 2009a), escitalopram (Cipriani 2009b), mirtazapine (Watanabe 2011), fluvoxamine (Omori 2010), milnacipran (Nakagawa 2009), and a number of other reviews are now underway.

Objectives

  1. To determine the efficacy of paroxetine in comparison with other anti-depressive agents in alleviating the acute symptoms of Major Depressive Disorder.

  2. To review acceptability of treatment with paroxetine in comparison with other anti-depressive agents.

  3. To investigate the adverse effects of paroxetine in comparison with other anti-depressive agents.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing paroxetine with all other active anti-depressive agents as monotherapy in the acute-phase treatment of major depression were included. Quasi-randomised trials, such as those allocating by using alternate days of the week, were excluded. Cluster-randomised trials were eligible for inclusion. For trials which have a cross-over design only results from the first randomisation phase were considered.

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 seasonal pattern. We included studies in which up to 20% of participants presented 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 paroxetine in comparison with conventional treatments for acute depression. We also examined paroxetine in comparison with the non-conventional  antidepressant hypericum.

We excluded trials in which paroxetine was compared with another type of psychopharmacological agent (i.e., anxiolytics, anticonvulsants, antipsychotics or mood-stabilisers), and trials in which paroxetine was used as an augmentation strategy.

Eligible intervention

1. Paroxetine: any dose and pattern of administration

Eligible comparators

Conventional anti-depressive agents: any dose and mode or pattern of administration:

1. Older ADs:

  • Tricyclics;

  • Heterocyclics;

  • MAOIs.

2. SSRIs

3. Newer or non-conventional anti-depressive agents, for example:

  • SNRIs;

  • Hypericum.

Types of outcome measures

Primary outcomes
1. Efficacy: response rate

(1) Number of patients who responded to treatment, showing a reduction of at least 50% on the Hamilton rating scale for depression (HDRS) (Hamilton 1960) or Montgomery and Asberg Depression Rating Scale (MADRS) (Montgomery 1979), or any other depression scale, or "much or very much improved" (score one or two) on Clinical Global Impression (CGI) - Improvement. All response rates were calculated out of the total number of randomised patients. Where more than one criterion was provided, we preferred the former criterion for judging response. We used the first criterion whenever possible, even when we needed to impute standard deviations (SDs) or response rates according to the procedures described below. We applied intention-to-treat (ITT) analyses, whereby all the dropouts not included in the analyses were considered non-responders.

When studies reported response rates at various time points of the trial, we decided a priori to subdivide the treatment indices as follows.

(a) Early response: between one and four weeks; the time point closest to two weeks was given preference.
(b) Acute phase treatment response: between six and 12 weeks; the time point given in the original study as the study endpoint was given preference.
(c) Follow-up response: between four and six months; the time point closest to 24 weeks was given preference.

The acute phase treatment response (between six and 12 weeks) was our primary outcome of interest.

Secondary outcomes
2. Efficacy: remission rate and continuous outcomes

(1) Number of patients who achieved remission. The cut-off point for remission was set a priori:

(a) at seven or less on the 17-item HDRS and at eight or less for all the other longer versions of HDRS, or

(b) at 10 or less on the MADRS (Zimmerman 2004), or

(c) "not ill or borderline mentally ill" (score one or two) on CGI-Severity (Guy 1970).

All remission rates were calculated out of the total number of randomised patients. Where two or more were provided, we preferred the first criteria for judging remission. We applied the ITT analyses, whereby all the dropouts not included in the analyses were considered non-remitters.

(2) Change scores from baseline to the time point in question (early response, acute phase response, or follow-up response as defined above) on HDRS or MADRS, or any other depression scale. We applied a looser form of ITT analyses, whereby all the patients with at least one post-baseline measurement were represented by their Last Observations Carried Forward (LOCF).

(3) Social adjustment, social functioning including the Global Assessment of Function (GAF) (Luborsky 1962) scores.

(4) Health-related quality of life: we limited ourselves to SF-12/SF-36 (Ware 1993), HoNOS (Wing 1994) and WHO-QOL (WHOQOL Group 1998).

(5) Costs to healthcare services.

3. Acceptability

(1) Number of patients who dropped out during the trial as a proportion of the total number of randomised patients - Total dropout rate.

(2) Number of patients who dropped out due to inefficacy during the trial as a proportion of the total number of randomised patients - Dropout rates due to inefficacy.

(3) Number of patients who dropped out due to side effects during the trial as a proportion of the total number of randomised patients - Dropout rates due to side effects.

4. Tolerability

(1) Total number of patients experiencing at least some side effects.

(2) Total number of patients experiencing the following specific side effects.

(a) Sleepiness/drowsiness.
(b) Insomnia.
(c) Dry mouth.
(d) Constipation.
(e) Urination problem.
(f) Hypotension.
(g) Agitation/anxiety.
(h) Suicide wishes/gestures/attempts.
(i) Completed suicide.
(j) Vomiting/nausea.
(k) Diarrhoea.

In order not to miss any relatively rare or unexpected yet important side effects, in the data extraction phase, we collected all side effects data reported in the literature and discussed ways to summarise them post hoc.

Search methods for identification of studies

The Cochrane, Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR)

The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) registers were searched up to September, 2012. The CCDAN maintain 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 handsearching 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

1. CCDANCTR

CDANCTR-Studies was searched using the following search strategy:
Diagnosis = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood Disorder*" or "Affective Disorder" or "Affective Symptoms"
and
Intervention = Paroxetine

CCDANCTR-References was searched using a similar set of terms to find additional untagged/uncoded references:
Keyword = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood Disorder*" or "Affective Disorder" or "Affective Symptoms"
and
Free-Text = Paroxetine

There was no restriction on date, language or publication status applied to the search.

2. International Regulatory Authorities and Trial Registries

Websites of the following drug regulatory authorities were searched for additional unpublished data: The Food and Drug Administration (FDA) in the USA, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, the European Medicines Agency (EMEA) in the EU, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the Therapeutic Goods Administration (TGA) in Australia). International trial registries were also searched for unpublished or ongoing research: Clinicaltrials.gov, ISRCTN, Nederlands Trial Register, EUDRACT, UMIN-CTR and the Australian New Zealand Clinical Trials Registry.

Searching other resources

Personal communication

Pharmaceutical companies and experts in this field were contacted for additional information on studies meeting the inclusion criteria for this review.

Handsearching

Appropriate journals and conference proceedings relating to the treatment of depression with paroxetine have already been handsearched and incorporated into the CCDANCTR.

Reference lists of all included studies, previous systematic reviews and major textbooks of affective disorder written in English were checked for published reports and citations of unpublished research. A cited reference search was conducted (on the Web of Science) to identify new reports citing any of the included studies.

Data collection and analysis

Data were entered into RevMan 5.2 (RevMan 2012) software by two review authors (DP and CT) (double data entry).

Selection of studies

Studies which met the following rough inclusion criteria constituted the preliminary list and their full texts were retrieved. The rough inclusion criteria were:
(a) randomised trial;
(b) comparing paroxetine against any other antidepressant;
(c) patients with major depression, regardless of the diagnostic criteria used.

Studies relating to paroxetine generated by the search strategies of the CCDANCTR-References and the other complementary searches were checked by review authors CR and CT to see if they meet the rough inclusion criteria, firstly based on the title and abstracts. All the studies rated as possible candidates by either of the two review authors were added to the preliminary list and their full texts retrieved. All the full text articles in this preliminary list were then assessed by MP and DP to see if they met the strict inclusion criteria. If the raters disagreed the final rating was made by consensus with the involvement (if necessary) of CB. Considerable care was taken to exclude duplicate publications.

Data extraction and management

Two review authors, working independently and in duplicate (CR and CT) extracted data from the included studies. Data were extracted on: participant characteristics (age, sex, depression diagnosis, comorbidity, depression severity, antidepressant treatment history for the index episode, study setting); intervention details (dosage range, mean daily dosage actually prescribed, co-intervention if any, paroxetine as investigational drug or as comparator drug, sponsorship); and outcome measures of interest from the included studies. The results were compared with those in the completed reviews of individual antidepressants in The Cochrane Library. If there were any discrepancies, a third review author (AC) intervened and the agreed-upon results were used in the review as well as fed back to the authors of the completed reviews. If the trial was a three (or more) -armed trial involving a placebo arm, the data were extracted from the placebo arm as well.

Assessment of risk of bias in included studies

Two review authors (MP and CR) independently assessed trial risk of bias in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The Cochrane Collaboration’s tool for assessing risk of bias covers six domains of bias: selection bias (random sequence generation, allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias not covered elsewhere. Particular attention was given to the adequacy of the random allocation concealment and double blinding. Where inadequate details of methodological characteristics of trials were provided, the authors were contacted in order to obtain further information. If the raters disagreed the final rating was made by consensus with the involvement (if necessary) of another member of the review group (CB). 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 paroxetine and comparator ADs considered as individual ADs and as a class.

Dichotomous data

For dichotomous data, odds ratios (ORs) were calculated with a 95% confidence interval (CI). For statistically significant results, we calculated the number needed to treat to provide benefit (NNTb) and the number needed to treat to induce harm (NNTh).

Continuous data

For continuous data we calculated the standardized mean differences (SMDs) with a 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 (e.g. 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, despite 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

No cluster-randomised trials were identified for this version of the review. Should they be identified in a future update, we plan to use the generic inverse variance technique, if such trials have been appropriately analysed taking into account intra-class correlation coefficients to adjust for cluster effects.

Multiple intervention groups

Studies that compared more than two intervention groups of the same drug (i.e. different dosages) were included in meta-analysis by combining group arms of the study into a single group, for the intervention and for the control group respectively, as recommended in section 16.5 of the Cochrane Handbook (Higgins 2011).

Dealing with missing data

When dichotomous or continuous outcomes were not reported, we asked the trial authors to supply the data.

For dichotomous data, we applied intention-to-treat (ITT) analyses, whereby all the dropouts not included in the analyses were considered as non-responders or non-remitters (i.e. it was assumed they would have experienced the negative outcome by the end of the trial, e.g. failure to respond to treatment).

For continuous data, we applied a looser form of ITT analyses, whereby all patients with at least one post-baseline measurement were represented by their Last Observations Carried Forward (LOCF). When only the standard error (SE) or t-statistics or P values were reported, standard deviations (SDs) were calculated according to Altman (Altman 1996).

In the absence of supplemental data from the authors, the SDs of the HDRS (or any other depression scale) and response/remission rates were calculated according to the validated imputation methods (Furukawa 2005; Furukawa 2006). We examined the validity of these imputations in the sensitivity analyses.

Assessment of heterogeneity

Skewed data and non-quantitative data were presented descriptively. An outcome whose minimum score is zero could be considered skewed when the mean was smaller than twice the SD. Heterogeneity between studies was investigated using the I2 statistic (Higgins 2003; Ioannidis 2008) and by visual inspection of the forest plots.

According to the Cochrane Handbook (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, 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 (Higgins 2011). When evidence of small-study effects was identified, possible reasons for funnel plot asymmetry, including publication bias, were investigated.

Data synthesis

For dichotomous data, odds ratios (OR) were calculated with 95% confidence intervals. The primary analysis used a random-effects model, which had the highest generalisability in our empirical examination of summary effect measures for meta-analyses (Furukawa 2002a). The robustness of this summary measure was routinely examined by checking the results under a fixed-effect model. Material differences between the models were reported.

Continuous data were analysed using standardized mean differences (SMD) (with 95% CIs) as different measurement scales were used. A random-effects model was employed. Fixed-effect analyses were used routinely for continuous outcomes 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

Subgroup analyses should be performed and interpreted with caution because multiple analyses will lead to false positive conclusions (Oxman 1992). However, we performed the following subgroup analyses for the following a priori reasons.

  1. Paroxetine dosing (fixed low dosage, fixed standard dosage, fixed high dosage; flexible low dosage, flexible standard dosage, flexible high dosage), because there is evidence to suspect that low dosage antidepressant may be associated with better outcomes both in terms of effectiveness and side effects than standard or high dosage antidepressants (Bollini 1999; Furukawa 2002b) and also because fixed versus flexible dosing schedule may affect estimates of treatment effectiveness (Khan 2003).

  2. Comparator dosing (low effective range, medium to high effective range), as it is easy to imagine that there are greater chances of completing the study on the experimental drug than on the comparator drug that is increased to the maximum dosage.

  3. Depression severity (severe major depression, moderate/mild major depression).

  4. Treatment settings (psychiatric inpatients, psychiatric outpatients, primary care).

  5. Elderly patients (> 65 years of age), separately from other adult patients.

Sensitivity analysis

Funnel plot analysis was performed to check for existence of small-study effects including publication bias. We performed the following sensitivity analyses. By limiting the studies to be included to those with higher quality, we examined if the results changed, and checked for the robustness of the observed findings.

  1. Excluding trials with unclear concealment of random allocation and/or unclear double blinding.

  2. Excluding trials whose dropout rate was greater than 20%.

  3. Performing the worst-case scenario ITT (all the patients in the experimental group experienced the negative outcome and all those allocated to the comparison group experienced the positive outcome) and the best-case scenario ITT (all the patients in the experimental group experienced the positive outcome and all those allocated to the comparison group experienced the negative outcome).

  4. Excluding trials for which the response rates had to be calculated based on the imputation method (Furukawa 2005) and those for which the SD had to be borrowed from other trials (Furukawa 2006).

  5. Examination of "wish bias" by comparing paroxetine as investigational drug versus paroxetine as comparator, as there is evidence to suspect that a new antidepressant might perform worse when used as a comparator than when used as an experimental agent (Barbui 2004; Lundh 2012).

  6. Excluding studies funded by the pharmaceutical company marketing paroxetine. This sensitivity analysis is particularly important in view of the recent repeated findings that funding strongly affects outcomes of research studies (Als-Nielsen 2003; Bhandari 2004; Lexchin 2003; Montgomery 2004b; Perlis 2005; Procyshyn 2004) and because industry sponsorship and authorship of clinical trials are increasing over 20 years (Buchkowsky 2004).

We planned that if subgroups within any of the subgroup or sensitivity analyses turned out to be significantly different from one another, we would run meta-regression for exploratory analyses of additive or multiplicative influences of the variables in question. Our routine application of random-effects and fixed-effect models as well as our secondary outcomes of remission rates and continuous severity measures may be considered additional forms of sensitivity analyses.

Summary of findings

The GRADE approach was employed to interpret findings (Langendam 2013) and the GRADE profiler (GRADEPRO) allowed us to import data from Review Manager 5.2 (Review Manager ) to create 'Summary of findings' tables. These tables provide outcome-specific information concerning the overall quality of evidence from studies included in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes we considered.

The following outcomes were included in the 'Summary of findings' tables.

  1. Failure to respond at endpoint (six to 12 weeks).

  2. Failure to respond at one to four weeks.

  3. Failure to respond at 16 to 24 weeks.

  4. Failure to remit at endpoint.

  5. SMD at endpoint.

  6. Failure to complete - any cause.

  7. Participants with at least some SE.

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 691 records: after reading abstracts, 187 papers were considered potentially relevant for this review. Of these, 13 were excluded because of the not relevant diagnostic status or other reasons, 58 studies were defined as awaiting assessment and one study was ongoing. The remaining 115 studies, retrieved for more detailed evaluation, met the inclusion criteria and were included in the review. A total of 94 studies contributed to the quantitative synthesis (meta-analysis) (see Figure 1).

Figure 1.

Flow diagram.

Included studies

See: Characteristics of included studies

Overall, a total of 115 studies (of which 25 were unpublished) were included in the present systematic review (26,134 participants). Unpublished data were obtained from the websites of pharmaceutical industries sponsoring the drugs under evaluation (23 trials), from the European Medicine Agency (one trial) and from conference proceedings (one trial).

Design

The great majority of included studies were reported to be double-blind (99 out of 115 RCTs, that is 86%). The participants were followed up for six weeks (range: three to 52 weeks) in 57 trials.

Sample sizes

The mean number of participants per study was 226, with a minimum sample size of 10 (Javors 2000) and a maximum of 1057 (NCT00463242).

Setting

A total of 54 trials enrolled only outpatients, 14 trials enrolled only inpatients, and both inpatients and outpatients were enrolled in 18 trials. Twelve trials were conducted in general practice setting and for the remaining 17 trials the setting was unclear. Fifty-two out of 115 trials took place in Europe; 34 trials took place in America (United States, Central America) and Canada; nine trials took place in Asia and two in Australia, For the remaining trials the country was unclear.

Participants

The majority of included trials (100 RCTs) enrolled patients with a diagnosis of major depression based on DSM-III (30 studies), DSM-III-R (26 studies), DSM-IV or ICD 10 criteria (44 studies). The remaining studies used other diagnostic criteria (15 studies). Forty-one trials excluded patients over 65 years, while 15 trials included only elderly patients. We also included a minority of studies in which up to 20% of patients presented depressive episodes in bipolar disorder (six studies).

Intervention and Comparators

In 54 studies paroxetine was compared with older ADs (two RCTs versus dothiepin, two RCTs versus nortriptyline, 19 RCTs versus amitriptyline, 12 RCTs versus imipramine, three RCTs versus desipramine, three RCTs versus maprotiline, five RCTs versus mianserin, five RCTs versus clomipramine, two RCTs versus lofepramine, and one RCT versus doxepine). Twenty-one RCTs compared paroxetine with other SSRIs (one RCT versus sertraline, two RCTs versus escitalopram, 14 RCTs versus fluoxetine and two RCTs versus fluvoxamine. There was one three-armed study comparing paroxetine with fluoxetine and sertraline (Fava 2002), and one three-armed study comparing paroxetine with citalopram and sertraline (Jefferson 2001 29060/785)). Forty studies compared paroxetine with newer or non-conventional ADs (one RCT versus trazodone, three RCTs versus milnacipran, eight RCTs versus venlafaxine, two RCTs versus nefazodone, three RCTs versus reboxetine, two RCTs versus bupropion, one RCT versus hypericum, three RCTs versus tianeptine, four RCTs versus mirtazapine, six RCTs versus duloxetine, one RCT versus amisulpride, four RCTs versus agomelatine,one RCT versus aprepitant (MK-869), and one RCT versus substance P).

Outcomes

At the end of the reviewing process, 94 RCTs were included in the meta-analysis. For efficacy outcomes, 76 RCTs provided continuous data, and 81 dichotomous data. For acceptability outcomes, 94 RCTs provided data on total dropouts, 61 on dropouts due to inefficacy and 78 on dropouts due to side effects. In the majority of trials (93 out of 115, 81%) the HDRS scale was used for reporting outcomes.

Overall, 15,863 patients were included in the efficacy analysis, dichotomous outcome (7776 participants randomised to paroxetine and 8087 randomised to another antidepressant) and 14,637 were included in the efficacy analysis, continuous outcome (7326 participants randomised to paroxetine and 7311 randomised to another antidepressant). A total of 18,658 patients were included in the acceptability analysis (9037 partIcipants randomised to paroxetine and 9621 randomised to another antidepressant).

Excluded studies

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

Thirteen articles initially selected did not meet our inclusion criteria and were excluded because of the wrong diagnosis or other reasons A total of 58 records were classified as "awaiting classification".

Ongoing studies

There is one ongoing study (Thomas 2008), This is a large multicentre trial including more than 500 participants with a primary diagnosis of major depression.

See Characteristics of ongoing studies

Studies awaiting classification

There were 58 studies for which sufficient information was not currently available to make a decision about inclusion or exclusion. The majority of studies in this section were written in Chinese (39 out of 58 studies). For the remaining studies, the number of participants or the outcomes were unclear.

See Characteristics of studies awaiting classification

Risk of bias in included studies

See:Characteristics of included studies.

Our judgment about the overall risk of bias in the individual studies is illustrated in Figure 2 and Figure 3. The Cochrane 'Risk of bias' tool highlighted poor reporting for a number of items in many of the included studies, although judging articles from some time ago by today’s standards can be problematic (Begg 1996; Turner 2012). Moreover, many articles failed to report methodologically relevant information on study procedure (in these cases the judgement was defined as "unclear"). In general, the reporting of studies was not good. This type of reporting has been associated with an overestimate of the estimate of effect (Schulz 1995) and this should be considered when interpreting the results.

Figure 2.

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

Figure 3.

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

Allocation

Random sequence generation

The majority of studies (96 RCTs) did not report the methods of random sequence generation, while 18 studies (CL3-023; 29060III/85/038; Aberg-Wistedt 2000; Baldwin 2006; Boulenger 2006; Christiansen 1996; Freed 1996; Gallen 2001; Goldstein 2004 (HMAT B); Higuchi 2009; M/2020/0047; M/2020/0052; Owens 2008; Ravindran 1997; Shinkai 2004; Szegedi 2005; Wade 2003; Yoshimura 2007) specified this information, and they were classified as "low risk of bias".

Allocation concealment

Only a few trials (seven out of 115) (Baldwin 2006; Boulenger 2006; Gallen 2001; Higuchi 2009; M/2020/0047; M/2020/0052; Szegedi 2005) reported details on allocation concealment and were classified as "low risk".

Blinding

The great majority of included trials were undertaken under double-blind conditions (99 out of 115 RCTs), however in many cases blinding was stated but not tested; two trials employed an open-label design and for the remaining studies the design was unclear.

Incomplete outcome data

Twenty-four trials were rated as "low" in terms of addressing incomplete outcome data, while 60 studies were classified as "unclear risk" and 31 as "high risk".

Selective reporting

The study protocol was not available for almost all studies so it is difficult to make a judgment on the possibility of outcome reporting bias. However, in 28 studies results were consistent with what was stated in the study protocols.

Other potential sources of bias

Most of the included studies were funded by the pharmaceutical industry or do not specify the source of funding. Seven studies were independent from commercial sponsorship (Javors 2000; Laghrissi-Thode 1995; Laursen 1985; Montgomery 2004; Shinkai 2004; Steinmeyer 1992; Lepine 2001).

Effects of interventions

See: Summary of findings for the main comparison Paroxetine compared with older ADs for depression; Summary of findings 2 Paroxetine compared with agomelatine for depression; Summary of findings 3 Paroxetine compared with amisulpride for depression; Summary of findings 4 Paroxetine compared with aprepitant for depression; Summary of findings 5 Paroxetine compared with bupropion for depression; Summary of findings 6 Paroxetine compared with citalopram for depression; Summary of findings 7 Paroxetine compared with duloxetine for depression; Summary of findings 8 Paroxetine compared with escitalopram for depression; Summary of findings 9 Paroxetine compared with fluoxetine for depression; Summary of findings 10 Paroxetine compared with fluvoxamine for depression; Summary of findings 11 Paroxetine compared with hypericum for depression; Summary of findings 12 Paroxetine compared with milnacipran for depression; Summary of findings 13 Paroxetine compared with mirtazapine for depression; Summary of findings 14 Paroxetine compared with nefazodone for depression; Summary of findings 15 Paroxetine compared with reboxetine for depression; Summary of findings 16 Paroxetine compared with sertraline for depression; Summary of findings 17 Paroxetine compared with tianeptine for depression; Summary of findings 18 Paroxetine compared with trazodone for depression; Summary of findings 19 Paroxetine compared with venlafaxine for depression

All the results of this systematic review need to be interpreted considering the characteristics and the risk of bias profile of each included study (Characteristics of included studies).

Comparison 1: Paroxetine versus older ADs

Pirmary outcome: Efficacy. Number of patients who responded to treatment
1.1 Responders at endpoint (six to 12 weeks)

We found no statistically significant difference in terms of response rate between paroxetine and older ADs as a class (odds ratio (OR): 1.04, 95% confidence interval (CI) 0.92 to 1.17, 34 RCTs, 4647 participants), and in head-to-head comparisons (see Analysis 1.1).

1.2 Early response rate (one to four weeks)

We found no difference between paroxetine and older ADs for this outcome (see Analysis 2.1).

1.3 Follow-up response rate (16 to 24 weeks)

No studies provided data for this outcome.

Secondary outcome: Efficacy. Number of patients who remitted
1.4 Remission at endpoint (six to 12 weeks)

There was no evidence that paroxetine was more effective than older ADs as a class in terms of remission rates at endpoint (see Analysis 4.1). In head-to-head comparisons we found a difference in favour of clomipramine over paroxetine (OR: 3.39, 95% CI 1.50 to 7.65, number needed to treat to provide benefit (NNTb) = 4, 95% CI 2 to 11, 1 RCT, 120 participants).

1.5. Early remission rate (one to four weeks)

There was no evidence that paroxetine was more effective than older ADs in terms of early remissions (see Analysis 5.1).

1.6. Follow-up remission rate (16 to 24 weeks)

No studies provided data for this outcome.

Secondary outcome: Efficacy. Standardized mean difference (SMD)
1.7 Standardized mean difference at endpoint (six to 12 weeks)

On this outcome, we found no statistically significant differences between paroxetine and older ADs (SMD: 0.01, 95% CI -0.08 to 0.10, 34 RCTs, 4712 participants), nor between paroxetine and individual ADs (see Analysis 7.1).

1.8 Standardized mean difference at one to four weeks

We found a difference in favour of desipramine over paroxetine (SMD: 0.86, 95% CI 0.28 to 1.44, 1 RCT, 50 participants) (see Analysis 8.1).

1.9 Standardized mean difference at 16 to 24 weeks

No studies provided data for this outcome.

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

In terms of participants who dropped out due to any cause, we found a difference between paroxetine and older ADs as a class (OR: 0.84, 95% CI 0.73 to 0.96, number needed to treat to induce harm (NNTh) = 23, 95% CI 15 to 44, 43 RCTs, 6777 participants). In head-to-head comparisons paroxetine was better tolerated than clomipramine (OR: 0.67, 95% CI 0.52 to 0.87, NNTh = 14, 95% CI 8 to 39, 4 RCTs, 1273 participants), and than imipramine (OR: 0.65, 95% CI 0.50 to 0.85, NNTh= 8, 95% CI 6 to 14, 9 RCTs, 1268 participants) (see.Analysis 10.1)

1.11 Failure to complete due to inefficacy

We found no differences in terms of dropouts due to inefficacy between paroxetine and older ADs (OR: 1.22, 95% CI 0.93 to 1.61, 27 RCTs, 4436 participants) (see Analysis 11.1).

1.12 Failure to complete due to side effects

The analysis of dropouts due to side effects revealed that amitriptyline (OR: 0.74, 95% CI 0.56 to 0.98, NNTh = 29, 95% CI 15 to 1318, 12 RCTs, 1698 participants), clomipramine (OR: 0.59, 95% CI 0.41 to 0.84, NNTh = 19, 95% CI 11 to 61, 4 RCTs, 1273 participants), imipramine (OR: 0.58, 95% CI 0.43 to 0.77, NNTh = 10, 95% CI 7 to 17, 9 RCTs, 1268 participants) and overall older ADs (OR: 0.76, 95% CI 0.63 to 0.92, NNTh = 25, 95% CI 17 to 49, 34 RCTs, 5175 participants) were significantly less well tolerated than paroxetine (see Analysis 12.1).

Secondary outcome: Tolerability
1.13 Total number of patients experiencing at least some side effects

There was evidence that paroxetine was associated with a lower rate of adverse events than amitriptyline (OR: 0.53, 95% CI 0.39 to 0.72, NNTh = 7, 95% CI 6 to 10, 16 RCTs, 2492 participants), imipramine (OR: 0.62, 95% CI 0.42 to 0.94, NNTh = 10, 95% CI 7 to 19, 9 RCTs, 1189 participants) and than older ADs as a class (OR: 0.64, 95% CI 0.53 to 0.77, NNTh = 11, 95% CI 9 to 14, 41 RCTs, 6099 participants) (see Analysis 13.1).

1.14 Number of patients experiencing specific side effects

(a) Sleepiness/drowsiness. We found a difference in favour of paroxetine over maprotiline (OR: 0.37, 95% CI 0.17 to 0.82, NNTh = 13, 95% CI 7 to 52, 2 RCTs, 358 participants) (see Analysis 79.1).

(b) Insomnia. There was evidence that paroxetine was associated with a higher rate of insomnia than older ADs (OR: 2.17, 95% CI 1.51 to 3.12, NNTh = 17, 95% CI 12 to 29, 15 RCTs, 1986 participants). In head-to-head comparisons, paroxetine was associated with a higher rate of insomnia than amitriptyline (OR: 3.66, 95% CI 1.36 to 9.85, NNTh = 13, 95% CI 8 to 36, 4 RCTs, 352 participants), dothiepin (OR: 2.34, 95% CI 1.03 to 5.31, NNTh = 19, 95% CI 10 to 246, 2 RCTs, 405 participants) and than maprotiline (OR: 4.38, 95% CI 1.72 to 11.15, NNTh = 9, 95% CI 6 to 22, 1 RCTs, 298 participants) (see Analysis 54.1).

(c) Dry mouth. Paroxetine was associated with a lower rate of dry mouth than amitriptyline (OR: 0.27, 95% CI 0.17 to 0.43, NNTh = 4, 95% CI 4 to 5, 12 RCTs, 1576 participants), clomipramine (OR: 0.35, 95% CI 0.26 to 0.48, NNTh = 6, 95% CI 5 to 8, 2 RCTs, 1111 participants), dothiepin (OR: 0.22, 95% CI 0.10 to 0.50, NNTh = 3, 95% CI 3 to 5, 2 RCTs, 405 participants), imipramine (OR: 0.16, 95% CI 0.10 to 0.26, NNTh = 3, 95% CI 2 to 3, 8 RCTs, 835 participants), maprotiline (OR: 0.13, 95% CI 0.08 to 0.23, NNTh = 3, 95% CI 2 to 4, 3 RCTs, 429 participants), and older ADs as a class (OR: 0.23, 95% CI 0.18 to 0.30, NNTh = 4, 95% CI 3 to 5, 29 RCTs, 4578 participants) (see Analysis 38.1).

(d) Constipation. Paroxetine was associated with a lower rate of constipation than older ADs as a class (OR: 0.49, 95% CI 0.40 to 0.60, NNTh = 12, 95% CI 9 to 16, 26 RCTs, 3934 participants). In head-to-head comparisons, paroxetine was associated with a lower rate of constipation than amitriptyline (OR: 0.61, 95% CI 0.37 to 0.99, NNTh = 18, 95% CI 11 to 65, 10 RCTs, 1146 participants), clomipramine (OR: 0.57, 95% CI 0.38 to 0.85, NNTh = 19, 95% CI 12 to 64, 2 RCTs, 1111 participants), dothiepin (OR: 0.57, 95% CI 0.32 to 0.99, NNTh = 10, 95% CI 5 to 378, 1 RCT, 271 participants), imipramine (OR: 0.40, 95% CI 0.25 to 0.63, NNTh = 6, 95% CI 5 to 11, 7 RCTs, 633 participants), and maprotiline (OR: 0.31, 95% CI 0.17 to 0.55, NNTh = 7, 95% CI 5 to 12, 3 RCTs, 429 participants) (see Analysis 31.1).

(e) Urination/Urogenital problems. There was evidence in favour of paroxetine over imipramine for urinary retention (OR: 0.04, 95% CI 0.00 to 0.73, NNTh = 4, 95% CI 3 to 10, 1 RCT, 80 participants) (see Analysis 90.4) and for urogenital problems (Not Otherwise Specified) (OR: 0.10, 95% CI 0.01 to 0.82, NNTh = 10, 95% CI 6 to 38, 1 RCT, 159 participants) (see Analysis 90.5).

(f) Hypotension. We found no difference between paroxetine and older ADs (see Analysis 50.1).

(g) Agitation/anxiety. We found no difference between paroxetine and older ADs (see Analysis 18.1).

(h) Suicide wishes/gestures/attempts. We found no difference between paroxetine and older ADs (see Analysis 96.1; Analysis 96.3).

(i) Completed suicide. We found no difference between paroxetine and older ADs (see Analysis 96.2).

(j) Vomiting/nausea. Paroxetine was associated with a higher rate of vomiting/nausea than older ADs as a class (OR: 2.10, 95% CI 1.59 to 2.77, NNTh = 12, 95% CI 10 to 17, 30 RCTs, 4545 participants). In head-to-head comparisons we found evidence in favour of amitriptyline (OR: 2.17, 95% CI 1.43 to 3.29, NNTh = 15, 95% CI 10 to 29, 10 RCTs, 1282 participants), dothiepin (OR: 3.12, 95% CI 1.1 to 8.78, NNTh = 8, 95% CI 5 to 15, 2 RCTs, 405 participants), imipramine (OR: 2.05, 95% CI 1.23 to 3.42, NNTh = 11, 95% CI 7 to 26, 8 RCTs, 835 participants), and lofepramine (OR: 2.97, 95% CI 1.12 to 7.92, NNTh = 9, 95% CI 5 to 34, 2 RCTs, 228 participants) over paroxetine (see Analysis 59.1).

(k) Diarrhoea. We found that paroxetine was associated with a higher rate of diarrhoea than older ADs as a class (OR: 2.41, 95% CI 1.56 to 3.73, NNTh = 20, 95% CI 14 to 36, 13 RCTs, 1743 participants) and than dothiepin (OR: 3.47, 95% CI 1.23 to 9.75, NNTh = 12, 95% CI 7 to 56, 1 RCTs, 271 participants) and maprotiline (OR: 2.94, 95% CI 1.34 to 6.47, NNTh = 11, 95% CI 7 to 33, 2 RCTs, 358 participants) (see Analysis 36.1).

(l) Other side effects. Other statistically significant side effects are reported in Table 1.

Table 1. Other significant tolerability outcomes not a priori listed in the protocol
Adverse eventStudyParoxetineComparatorOdds Ratio, Random [95% CI]NNTh [95% CI]
EventsTotalEventsTotal
Paroxetine versus older antidepressants 
Paroxetine vs amitriptyline 
Anticholinergic Hutchinson 1992; Staner 199557912510.22 [0.07 to 0.76]6 [3 to 23]
Body as a whole 29060/281 PAR; PAR MDUK 03254111371101.87 [1.08 to 3.23]7 [4 to 46]
Dizziness 29060/299; 29060.07.001; Hutchinson 1992; Kuhs 1989; Laursen 1985; Sacchetti 2002; SER-CHN-131398573790.42 [0.25 to 0.72]14 [9 to 36]
Behaviour (irritability) Battegay 198571111015.75 [1.42 to 174.25]2 [1 to 5]
Palpitations Battegay 1985; Bignamini 1992; Laursen 19854188131860.42 [0.06 to 2.74]21 [11 to 152]
Tachycardia Sacchetti 2002; SER-CHN-16177211830.43 [0.04 to 4.44]12 [7 to 36]
Tremor 29060/299; 29060.07.001; Battegay 1985; Geretsegger 1995; Laursen 1985; Sacchetti 2002; SER-CHN-1; Staner 1995; Stuppaeck 199425508535060.44 [0.22 to 0.90]18 [11 to 44]
Paroxetine vs clomipramine 
Anticholinergic Guillibert 198974016390.30 [0.11 to 0.86]4 [2 to 24]
Paroxetine vs dothiepin 
Headache 29060/056/UK; Dunner 199239203182022.46 [1.35 to 4.48]10 [6 to 28]
Paroxetine vs imipramine 
Dyspnea 29060/40943812370.25 [0.07 to 0.85]5 [3 to 25]
Sweating Cohn 1990; Feighner 1989; Peselow 1989; Shrivastava 1992;029060/1/CPMS-095; Fabre 1992; Ohrberg 199261373973080.43 [0.29 to 0.65]7 [5 to 11]
Weight gain Ohrberg 19921798800.12 [0.01 to 0.95]11 [6 to 58]
Paroxetine vs maprotiline 
Appetite decreased Szegedi 19951214521536.81 [1.50 to 30.99]14 [8 to 47]
Headache 29060.065.BE; Schnyder 1996; Szegedi 199551210302091.96 [1.13 to 3.39]10 [6 to 41]
Weight gain 29060.065.BE; Schnyder 19960658660.10 [0.01 to 0.81]8 [5 to 24]
Paroxetine vs mianserin 
Nervous system 29060/III/85/030; Dorman 1992154725430.25 [0.09 to 0.67]4 [2 to 16]
Gastrointestinal 29060/III/83/022; 29060/III/85/030;Dorman 1992326513613.56 [1.63 to 7.79]4 [2 to 8]
Paroxetine versus other SSRIs 
Paroxetine vs fluoxetine 
Dizziness 29060/356; Gagiano 1993; Geretsegger 1994; MY-1045/BRL-029060/1; Ontiveros 1994114868818691.50 [1.11 to 2.04]26 [15 to 118]
Fatigue 29060/3562689700.21 [0.04 to 0.99]10 [5 to 90]
Nervous system Cassano 2002; De Wilde 199324173471690.41 [0.24 to 0.72]7 [4 to 18]
Sexual problems (ejaculation disorders) MY-1045/BRL-029060/136357123513.17 [1.62 to 6.20]15 [10 to 33]
Paroxetine vs fluvoxamine 
Sweating Kiev 199710303304.50 [1.09 to 18.50]4 [2 to 30]
Paroxetine vs sertraline 
Fatigue Aberg-Wistedt 2000; Fava 200297273482722.41 [1.21 to 4.77]6 [4 to 9]
Sexual problems (ejaculation disorders) Aberg-Wistedt 2000; Fava 200232273102723.50 [1.68 to 7.28]12 [8 to 28]
Tremor Aberg-Wistedt 2000; Fava 200242273252721.82 [1.07 to 3.09]16 [9 to 142]
Paroxetine versus newer or non-conventional antidepressants and other agents 
Paroxetine vs aprepitant 
Sexual problems (ejaculation disorders) Kramer 199814722718.33 [1.82 to 38.16]6 [4 to 15]
Paroxetine vs hypericum 
Dizziness Szegedi 20052412691253.03 [1.35 to 6.82]8 [5 to 2]8
Paroxetine vs mirtazapine 
Fatigue Benkert 1999; Schatzberg 2002; Wade 200333360543660.47 [0.22 to 0.99]12 [7 to 43]
Flatulence Schatzberg 20021512641284.19 [1.35 to 13.00]11 [7 to 42]
Headache Benkert 1999; Schatzberg 2002; Wade 200373360463661.77 [1.12 to 2.79]11 [7 to 28]
Sexual problems (general) Benkert 19991813641395.15 [1.69 to 15.64]10 [6 to 25]
Sweating Benkert 1999; Schatzberg 2002; Wade 200338360133663.12 [1.61 to 6.03]14 [9 to 30]
Tremor Benkert 1999; Schatzberg 20022126262673.67 [1.43 to 9.42]17 [11 to 49]
Weight gain Benkert 1999; Schatzberg 2002; Wade 200312360463660.25 [0.13 to 0.47]11 [8 to 19]
Paroxetine vs nefazodone 
Sweating Hicks 200272002022.78 [1.20 to 432.58]3 [2 to 7]
Paroxetine vs reboxetine 
Asthenia Gallen 2001; M/2020/0047; M/2020/005291693486822.01 [1.39 to 2.91]16 [11 to 34]
Chills Gallen 2001; M/2020/0047; M/2020/005213693366820.34 [0.18 to 0.65]29 [19 to 69]
Dyspnea M/2020/0047; M/2020/00521342834174.32 [1.22 to 15.31]43 [24 to 200]
Paraesthesia Gallen 2001; M/2020/0047; M/2020/005210693226820.44 [0.20 to 0.96]56 [30 to 535]
Sexual problems (anorgasmia) Gallen 2001; M/2020/0047; M/2020/00522469316829.84 [2.23 to 43.46]30 [21 to 52]
Sexual problems (libido decreased) Gallen 2001; M/2020/0047; M/2020/005226693116822.34 [1.14 to 4.82]47 [26 to 229]
Sleep disorders Gallen 2001; M/2020/0047; M/2020/00521669346823.67 [1.29 to 10.45]58 [34 to 215]
Sweating Gallen 2001; M/2020/0047; M/2020/0052556931046820.48 [0.34 to 0.68]14 [9 to 25]
Tremor Gallen 2001; M/2020/0047; M/2020/005231693116822.75 [1.35 to 5.57]35 [21 to 95]
Weight gain Gallen 2001; M/2020/00521043124244.12 [1.02 to 16.62]54 [29 to 351]
Yawning Gallen 2001;M/2020/004711527052312.13 [1.57 to 93.64]48 [30 to 115]
Paroxetine vs tianeptine 
Dizziness Lepine 2001; Waintraub 20021030413007.02 [1.25 to 39.32]34 [20 to 118]

Comparison 2: Paroxetine versus SSRIs

Primary outcome: Efficacy. Number of patients who responded to treatment
2.1 Responders at endpoint (six to 12 weeks)

We found a difference in favour of citalopram over paroxetine (OR: 1.54, 95% CI 1.04 to 2.28, NNTb = 9, 95% CI 5 to 102, 1 RCT, 406 participants).

2.2 Early response rate (one to four weeks) and follow-up response rate (16 to 24 weeks)

We found no differences between paroxetine and individual SSRIs (see Analysis 2.2; Analysis 3.1).

Secondary outcome: Efficacy. Number of patients who remitted
2.3 Remission rate at endpoint (six to 12 weeks)

We found no differences between paroxetine and individual SSRIs (see Analysis 4.2).

2.4 Early remission rate (one to four weeks)

We found no difference between paroxetine and other SSRIs in terms of early remission rates (see Analysis 5.2).

2.5. Follow-up remission rate (16 to 24 weeks)

No studies provided data for this outcome.

Secondary outcome: Efficacy. Standardized mean difference
2.6 Standardized mean difference at endpoint (six to 12 weeks)

For this continuous outcome at endpoint, we found no difference between paroxetine and other SSRIs (see Analysis 7.2).

2.7 Standardized mean difference at one to four weeks

For this outcome we found no difference between paroxetine and other SSRIs (see Analysis 8.2).

2.8 Standardized mean difference at 16 to 24 weeks

No difference was found for this outcome.

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

In terms of patients who dropped out during the trial for any reason, we found no difference between paroxetine and individual SSRIs (see Analysis 10.2).

2.10 Failure to complete due to inefficacy

We found no difference in terms of dropouts due to inefficacy (see Analysis 11.2).

2.11 Failure to complete due to side effects

In terms of dropouts due to side effects, we found that paroxetine was less well tolerated than fluoxetine (OR: 1.34, 95% CI 1.06 to 1.70, NNTh = 29, 95% CI 16 to 137, 11 RCTs, 2491 participants) (see Analysis 12.2).

Secondary outcome: Tolerability
2.13 Total number of patients experiencing at least some side effects

We found no difference between paroxetine and other SSRIs in terms of number of patients experiencing side effects (see Analysis 13.2).

2.14 Number of patients experiencing specific side effects

(a) Sleepiness/drowsiness. We found a difference in favour of fluoxetine over paroxetine (OR: 1.48, 95% CI 1.16 to 1.88, NNTh = 20, 95% CI 12 to 53, 8 RCTs, 2116 participants) (see Analysis 79.2).

(b) Insomnia. We found no difference between paroxetine and SSRIs (see Analysis 54.2).

(c) Dry mouth. Paroxetine was associated with a higher rate of dry mouth than fluoxetine (OR: 1.67, 95% CI 1.17 to 2.38, NNTh = 18, 95% CI 12 to 38, 6 RCTs, 1920 participants) (see Analysis 38.2).

(d) Constipation. Paroxetine was associated with a higher rate of constipation than fluoxetine (OR: 2.71, 95% CI 1.47 to 5.01, NNTh = 14, 95% CI 9 to 26, 3 RCTs, 1001 participants) and sertraline (OR: 3.26, 95% CI 1.73 to 6.14, NNTh = 10, 95% CI 7 to 20, 2 RCTs, 545 participants) (see Analysis 31.2).

(e) Urination/Urogenital problems. There was difference in favour of sertraline over paroxetine for this outcome (OR: 11.60, 95% CI 1.48 to 90.81, NNTh = 18, 95% CI 11 to 52, 1 RCT, 353 participants) (see Analysis 90.5).

(f) Hypotension. We found no difference between paroxetine and other SSRIs (see Analysis 50.2).

(g) Agitation/anxiety. We found no difference between paroxetine and other SSRIs (see Analysis 18.2).

(h) Suicide wishes/gestures/attempts. We found no difference between paroxetine and other SSRIs (see Analysis 96.1; Analysis 96.3)..

(i) Completed suicide. We found no difference between paroxetine and other SSRIs (see Analysis 96.2).

(j) Vomiting/nausea. We found a difference in favour of fluoxetine over paroxetine (OR: 1.24, 95% CI 1.02 to 1.51, NNTh = 26, 95% CI 14 to 298, 10 RCTs, 2336 participants) (see Analysis 59.2).

(k) Diarrhoea. We found a difference in favour of paroxetine over sertraline (OR: 0.40, 95% CI 0.26 to 0.60, NNTh = 6, 95% CI 4 to 11, 2 RCTs, 545 participants) (see Analysis 36.2).

(l) Other side effects. Other statistically significant side effects are reported in Table 1.

Comparison 3: Paroxetine versus newer or non-conventional ADs

Primary outcome: Efficacy. Number of patients who responded to treatment
3.1 Responders at endpoint (six to 12 weeks)

In terms of efficacy as number of patients who responded to treatment, there was a trend in favour of paroxetine over reboxetine (OR: 0.82, 95% CI 0.66 to 1.02, 3 RCTs, 1369 participants) (see Analysis 1.3).

3.2 Early response rate (one to four weeks)

In terms of efficacy as number of patients who responded to treatment at one to four weeks, we found a difference in favour of paroxetine over reboxetine (OR: 0.66, 95% CI 0.50 to 0.87, NNTb = 16, 95% CI 10 to 50, 3 RCTs, 1375 participants). By contrast, we found a difference in favour of mirtazapine over paroxetine for this outcome (OR: 2.39, 95% CI 1.42 to 4.02, NNTb = 8, 95% CI 5 to 14, 3 RCTs, 726 participants) (see Analysis 2.3).

3.3 Follow-up response rate (16 to 24 weeks)

In terms of efficacy as number of patients who responded to treatment at 16-24 weeks, we found no difference between paroxetine and newer or non-conventional ADs (see Analysis 3.2).

Secondary outcome: Efficacy. Number of patients who remitted
3.4 Remission rate at endpoint (six to 12 weeks)

In terms of efficacy as number of patients who remitted, we found a difference in favour of hypericum (OR: 1.84, 95% CI 1.11 to 3.06, NNTb = 7, 95% CI 4 to 38, 1 RCT, 251 participants), mirtazapine (OR: 1.52, 95% CI 1.13 to 2.06, NNTb = 11, 95% CI 6 to 37, 4 RCTs, 766 participants) and venlafaxine (OR: 1.57, 95% CI 1.08 to 2.29, NNTb = 11, 95% CI 6 to 54, 4 RCTs, 807 participants) over paroxetine (see Analysis 4.3).

3.5 Early remission rate (one to four weeks)

In terms of efficacy as number of patients who remitted at one to four weeks, we found a difference between paroxetine and mirtazapine, in favour of mirtazapine (OR: 2.31, 95% CI 1.04 to 5.11, NNTb = 18, 95% CI 11 to 54, 3 RCTs, 726 participants) (see Analysis 5.3).

3.6. Follow-up remission rate (16 to 24 weeks)

We found a difference in favour of mirtazapine over paroxetine for this outcome (OR: 1.89, 95% CI 1.01 to 3.54, NNTb = 8, 95% CI 4 to 265, 1 RCT, 197 participants) (see Analysis 6.1).

Secondary outcome: Efficacy. Standardized mean difference
3.7 Standardized mean difference at endpoint (six to 12 weeks)

In terms of continuous outcomes at 6-12 weeks, we found a difference in favour of mirtazapine over paroxetine (SMD: 0.33, 95% CI 0.08 to 0.58, 1 RCTs, 246 participants). Moreover, there was a trend in favour of paroxetine over reboxetine (SMD: -0.10, 95% CI -0.21 to 0.00, 3 RCTs, 1291 participants). There was no evidence that paroxetine was different from other newer or non-conventional ADs (see Analysis 7.3).

3.8 Standardized mean difference at one to four weeks

For this outcome we found a difference in favour of paroxetine over reboxetine (SMD: -0.17, 95% CI -0.31 to -0.03, 2 RCTs, 805 participants) (see Analysis 8.3).

3.9 Standardized mean difference at 16 to 24 weeks

For this outcome, we found no difference between paroxetine and newer or non-conventional ADs (see Analysis 9.2).

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

In terms of patients who dropped out for any reason, we found no difference between paroxetine and newer or non-conventional ADs (see Analysis 10.3).

3.11 Failure to complete due to inefficacy

No difference was found between paroxetine and newer or non-conventional ADs in terms of discontinuation due to inefficacy (see Analysis 11.3).

3.12 Failure to complete due to side effects

In terms of patients who dropped out due to side effects, we found a difference between paroxetine and reboxetine (OR: 0.38, 95% CI 0.17 to 0.86, NNTh = 16, 95% CI 10 to 30, 3 RCTs, 1375 participants) in favour of paroxetine; and a difference between paroxetine and tianeptine (OR: 3.38, 95% CI 1.31 to 8.71, NNTh = 13, 95% CI 7 to 47, 1 RCT, 327 participants) in favour of tianeptine (see Analysis 12.3).

Secondary outcome: Tolerability
3.13 Total number of patients experiencing at least some side effects

There was evidence that paroxetine was less well tolerated than hypericum (OR: 2.60, 95% CI 1.51 to 4.46, NNTh = 5, 95% CI 3 to 10, 1 RCT, 251 participants) (see Analysis 13.3).

3.14 Number of patients experiencing specific side effects

(a) Sleepiness/drowsiness. We found a difference in favour of bupropion (OR: 7.63, 95% CI 2.51 to 23.16, NNTh = 5, 95% CI 4 to 9, 2 RCTs, 240 participants) and in favour of reboxetine (OR: 2.66, 95% CI 1.45 to 4.89, NNTh = 13, 95% CI 9 to 22, 3 RCTs, 1375 participants) over paroxetine (see Analysis 79.3).

(b) Insomnia. There was evidence that paroxetine was associated with a lower rate of insomnia than reboxetine (OR: 0.48, 95% CI 0.31 to 0.74, NNTh = 8, 95% CI 6 to 11, 3 RCTs, 1375 participants) (see Analysis 54.3).

(c) Dry mouth. Paroxetine was associated with a lower rate of dry mouth than reboxetine (OR: 0.35, 95% CI 0.27 to 0.45, NNTh = 5, 95% CI 4 to 6, 3 RCTs, 1375 participants). By contrast, we found a difference in favour of hypericum (OR: 2.62, 95% CI 1.36 to 5.04, NNTh = 7, 95% CI 4 to 19, 1 RCT, 251 participants) over paroxetine (see Analysis 38.3).

(d) Constipation. Paroxetine was associated with a lower rate of constipation than reboxetine (OR: 0.48, 95% CI 0.36 to 0.63, NNTh = 9, 95% CI 7 to 15, 3 RCTs, 1375 participants) (see Analysis 31.3).

(e) Urination/Urogenital problems. There was evidence in favour of paroxetine over reboxetine, in particular for dysuria (OR: 0.16, 95% CI 0.04 to 0.75, NNTh = 42, 95% CI 25 to 151, 2 RCTs, 855 participants) (see Analysis 90.2) and urinary retention (OR: 0.28, 95% CI 0.14 to 0.54, NNTh = 22, 95% CI 15 to 40, 3 RCTs, 1375 participants) (see Analysis 90.4).

(f) Hypotension. We found a difference in favour of paroxetine over reboxetine (OR: 0.37, 95% CI 0.19 to 0.75, NNTh = 19, 95% CI 13 to 36, 3 RCTs, 1375 participants) (see Analysis 50.3).

(g) Agitation/anxiety. We found no difference between paroxetine and newer or non-conventional ADs (see Analysis 18.3).

(h) Suicide wishes/gestures/attempts. We found no difference between paroxetine and newer or non-conventional ADs (see Analysis 96.1; Analysis 96.3).

(i) Completed suicide. We found no difference between paroxetine and newer or non-conventional ADs (see Analysis 96.2) .

(j) Vomiting/nausea. Paroxetine was associated with a higher rate of vomiting/nausea than agomelatine (OR: 6.81, 95% CI 2.31 to 20.14, NNTh = 7, 95% CI 5 to 14, 1 RCT, 284 participants), amisulpride (OR: 7.13, 95% CI 2.06 to 24.68, NNTh = 9, 95% CI 6 to 19, 1 RCT, 277 participants), hypericum (OR: 2.58, 95% CI 1.13 to 5.88, NNTh = 11, 95% CI 6 to 65, 1 RCT, 251 participants), mirtazapine (OR: 3.03, 95% CI 1.91 to 4.82, NNTh = 8, 95% CI 6 to 14, 3 RCTs, 726 participants), reboxetine (OR: 2.07, 95% CI 1.60 to 2.69, NNTh = 8, 95% CI 6 to 12, 3 RCTs, 1375 participants) and tianeptine (OR: 2.54, 95% CI 1.38 to 4.67, NNTh = 14, 95% CI 9 to 38, 2 RCTs, 604 participants). By contrast, paroxetine was better than duloxetine (OR: 0.68, 95% CI 0.52 to 0.88, NNTh = 34, 95% CI 14 to 78, 5 RCTs, 1573 participants) (see Analysis 59.3).

(k) Diarrhoea. We found that paroxetine was associated with a higher rate of diarrhoea than bupropion (OR: 3.03, 95% CI 1.35 to 6.84, NNTh = 8, 95% CI 5 to 25, 2 RCTs, 240 participants) and reboxetine (OR: 3.45, 95% CI 2.31 to 5.15, NNTh = 9, 95% CI 7 to 13, 3 RCTs, 1375 participants). Moreover, a trend in favour of hypericum over paroxetine (OR: 2.10, 95% CI 1.00 to 4.44, 1 RCT, 251 participants) was found (see Analysis 36.3).

(l) Other side effects. Other statistically significant side effects are reported in Table 1.

Subgroup analyses

1. Paroxetine dosing

The great majority of studies used paroxetine within the standard dose range of 20-40 mg/day. Therefore, it was not meaningful to carry out this pre-planned subgroup analysis.

2. Comparator dosing

All comparator doses were within the therapeutic range. Due to the small number of trials outside the therapeutic range, it was not considered meaningful to carry out this pre-planned subgroup analysis.

3. Depression severity

The great majority of studies reported a mean baseline score corresponding to moderate to severe major depression. Therefore, it was not meaningful to carry out this pre-planned subgroup analysis.

4. Treatment settings

Results from this subgroup analysis did not materially change the main findings (full details available on request from authors).

5. Elderly patients

Results from this subgroup analysis did not materially change the main findings (full details available on request from authors).

Sensitivity analysis

1. Excluding trials with unclear concealment of random allocation and/or unclear double blinding

Although technically possible to carry out these sensitivity analyses, they were not performed, because they would not have contributed useful information due to the small number of studies (only seven out of 115 trials) reporting clear details on concealment of random allocation (Baldwin 2006; Boulenger 2006; Gallen 2001; Higuchi 2009; M/2020/0047; M/2020/0052; Szegedi 2005).

2. Excluding trials whose dropout rate was greater than 20%

It was not meaningful to carry out this pre-planned sensitivity analysis.

3. Performing the worst- and best-case scenario analyses

Results from these sensitivity analyses did not materially change the main findings (full details available on request from authors).

4. Excluding trials for which the imputation methods were used

Excluding trials for which the SDs had to be borrowed from other trials, results for all comparisons did not materially change.

5. Examination of “wish bias” and exclusion of studies funded by the pharmaceutical company marketing paroxetine

These pre-planned sensitivity analyses were not carried out because we found only a few studies per comparison.

6. Excluding studies funded by the pharmaceutical company marketing paroxetine

These pre-planned sensitivity analyses were not carried out because we found only a few studies per comparison.

Assessment of heterogeneity

For primary outcomes (response rate at endpoint), we found I2 indicative of substantial heterogeneity level (I2 between 50 and 90%) in the comparison between paroxetine and mianserin (I2 = 61%), and between paroxetine and venlafaxine (I2 = 76%) . For the secondary outcome failure to remit at endpoint, substantial heterogeneity was found in the comparison between paroxetine and older ADs as a class (I2 = 79%) and between paroxetine and escitalopram (I2 = 81%). Moreover, for the secondary outcome standardized mean difference at endpoint, substantial heterogeneity was found in the comparison between paroxetine and clomipramine (I2 = 78%) and between paroxetine and escitalopram (I2 = 78%). For the outcome failure to complete (any cause), substantial heterogeneity was found in the comparisons between paroxetine and lofepramine (I2 = 68%), sertraline (I2 = 69%) and reboxetine (I2 = 65%). For the outcome failure to complete (due to side effects) heterogeneity was found in the comparison between paroxetine and maprotiline (I2 = 84%), fluvoxamine (I2 = 75%) and reboxetine (I2 = 71%) . For the secondary outcome failure to complete (due to inefficacy), substantial heterogeneity was found in the comparison between paroxetine and tianeptine (I2 = 74%).

Assessment of publication bias

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

Discussion

Summary of main results

The present systematic review included a total of 115 randomised controlled trials (RCTs), involving 26,134 participants. The included studies did not report all the outcomes that were pre-specified in the protocol and for some comparisons only a small number of trials provided data. Overall, we detected differences between paroxetine and some comparator ADs in terms of efficacy, acceptability and tolerability. For the primary outcome, response rate, paroxetine was less effective than citalopram at endpoint. In head-to-head comparisons with newer or non-conventional ADs, we found a difference in favour of paroxetine over reboxetine and in favour of mirtazapine over paroxetine in the early phase. For the secondary outcome remission rate, we found a difference in favour of clomipramine, hypericum, mirtazapine and venlafaxine over paroxetine. For the secondary outcome acceptability, paroxetine was better than reboxetine and amitriptyline (dropouts due to side effects) and better than clomipramine, imipramine and than older ADs as a class (dropouts due to side effects and dropouts due to any cause). By contrast, paroxetine was associated with a higher rate of dropouts due to side effects than fluoxetine and tianeptine. For the secondary outcome tolerability - number of patients experiencing at least some side effects - paroxetine was better than amitriptyline, imipramine and older ADs as a class, and worse than hypericum.

Overall completeness and applicability of evidence

All studies included in the present review recruited participants with a formal diagnosis of depression according to operationalised diagnostic criteria such as DSM-III or DSM-IV criteria, and therefore there was considerable homogeneity in the study populations. However, we have to consider that the majority of included studies were short in duration and some analyses were underpowered to demonstrate clinically meaningful differences between treatments. There was also considerable variation in the type of control medication used in the trials, and in some cases trials did not provide data for all the outcomes specified in the protocol, thus limiting the overall completeness of evidence. Another weakness of this analysis is that different subgroups of studies provided data for each efficacy and acceptability analyses, therefore raising the possibility of outcome reporting bias (Furukawa 2007).

The great majority of included trials were conducted in developed countries (Europe, United States, Canada) and this issue may be of limit in the application of these results in other countries of the world. Moreover, even though we collected a considerable amount of data on efficacy and acceptability, for some comparisons only a few trials were identified. In consequence, the reader is left with the decision of whether the findings from trials carried out in developed countries with standardized methods can be translated to routine clinical practice.

It has long been argued that placebo-controlled trials are required to adequately demonstrate the efficacy of novel antidepressant drugs (Cipriani 2009), however, in the present review we focused only on the comparison between paroxetine and other active treatments. The background logic that guided the development of the present review was based on two considerations. First, the efficacy of paroxetine versus placebo has already been quantified in a systematic review of published and unpublished studies (Barbui 2008); second, 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 paroxetine with another active treatment, as we reasoned that clinicians need to know how paroxetine, a reference AD agent, compares with a selection of possible comparator ADs. Although the search was thorough, and we did our very best to retrieve as much data as possible (through asking pharmaceutical companies and study authors to supply all available information and searching the GSK website to retrieve unpublished data), it is still possible that there are unpublished studies that have not been identified. Of consequence, we can assume that data from some trials are still lacking, most of which are likely to be studies with negative findings. We are also aware of the possibility that a number of further RCTs comparing paroxetine with other antidepressant drugs are currently being conducted and will be included in future updates of this review.

Quality of the evidence

The 'Risk of bias' assessment is crucial in influencing the results' interpretation and deserves therefore due attention. All included studies were RCTs and were very similar in design and conduct. Using high-quality research evidence is relevant to review results and to speed up the translation of research in a way that really responds to clinically relevant questions. However, the quality of RCTs is not easy to assess. Even though RCTs are the design of choice for evaluating the efficacy and acceptability of healthcare interventions (Jüni 2001; Purgato 2010), the evidence upon which the findings of this review are based is relatively poor as evaluated with the Cochrane 'Risk of bias' tool, and this is also reflected in our grading within the 'Summary of findings' tables. For example, allocation concealment and blinding of outcome assessment were "unclear" in the great majority of included studies and there is evidence that non-blinded assessors in RCTs might generate biased results (Hróbjartsson 2013). The great majority of studies included in our review were described as "double-blind", but information on the procedure followed to guarantee the blindness, and if blindness was successful was not reported in many cases. The investigators' and participants' belief about what treatment the participant is taking is a crucial issue that could influence the trIal's results. Also, the reporting of outcomes was often unclear or incomplete (for example, many RCTs did not report SDs) and the figures used to report or summarise the analyses were not immediately understandable. However, we have to consider that the scant information about allocation concealment may be a matter of reporting in the text than a real defect in the study design. The quality of evidence evaluated with the GRADE methodology (within-study risk of bias, directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias) was in general, from moderate to low.

Potential biases in the review process

Some possible limitations of this review should be noted and this means that the interpretation of results should remain tentative.

Although the search was thorough, it is possible that there are still unpublished studies which have not been identified. Moreover, the search date is September 2012 and there are a number of studies classified as "awaiting assessment", the eligibility of which has yet to be determined and the impact of which on the results of the review is uncertain.

It is important to bear in mind that the majority of the included studies were funded by the pharmaceutical industry;Hamilton 1960.

To assess efficacy, we used rating scales administered by clinicians or expert assessors. Even though both the Hamilton rating scale for depression (HDRS) and Montgomery and Asberg Depression Rating Scale (MADRS) are standardized tools commonly used in antidepressant trials, they are all potentially prone to observer bias. Self-administered questionnaires were not used in the included studies, so this might represent a limitation of the methods used in the primary studies of the present review.

In this review we decided to consider the response rate as the primary outcome 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 partial response (without remission). Thus, one important limitation of the included trials (and consequently of the present review) is that only a few studies reported remission rates, underpowering the analysis and undermining the possibility to find significant differences between comparisons. Moreover, outcomes of clear relevance to patients and clinicians, in particular, patients’ and their carers’ attitudes to treatment, and the patient's ability to return to work and resume normal social functioning, were not reported in the included studies.

Agreements and disagreements with other studies or reviews

Even though it is a matter of ongoing discussion in the scientific literature (Gartlehner 2011), there is now robust evidence that there are statistically and clinically significant differences among antidepressants (Cipriani 2009). Results from this review suggest some differences in terms of efficacy, acceptability and tolerability between paroxetine and certain ADs, and might contribute to developing and keeping up to date an evidence-based hierarchy of antidepressants to be used by clinicians (both specialists and general practitioners) when prescribing an antidepressant drug for moderate to severe acute major depression.

Authors' conclusions

Implications for practice

The effects we have found in terms of efficacy, acceptability and tolerability of paroxetine compared with certain antidepressants (ADs), are of generally moderate quality. Data from the present review suggest some possible differences between paroxetine and other ADs, but the clinical meaning of these differences is uncertain, and no definitive implications for clinical practice can be drawn. 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.

Implications for research

Results described in this systematic review come from evidence assessed as of low or moderate quality according to the GRADE methodology, a tool providing outcome-specific information concerning the overall quality of evidence from each included study in the comparison and the magnitude of effect of the interventions examined. Moreover, in many cases studies were 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. Often, patients with medical and psychiatric comorbidity or taking concomitant medication are excluded. Moreover, it is known that economic support by drug manufacturers can strongly influence progress of research and its results. Consequently, there is a risk that these studies do not provide sufficient and adequate information to clinicians in real-world settings. Studies should be conducted following high methodological standards and with the primary intent of providing clinicians with useful practical data regarding the comparative effectiveness of marketed medications, and consider rating scales but also pragmatic outcome measures (for example hospitalisations, return to work, social functioning and so on). If not, there is a risk that research will be guided only by economic interests instead of being based on clinical grounds.

Moreover, when dealing with summary statistics, the quality and the completeness of information is important. Meta-analyses of poor quality studies may be seriously misleading (Savović 2012), because the bias associated with defects in the conduct of primary studies (randomised trials) can seriously affect the overall estimate of intervention. Systematic review authors (not only within The Cochrane Collaboration) should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias (Wood 2008).

Acknowledgements

We would like to thank the CCDAN Editorial Team for their support, information and advice.

We also would like to thank all authors that provided additional data to be used in the present report and especially Drs. Jonathan Davidson, Stuart Montgomery and David Baldwin.

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 therein are those of the review authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

Comparison 1. Failure to respond at endpoint (6 - 12 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs344647Odds Ratio (M-H, Random, 95% CI)1.04 [0.92, 1.17]
1.1 versus amitriptyline131671Odds Ratio (M-H, Random, 95% CI)1.12 [0.92, 1.37]
1.2 versus clomipramine41273Odds Ratio (M-H, Random, 95% CI)0.92 [0.73, 1.15]
1.3 versus desipramine157Odds Ratio (M-H, Random, 95% CI)1.90 [0.66, 5.46]
1.4 versus dothiepin1134Odds Ratio (M-H, Random, 95% CI)1.43 [0.73, 2.83]
1.5 versus imipramine6587Odds Ratio (M-H, Random, 95% CI)0.84 [0.57, 1.24]
1.6 versus lofepramine2228Odds Ratio (M-H, Random, 95% CI)0.79 [0.47, 1.34]
1.7 versus maprolitine3429Odds Ratio (M-H, Random, 95% CI)1.24 [0.84, 1.82]
1.8 versus mianserin4268Odds Ratio (M-H, Random, 95% CI)1.30 [0.56, 3.05]
2 Paroxetine versus other SSRIs17 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)1.54 [1.04, 2.28]
2.2 versus escitalopram2784Odds Ratio (M-H, Random, 95% CI)1.12 [0.76, 1.65]
2.3 versus fluoxetine102353Odds Ratio (M-H, Random, 95% CI)0.98 [0.77, 1.24]
2.4 versus fluvoxamine3261Odds Ratio (M-H, Random, 95% CI)1.19 [0.72, 1.94]
2.5 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)1.21 [0.85, 1.73]
3 Paroxetine versus newer or non-conventional ADs27 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)1.25 [0.78, 2.01]
3.2 versus amisulpride1277Odds Ratio (M-H, Random, 95% CI)0.65 [0.36, 1.15]
3.3 versus bupropion1100Odds Ratio (M-H, Random, 95% CI)0.73 [0.30, 1.79]
3.4 versus duloxetine61821Odds Ratio (M-H, Random, 95% CI)0.89 [0.70, 1.14]
3.5 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)1.60 [0.95, 2.69]
3.6 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)0.93 [0.59, 1.47]
3.7 versus mirtazapine4766Odds Ratio (M-H, Random, 95% CI)1.20 [0.90, 1.61]
3.8 versus nefazodone140Odds Ratio (M-H, Random, 95% CI)0.31 [0.07, 1.25]
3.9 versus reboxetine31369Odds Ratio (M-H, Random, 95% CI)0.82 [0.66, 1.02]
3.10 versus tianeptine3648Odds Ratio (M-H, Random, 95% CI)1.04 [0.71, 1.53]
3.11 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)0.71 [0.21, 2.41]
3.12 versus venlafaxine4747Odds Ratio (M-H, Random, 95% CI)1.10 [0.58, 2.11]
Analysis 1.1.

Comparison 1 Failure to respond at endpoint (6 - 12 weeks), Outcome 1 Paroxetine versus older ADs.

Analysis 1.2.

Comparison 1 Failure to respond at endpoint (6 - 12 weeks), Outcome 2 Paroxetine versus other SSRIs.

Analysis 1.3.

Comparison 1 Failure to respond at endpoint (6 - 12 weeks), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 2. Failure to respond (at 1 - 4 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs4526Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.61, 1.33]
1.1 versus amitriptyline1153Odds Ratio (M-H, Fixed, 95% CI)1.06 [0.52, 2.15]
1.2 versus clomipramine192Odds Ratio (M-H, Fixed, 95% CI)0.58 [0.25, 1.37]
1.3 versus imipramine1159Odds Ratio (M-H, Fixed, 95% CI)1.43 [0.61, 3.33]
1.4 versus lofepramine1122Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.35, 1.55]
2 Paroxetine versus SSRIs3 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 versus fluvoxamine3281Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.41, 1.24]
3 Paroxetine versus newer or non-conventional ADs7 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)2.39 [1.42, 4.02]
3.2 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.66 [0.50, 0.87]
3.3 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)0.54 [0.25, 1.19]
Analysis 2.1.

Comparison 2 Failure to respond (at 1 - 4 weeks), Outcome 1 Paroxetine versus older ADs.

Analysis 2.2.

Comparison 2 Failure to respond (at 1 - 4 weeks), Outcome 2 Paroxetine versus SSRIs.

Analysis 2.3.

Comparison 2 Failure to respond (at 1 - 4 weeks), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 3. Failure to respond (at 16 - 24 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus SSRIs1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 versus escitalopram1459Odds Ratio (M-H, Fixed, 95% CI)1.36 [0.87, 2.12]
2 Paroxetine versus newer or non-conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus mirtazapine1197Odds Ratio (M-H, Random, 95% CI)1.41 [0.81, 2.48]
2.2 versus nefazodone140Odds Ratio (M-H, Random, 95% CI)0.64 [0.17, 2.38]
Analysis 3.1.

Comparison 3 Failure to respond (at 16 - 24 weeks), Outcome 1 Paroxetine versus SSRIs.

Analysis 3.2.

Comparison 3 Failure to respond (at 16 - 24 weeks), Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 4. Failure to remit at endpoint (6 - 12 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs3401Odds Ratio (M-H, Random, 95% CI)1.23 [0.49, 3.07]
1.1 versus clomipramine1120Odds Ratio (M-H, Random, 95% CI)3.39 [1.50, 7.65]
1.2 versus imipramine1159Odds Ratio (M-H, Random, 95% CI)0.75 [0.39, 1.43]
1.3 versus lofepramine1122Odds Ratio (M-H, Random, 95% CI)0.80 [0.38, 1.66]
2 Paroxetine versus other SSRIs7 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus escitalopram2784Odds Ratio (M-H, Random, 95% CI)1.15 [0.60, 2.22]
2.2 versus fluvoxamine3261Odds Ratio (M-H, Random, 95% CI)0.78 [0.44, 1.38]
2.3 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)0.94 [0.67, 1.34]
3 Paroxetine versus newer or non-conventional ADs20 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)1.27 [0.75, 2.14]
3.2 versus amisulpride1277Odds Ratio (M-H, Random, 95% CI)0.85 [0.49, 1.46]
3.3 versus duloxetine61821Odds Ratio (M-H, Random, 95% CI)0.98 [0.80, 1.19]
3.4 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)1.84 [1.11, 3.06]
3.5 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)0.92 [0.57, 1.49]
3.6 versus mirtazapine4766Odds Ratio (M-H, Random, 95% CI)1.52 [1.13, 2.06]
3.7 versus tianeptine144Odds Ratio (M-H, Random, 95% CI)0.66 [0.18, 2.36]
3.8 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)1.06 [0.47, 2.38]
3.9 versus venlafaxine4807Odds Ratio (M-H, Random, 95% CI)1.57 [1.08, 2.29]
Analysis 4.1.

Comparison 4 Failure to remit at endpoint (6 - 12 weeks), Outcome 1 Paroxetine versus older ADs.

Analysis 4.2.

Comparison 4 Failure to remit at endpoint (6 - 12 weeks), Outcome 2 Paroxetine versus other SSRIs.

Analysis 4.3.

Comparison 4 Failure to remit at endpoint (6 - 12 weeks), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 5. Failure to remit (at 1 - 4 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs2279Odds Ratio (M-H, Random, 95% CI)2.38 [0.38, 14.85]
1.1 versus clomipramine1120Odds Ratio (M-H, Random, 95% CI)10.32 [0.54, 196.06]
1.2 versus imipramine1159Odds Ratio (M-H, Random, 95% CI)1.35 [0.45, 4.09]
2 Paroxetine versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluvoxamine3268Odds Ratio (M-H, Random, 95% CI)1.17 [0.41, 3.35]
3 Paroxetine versus newer or non-conventional ADs5 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus milnacipran141Odds Ratio (M-H, Random, 95% CI)0.62 [0.18, 2.13]
3.2 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)2.31 [1.04, 5.11]
3.3 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)0.68 [0.27, 1.73]
Analysis 5.1.

Comparison 5 Failure to remit (at 1 - 4 weeks), Outcome 1 Paroxetine versus older ADs.

Analysis 5.2.

Comparison 5 Failure to remit (at 1 - 4 weeks), Outcome 2 Paroxetine versus other SSRIs.

Analysis 5.3.

Comparison 5 Failure to remit (at 1 - 4 weeks), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 6. Failure to remit (at 16 - 24 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus newer or non-conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus mirtazapine1197Odds Ratio (M-H, Random, 95% CI)1.89 [1.01, 3.54]
1.2 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)1.06 [0.47, 2.38]
Analysis 6.1.

Comparison 6 Failure to remit (at 16 - 24 weeks), Outcome 1 Paroxetine versus newer or non-conventional ADs.

Comparison 7. Standardized mean difference at endpoint (6 - 12 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs344712Std. Mean Difference (IV, Random, 95% CI)0.01 [-0.08, 0.10]
1.1 versus amitriptyline131919Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.06, 0.20]
1.2 versus clomipramine51242Std. Mean Difference (IV, Random, 95% CI)0.14 [-0.21, 0.49]
1.3 versus doxepin2306Std. Mean Difference (IV, Random, 95% CI)-0.12 [-0.35, 0.10]
1.4 versus imipramine7572Std. Mean Difference (IV, Random, 95% CI)-0.10 [-0.37, 0.17]
1.5 versus lofepramine192Std. Mean Difference (IV, Random, 95% CI)-0.06 [-0.47, 0.35]
1.6 versus maprolitine2336Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.23, 0.20]
1.7 versus nortriptyline156Std. Mean Difference (IV, Random, 95% CI)0.20 [-0.32, 0.73]
1.8 versus mianserin3189Std. Mean Difference (IV, Random, 95% CI)-0.21 [-0.50, 0.07]
2 Paroxetine versus other SSRIs13 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 versus citalopram1201Std. Mean Difference (IV, Random, 95% CI)-0.16 [-0.44, 0.11]
2.2 versus escitalopram2772Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.26, 0.36]
2.3 versus fluoxetine82044Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.05, 0.12]
2.4 versus fluvoxamine158Std. Mean Difference (IV, Random, 95% CI)0.09 [-0.43, 0.60]
2.5 versus sertraline1353Std. Mean Difference (IV, Random, 95% CI)-0.13 [-0.34, 0.07]
3 Paroxetine versus newer or non-conventional ADs27 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 versus agomelatine41074Std. Mean Difference (IV, Random, 95% CI)-0.18 [-0.38, 0.02]
3.2 versus amisulpride1272Std. Mean Difference (IV, Random, 95% CI)-0.13 [-0.37, 0.10]
3.3 versus aprepitant (MK-869)1102Std. Mean Difference (IV, Random, 95% CI)-0.00 [-0.39, 0.39]
3.4 versus bupropion1132Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.38, 0.30]
3.5 versus duloxetine61481Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.06, 0.15]
3.6 versus hypericum1244Std. Mean Difference (IV, Random, 95% CI)0.35 [0.09, 0.60]
3.7 versus milnacipran1299Std. Mean Difference (IV, Random, 95% CI)-0.05 [-0.28, 0.18]
3.8 versus mirtazapine1246Std. Mean Difference (IV, Random, 95% CI)0.33 [0.08, 0.58]
3.9 versus nefazodone2235Std. Mean Difference (IV, Random, 95% CI)-0.12 [-0.37, 0.14]
3.10 versus reboxetine31291Std. Mean Difference (IV, Random, 95% CI)-0.10 [-0.21, 0.00]
3.11 versus tianeptine3586Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.12, 0.20]
3.12 versus trazodone1108Std. Mean Difference (IV, Random, 95% CI)-0.08 [-0.46, 0.30]
3.13 versus venlafaxine2411Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.13, 0.26]
Analysis 7.1.

Comparison 7 Standardized mean difference at endpoint (6 - 12 weeks), Outcome 1 Paroxetine versus older ADs.

Analysis 7.2.

Comparison 7 Standardized mean difference at endpoint (6 - 12 weeks), Outcome 2 Paroxetine versus other SSRIs.

Analysis 7.3.

Comparison 7 Standardized mean difference at endpoint (6 - 12 weeks), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 8. Standardized mean difference (at 1 - 4 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs7723Std. Mean Difference (IV, Random, 95% CI)0.19 [-0.02, 0.39]
1.1 versus amitriptyline4566Std. Mean Difference (IV, Random, 95% CI)0.14 [-0.02, 0.31]
1.2 versus clomipramine184Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.58, 0.28]
1.3 versus desipramine150Std. Mean Difference (IV, Random, 95% CI)0.86 [0.28, 1.44]
1.4 versus imipramine123Std. Mean Difference (IV, Random, 95% CI)0.21 [-0.61, 1.03]
2 Paroxetine versus other SSRIs1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 versus fluoxetine1132Std. Mean Difference (IV, Random, 95% CI)-0.03 [-0.37, 0.32]
3 Paroxetine versus newer or non-conventional ADs6 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 versus aprepitant (MK-869)1121Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.50, 0.21]
3.2 versus duloxetine2353Std. Mean Difference (IV, Random, 95% CI)0.12 [-0.09, 0.33]
3.3 versus reboxetine2805Std. Mean Difference (IV, Random, 95% CI)-0.17 [-0.31, -0.03]
3.4 versus tianeptine1246Std. Mean Difference (IV, Random, 95% CI)0.13 [-0.12, 0.38]
Analysis 8.1.

Comparison 8 Standardized mean difference (at 1 - 4 weeks), Outcome 1 Paroxetine versus older ADs.

Analysis 8.2.

Comparison 8 Standardized mean difference (at 1 - 4 weeks), Outcome 2 Paroxetine versus other SSRIs.

Analysis 8.3.

Comparison 8 Standardized mean difference (at 1 - 4 weeks), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 9. Standardized mean difference (at 16 - 24 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus SSRIs1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 versus sertraline1353Std. Mean Difference (IV, Random, 95% CI)0.01 [-0.20, 0.22]
2 Paroxetine versus newer or non-conventional ADs1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 versus mirtazapine1177Std. Mean Difference (IV, Random, 95% CI)0.21 [-0.09, 0.51]
Analysis 9.1.

Comparison 9 Standardized mean difference (at 16 - 24 weeks), Outcome 1 Paroxetine versus SSRIs.

Analysis 9.2.

Comparison 9 Standardized mean difference (at 16 - 24 weeks), Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 10. Failure to complete (any cause)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs436777Odds Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.96]
1.1 versus amitriptyline192908Odds Ratio (M-H, Random, 95% CI)0.86 [0.70, 1.06]
1.2 versus clomipramine41273Odds Ratio (M-H, Random, 95% CI)0.67 [0.52, 0.87]
1.3 versus dothiepin3499Odds Ratio (M-H, Random, 95% CI)1.25 [0.84, 1.87]
1.4 versus imipramine91268Odds Ratio (M-H, Random, 95% CI)0.65 [0.50, 0.85]
1.5 versus lofepramine2228Odds Ratio (M-H, Random, 95% CI)0.94 [0.31, 2.80]
1.6 versus maprolitine3429Odds Ratio (M-H, Random, 95% CI)1.05 [0.49, 2.25]
1.7 versus mianserin292Odds Ratio (M-H, Random, 95% CI)0.84 [0.21, 3.41]
1.8 versus nortriptyline180Odds Ratio (M-H, Random, 95% CI)1.30 [0.50, 3.42]
2 Paroxetine versus other SSRIs19 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)0.99 [0.61, 1.60]
2.2 versus escitalopram2784Odds Ratio (M-H, Random, 95% CI)1.47 [0.77, 2.79]
2.3 versus fluoxetine122733Odds Ratio (M-H, Random, 95% CI)1.05 [0.89, 1.24]
2.4 versus fluvoxamine3261Odds Ratio (M-H, Random, 95% CI)0.96 [0.54, 1.72]
2.5 versus sertraline2426Odds Ratio (M-H, Random, 95% CI)1.37 [0.52, 3.60]
3 Paroxetine versus newer or non-conventional ADs29 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)0.99 [0.57, 1.71]
3.2 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)1.53 [0.76, 3.09]
3.3 versus bupropion2240Odds Ratio (M-H, Random, 95% CI)1.16 [0.62, 2.20]
3.4 versus duloxetine61821Odds Ratio (M-H, Random, 95% CI)0.97 [0.77, 1.23]
3.5 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)1.90 [0.98, 3.67]
3.6 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)1.26 [0.91, 1.74]
3.7 versus milnacipram2343Odds Ratio (M-H, Random, 95% CI)1.17 [0.67, 2.03]
3.8 versus nefazodone140Odds Ratio (M-H, Random, 95% CI)0.53 [0.11, 2.60]
3.9 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.78 [0.51, 1.19]
3.10 versus tianeptine3648Odds Ratio (M-H, Random, 95% CI)1.46 [0.75, 2.85]
3.11 versus venlafaxine61079Odds Ratio (M-H, Random, 95% CI)1.08 [0.82, 1.44]
Analysis 10.1.

Comparison 10 Failure to complete (any cause), Outcome 1 Paroxetine versus older ADs.

Analysis 10.2.

Comparison 10 Failure to complete (any cause), Outcome 2 Paroxetine versus other SSRIs.

Analysis 10.3.

Comparison 10 Failure to complete (any cause), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 11. Failure to complete (due to inefficacy)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs274436Odds Ratio (M-H, Random, 95% CI)1.22 [0.93, 1.61]
1.1 versus amitriptyline91191Odds Ratio (M-H, Random, 95% CI)1.20 [0.77, 1.86]
1.2 versus clomipramine41273Odds Ratio (M-H, Random, 95% CI)1.50 [0.76, 2.97]
1.3 versus dothiepin2405Odds Ratio (M-H, Random, 95% CI)0.59 [0.18, 1.96]
1.4 versus imipramine91268Odds Ratio (M-H, Random, 95% CI)1.27 [0.80, 2.02]
1.5 versus lofepramine2228Odds Ratio (M-H, Random, 95% CI)0.87 [0.13, 6.08]
1.6 versus maprolitine171Odds Ratio (M-H, Random, 95% CI)2.84 [0.11, 71.99]
2 Paroxetine versus other SSRIs13 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)1.75 [0.41, 7.43]
2.2 versus escitalopram2784Odds Ratio (M-H, Random, 95% CI)0.72 [0.09, 5.96]
2.3 versus fluoxetine82214Odds Ratio (M-H, Random, 95% CI)0.91 [0.60, 1.39]
2.4 versus fluvoxamine2180Odds Ratio (M-H, Random, 95% CI)1.00 [0.15, 6.93]
2.5 versus sertraline1192Odds Ratio (M-H, Random, 95% CI)0.53 [0.17, 1.65]
3 Paroxetine versus newer or non-conventional ADs19 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)1.15 [0.46, 2.87]
3.2 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.09]
3.3 versus duloxetine51557Odds Ratio (M-H, Random, 95% CI)1.05 [0.55, 2.00]
3.4 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.98]
3.5 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)0.63 [0.22, 1.83]
3.6 versus mirtazapine2451Odds Ratio (M-H, Random, 95% CI)0.41 [0.04, 4.58]
3.7 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.66 [0.20, 2.16]
3.8 versus tianeptine2371Odds Ratio (M-H, Random, 95% CI)1.22 [0.05, 27.06]
3.9 versus venlafaxine3774Odds Ratio (M-H, Random, 95% CI)0.75 [0.33, 1.66]
Analysis 11.1.

Comparison 11 Failure to complete (due to inefficacy), Outcome 1 Paroxetine versus older ADs.

Analysis 11.2.

Comparison 11 Failure to complete (due to inefficacy), Outcome 2 Paroxetine versus other SSRIs.

Analysis 11.3.

Comparison 11 Failure to complete (due to inefficacy), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 12. Failure to complete (due to side effects)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs345175Odds Ratio (M-H, Random, 95% CI)0.76 [0.63, 0.92]
1.1 versus amitriptyline121698Odds Ratio (M-H, Random, 95% CI)0.74 [0.56, 0.98]
1.2 versus clomipramine41273Odds Ratio (M-H, Random, 95% CI)0.59 [0.41, 0.84]
1.3 versus dothiepin2405Odds Ratio (M-H, Random, 95% CI)1.70 [0.78, 3.70]
1.4 versus imipramine91268Odds Ratio (M-H, Random, 95% CI)0.58 [0.43, 0.77]
1.5 versus lofepramine2228Odds Ratio (M-H, Random, 95% CI)1.19 [0.45, 3.15]
1.6 versus maprolitine2131Odds Ratio (M-H, Random, 95% CI)0.77 [0.01, 70.98]
1.7 versus mianserin292Odds Ratio (M-H, Random, 95% CI)2.26 [0.38, 13.50]
1.8 versus nortriptyline180Odds Ratio (M-H, Random, 95% CI)1.46 [0.43, 4.93]
2 Paroxetine versus other SSRIs17 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)1.15 [0.48, 2.78]
2.2 versus escitalopram2784Odds Ratio (M-H, Random, 95% CI)1.43 [0.51, 4.00]
2.3 versus fluoxetine112491Odds Ratio (M-H, Random, 95% CI)1.34 [1.06, 1.70]
2.4 versus fluvoxamine3261Odds Ratio (M-H, Random, 95% CI)1.16 [0.19, 7.16]
2.5 versus sertraline1192Odds Ratio (M-H, Random, 95% CI)1.94 [0.69, 5.48]
3 Paroxetine versus newer or non-conventional ADs24 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)0.84 [0.34, 2.04]
3.2 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)1.66 [0.67, 4.13]
3.3 versus bupropion2240Odds Ratio (M-H, Random, 95% CI)0.61 [0.24, 1.55]
3.4 versus duloxetine61821Odds Ratio (M-H, Random, 95% CI)0.84 [0.57, 1.25]
3.5 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)2.05 [0.60, 6.99]
3.6 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)1.17 [0.59, 2.33]
3.7 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)1.35 [0.83, 2.21]
3.8 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.38 [0.17, 0.86]
3.9 versus tianeptine1327Odds Ratio (M-H, Random, 95% CI)3.38 [1.31, 8.71]
3.10 versus venlafaxine5974Odds Ratio (M-H, Random, 95% CI)0.88 [0.50, 1.56]
Analysis 12.1.

Comparison 12 Failure to complete (due to side effects), Outcome 1 Paroxetine versus older ADs.

Analysis 12.2.

Comparison 12 Failure to complete (due to side effects), Outcome 2 Paroxetine versus other SSRIs.

Analysis 12.3.

Comparison 12 Failure to complete (due to side effects), Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 13. SE - Participants with at least one TEAE
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs416099Odds Ratio (M-H, Random, 95% CI)0.64 [0.53, 0.77]
1.1 versus amitriptyline162492Odds Ratio (M-H, Random, 95% CI)0.53 [0.39, 0.72]
1.2 versus clomipramine41273Odds Ratio (M-H, Random, 95% CI)0.56 [0.28, 1.10]
1.3 versus dothiepin2405Odds Ratio (M-H, Random, 95% CI)1.04 [0.61, 1.76]
1.4 versus imipramine91189Odds Ratio (M-H, Random, 95% CI)0.62 [0.42, 0.94]
1.5 versus lofepramine2228Odds Ratio (M-H, Random, 95% CI)1.25 [0.74, 2.12]
1.6 versus maprolitine2131Odds Ratio (M-H, Random, 95% CI)0.66 [0.28, 1.55]
1.7 versus mianserin5301Odds Ratio (M-H, Random, 95% CI)0.71 [0.41, 1.22]
1.8 versus nortriptyline180Odds Ratio (M-H, Random, 95% CI)1.46 [0.43, 4.93]
2 Paroxetine versus other SSRIs14 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)0.74 [0.46, 1.21]
2.2 versus escitalopram1454Odds Ratio (M-H, Random, 95% CI)1.28 [0.86, 1.91]
2.3 versus fluoxetine92255Odds Ratio (M-H, Random, 95% CI)0.94 [0.69, 1.28]
2.4 versus fluvoxamine3261Odds Ratio (M-H, Random, 95% CI)1.12 [0.42, 2.97]
3 Paroxetine versus newer or non-conventional ADs23 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)1.60 [0.99, 2.59]
3.2 versus amisulpride1277Odds Ratio (M-H, Random, 95% CI)1.49 [0.89, 2.50]
3.3 versus bupropion1140Odds Ratio (M-H, Random, 95% CI)1.60 [0.43, 5.92]
3.4 versus duloxetine61870Odds Ratio (M-H, Random, 95% CI)0.81 [0.64, 1.01]
3.5 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)2.60 [1.51, 4.46]
3.6 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)0.69 [0.41, 1.15]
3.7 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)1.07 [0.76, 1.50]
3.8 versus nefazodone1206Odds Ratio (M-H, Random, 95% CI)0.69 [0.34, 1.40]
3.9 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)1.08 [0.74, 1.58]
3.10 versus tianeptine2604Odds Ratio (M-H, Random, 95% CI)1.26 [0.89, 1.78]
3.11 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)0.68 [0.30, 1.55]
3.12 versus venlafaxine2200Odds Ratio (M-H, Random, 95% CI)1.01 [0.52, 1.95]
Analysis 13.1.

Comparison 13 SE - Participants with at least one TEAE, Outcome 1 Paroxetine versus older ADs.

Analysis 13.2.

Comparison 13 SE - Participants with at least one TEAE, Outcome 2 Paroxetine versus other SSRIs.

Analysis 13.3.

Comparison 13 SE - Participants with at least one TEAE, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 14. SE - Abnormal dreams
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus maprolitine171Odds Ratio (M-H, Random, 95% CI)2.84 [0.11, 71.99]
2 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)13.16 [0.69, 249.48]
3 Paroxetine versus newer or non-conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)4.93 [0.23, 103.64]
3.2 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)0.99 [0.33, 2.99]
Analysis 14.1.

Comparison 14 SE - Abnormal dreams, Outcome 1 Paroxetine versus older ADs.

Analysis 14.2.

Comparison 14 SE - Abnormal dreams, Outcome 2 Paroxetine versus other SSRIs.

Analysis 14.3.

Comparison 14 SE - Abnormal dreams, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 15. SE - Abnormal laboratory values
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Abnormal white blood cells1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus fluoxetine1138Odds Ratio (M-H, Random, 95% CI)0.34 [0.01, 8.45]
2 Leucocytosis1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus amitriptyline140Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 17.18]
3 ALT/AST increase2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus amitriptyline2262Odds Ratio (M-H, Random, 95% CI)2.13 [0.27, 16.88]
4 NOS1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus clomipramine183Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.42]
Analysis 15.1.

Comparison 15 SE - Abnormal laboratory values, Outcome 1 Abnormal white blood cells.

Analysis 15.2.

Comparison 15 SE - Abnormal laboratory values, Outcome 2 Leucocytosis.

Analysis 15.3.

Comparison 15 SE - Abnormal laboratory values, Outcome 3 ALT/AST increase.

Analysis 15.4.

Comparison 15 SE - Abnormal laboratory values, Outcome 4 NOS.

Comparison 16. SE - Abnormal thinking
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus newer or non-conventional ADs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus duloxetine2528Odds Ratio (M-H, Random, 95% CI)0.93 [0.16, 5.46]
1.2 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)1.18 [0.06, 24.15]
Analysis 16.1.

Comparison 16 SE - Abnormal thinking, Outcome 1 Paroxetine versus newer or non-conventional ADs.

Comparison 17. SE - Accidental injury
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus fluoxetine1573Odds Ratio (M-H, Random, 95% CI)1.02 [0.49, 2.12]
2 Paroxetine versus newer or non-conventional ADs5 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 versus duloxetine2528Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.37, 2.72]
2.2 versus reboxetine31375Odds Ratio (M-H, Fixed, 95% CI)1.74 [0.88, 3.43]
Analysis 17.1.

Comparison 17 SE - Accidental injury, Outcome 1 Paroxetine versus other SSRIs.

Analysis 17.2.

Comparison 17 SE - Accidental injury, Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 18. SE - Agitation/anxiety
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs152240Odds Ratio (M-H, Random, 95% CI)1.12 [0.67, 1.86]
1.1 versus amitriptyline61001Odds Ratio (M-H, Random, 95% CI)1.21 [0.36, 4.03]
1.2 versus clomipramine192Odds Ratio (M-H, Random, 95% CI)0.2 [0.01, 4.28]
1.3 versus dothiepin1271Odds Ratio (M-H, Random, 95% CI)2.52 [0.86, 7.35]
1.4 versus imipramine2282Odds Ratio (M-H, Random, 95% CI)0.63 [0.18, 2.16]
1.5 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)0.28 [0.01, 7.06]
1.6 versus maprolitine3429Odds Ratio (M-H, Random, 95% CI)0.95 [0.38, 2.39]
1.7 versus mianserin159Odds Ratio (M-H, Random, 95% CI)2.0 [0.17, 23.34]
2 Paroxetine versus other SSRIs8 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine5713Odds Ratio (M-H, Random, 95% CI)1.15 [0.75, 1.77]
2.2 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)2.15 [0.36, 12.76]
2.3 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)1.19 [0.66, 2.13]
3 Paroxetine versus newer or non-conventional ADs14 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)0.74 [0.19, 2.81]
3.2 versus bupropion2240Odds Ratio (M-H, Random, 95% CI)0.45 [0.19, 1.08]
3.3 versus duloxetine41095Odds Ratio (M-H, Random, 95% CI)0.82 [0.35, 1.91]
3.4 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)0.73 [0.16, 3.30]
3.5 versus mirtazapine2472Odds Ratio (M-H, Random, 95% CI)1.40 [0.63, 3.15]
3.6 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.74 [0.47, 1.17]
3.7 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.14]
Analysis 18.1.

Comparison 18 SE - Agitation/anxiety, Outcome 1 Paroxetine versus older ADs.

Analysis 18.2.

Comparison 18 SE - Agitation/anxiety, Outcome 2 Paroxetine versus other SSRIs.

Analysis 18.3.

Comparison 18 SE - Agitation/anxiety, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 19. SE - Akathisia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 versus amitriptyline121Odds Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 7.57]
2 Paroxetine versus newer or non-conventional ADs2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 versus reboxetine21050Odds Ratio (M-H, Fixed, 95% CI)1.37 [0.55, 3.44]
Analysis 19.1.

Comparison 19 SE - Akathisia, Outcome 1 Paroxetine versus older ADs.

Analysis 19.2.

Comparison 19 SE - Akathisia, Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 20. SE - Anorexia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus fluoxetine1138Odds Ratio (M-H, Random, 95% CI)3.90 [0.78, 19.50]
2 Paroxetine versus newer or non-conventional ADs10 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)2.83 [0.72, 11.15]
2.2 versus bupropion1100Odds Ratio (M-H, Random, 95% CI)6.13 [0.71, 52.93]
2.3 versus duloxetine41299Odds Ratio (M-H, Random, 95% CI)0.64 [0.39, 1.05]
2.4 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.71 [0.47, 1.08]
2.5 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.14]
Analysis 20.1.

Comparison 20 SE - Anorexia, Outcome 1 Paroxetine versus other SSRIs.

Analysis 20.2.

Comparison 20 SE - Anorexia, Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 21. SE - Anticholinergic
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 paroxetine versus older ADs3 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 versus amitriptyline2130Odds Ratio (M-H, Fixed, 95% CI)0.22 [0.07, 0.76]
1.2 versus clomipramine179Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.11, 0.86]
2 paroxerine versus other SSRIs2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 versus fluoxetine2296Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.31, 2.05]
Analysis 21.1.

Comparison 21 SE - Anticholinergic, Outcome 1 paroxetine versus older ADs.

Analysis 21.2.

Comparison 21 SE - Anticholinergic, Outcome 2 paroxerine versus other SSRIs.

Comparison 22. SE - Appetite decreased
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs4685Odds Ratio (M-H, Random, 95% CI)4.00 [1.65, 9.71]
1.1 versus amitriptyline126Odds Ratio (M-H, Random, 95% CI)12.79 [0.61, 266.66]
1.2 versus imipramine2361Odds Ratio (M-H, Random, 95% CI)2.45 [0.76, 7.90]
1.3 versus maprotiline1298Odds Ratio (M-H, Random, 95% CI)6.81 [1.50, 30.99]
2 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine1122Odds Ratio (M-H, Random, 95% CI)0.58 [0.20, 1.70]
3 Paroxetine versus newer or non-conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus duloxetine2752Odds Ratio (M-H, Random, 95% CI)1.09 [0.59, 2.01]
3.2 versus reboxetine1325Odds Ratio (M-H, Random, 95% CI)0.76 [0.20, 2.88]
Analysis 22.1.

Comparison 22 SE - Appetite decreased, Outcome 1 Paroxetine versus older ADs.

Analysis 22.2.

Comparison 22 SE - Appetite decreased, Outcome 2 Paroxetine versus other SSRIs.

Analysis 22.3.

Comparison 22 SE - Appetite decreased, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 23. SE - Appetite increased
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus newer or non-conventional ADs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus bupropion1100Odds Ratio (M-H, Random, 95% CI)0.29 [0.03, 2.93]
1.2 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)1.43 [0.22, 9.41]
Analysis 23.1.

Comparison 23 SE - Appetite increased, Outcome 1 Paroxetine versus newer or non-conventional ADs.

Comparison 24. SE - Asthenia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs17 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus amitriptyline5779Odds Ratio (M-H, Random, 95% CI)0.44 [0.12, 1.55]
1.2 versus dothiepin2405Odds Ratio (M-H, Random, 95% CI)1.58 [0.30, 8.47]
1.3 versus imipramine6680Odds Ratio (M-H, Random, 95% CI)1.29 [0.73, 2.28]
1.4 versus lofepramine1122Odds Ratio (M-H, Random, 95% CI)4.36 [0.47, 40.16]
1.5 versus maprolitine3429Odds Ratio (M-H, Random, 95% CI)0.76 [0.49, 1.16]
2 Paroxetine versus other SSRIs7 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)0.59 [0.33, 1.04]
2.2 versus fluoxetine51680Odds Ratio (M-H, Random, 95% CI)1.27 [0.91, 1.77]
2.3 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)0.51 [0.13, 1.95]
3 Paroxetine versus newer ADs13 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)1.47 [0.61, 3.58]
3.2 versus bupropion1140Odds Ratio (M-H, Random, 95% CI)4.25 [0.87, 20.80]
3.3 versus duloxetine31006Odds Ratio (M-H, Random, 95% CI)0.79 [0.45, 1.38]
3.4 versus nefazodone2246Odds Ratio (M-H, Random, 95% CI)1.15 [0.36, 3.62]
3.5 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)2.07 [1.19, 3.60]
3.6 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)0.99 [0.06, 16.03]
3.7 versus venlafaxine1361Odds Ratio (M-H, Random, 95% CI)0.46 [0.17, 1.23]
3.8 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)3.17 [0.13, 79.60]
Analysis 24.1.

Comparison 24 SE - Asthenia, Outcome 1 Paroxetine versus older ADs.

Analysis 24.2.

Comparison 24 SE - Asthenia, Outcome 2 Paroxetine versus other SSRIs.

Analysis 24.3.

Comparison 24 SE - Asthenia, Outcome 3 Paroxetine versus newer ADs.

Comparison 25. SE - Behaviour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Euphoria1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus reboxetine1520Odds Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.71]
2 Hostility1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus reboxetine1325Odds Ratio (M-H, Random, 95% CI)0.48 [0.04, 5.30]
3 Impulsive1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.14]
4 Irritability4557Odds Ratio (M-H, Random, 95% CI)1.34 [0.15, 12.23]
4.1 versus amitriptyline121Odds Ratio (M-H, Random, 95% CI)15.75 [1.42, 174.25]
4.2 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)0.19 [0.02, 1.63]
4.3 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)0.38 [0.02, 9.43]
4.4 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)3.0 [0.12, 74.28]
5 Paranoid reaction1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus maprolitine171Odds Ratio (M-H, Random, 95% CI)4.86 [0.23, 104.92]
6 Psychotic symptoms1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
6.1 versus fluvoxamine181Odds Ratio (M-H, Random, 95% CI)9.23 [0.48, 177.35]
Analysis 25.1.

Comparison 25 SE - Behaviour, Outcome 1 Euphoria.

Analysis 25.2.

Comparison 25 SE - Behaviour, Outcome 2 Hostility.

Analysis 25.3.

Comparison 25 SE - Behaviour, Outcome 3 Impulsive.

Analysis 25.4.

Comparison 25 SE - Behaviour, Outcome 4 Irritability.

Analysis 25.5.

Comparison 25 SE - Behaviour, Outcome 5 Paranoid reaction.

Analysis 25.6.

Comparison 25 SE - Behaviour, Outcome 6 Psychotic symptoms.

Comparison 26. SE - Body as a whole
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs6463Odds Ratio (M-H, Random, 95% CI)1.40 [0.83, 2.36]
1.1 versus amitriptyline2221Odds Ratio (M-H, Random, 95% CI)1.87 [1.08, 3.23]
1.2 versus clomipramine183Odds Ratio (M-H, Random, 95% CI)0.40 [0.11, 1.41]
1.3 versus mianserin133Odds Ratio (M-H, Random, 95% CI)2.5 [0.41, 15.29]
1.4 versus mianserin3126Odds Ratio (M-H, Random, 95% CI)1.29 [0.48, 3.52]
2 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine1242Odds Ratio (M-H, Random, 95% CI)1.57 [0.65, 3.78]
Analysis 26.1.

Comparison 26 SE - Body as a whole, Outcome 1 Paroxetine versus older ADs.

Analysis 26.2.

Comparison 26 SE - Body as a whole, Outcome 2 Paroxetine versus other SSRIs.

Comparison 27. SE - Bronchitis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus fluoxetine1138Odds Ratio (M-H, Random, 95% CI)0.19 [0.02, 1.71]
2 Paroxetine versus newer or non-conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus reboxetine2845Odds Ratio (M-H, Random, 95% CI)0.42 [0.06, 2.85]
Analysis 27.1.

Comparison 27 SE - Bronchitis, Outcome 1 Paroxetine versus other SSRIs.

Analysis 27.2.

Comparison 27 SE - Bronchitis, Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 28. SE - Cardiovascular system
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Syncope1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus maprolitine160Odds Ratio (M-H, Random, 95% CI)1.16 [0.21, 6.27]
2 NOS8693Odds Ratio (M-H, Random, 95% CI)0.73 [0.41, 1.31]
2.1 versus amitriptyline3242Odds Ratio (M-H, Random, 95% CI)1.01 [0.24, 4.31]
2.2 versus clomipramine183Odds Ratio (M-H, Random, 95% CI)0.69 [0.20, 2.40]
2.3 versus fluoxetine1242Odds Ratio (M-H, Random, 95% CI)0.85 [0.32, 2.28]
2.4 versus mianserin3126Odds Ratio (M-H, Random, 95% CI)0.24 [0.05, 1.06]
Analysis 28.1.

Comparison 28 SE - Cardiovascular system, Outcome 1 Syncope.

Analysis 28.2.

Comparison 28 SE - Cardiovascular system, Outcome 2 NOS.

Comparison 29. SE - Chills
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus newer or non-conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.37 [0.18, 0.74]
Analysis 29.1.

Comparison 29 SE - Chills, Outcome 1 Paroxetine versus newer or non-conventional ADs.

Comparison 30. SE - Confusion
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs5738Odds Ratio (M-H, Random, 95% CI)0.48 [0.18, 1.30]
1.1 versus amitriptyline1153Odds Ratio (M-H, Random, 95% CI)0.96 [0.13, 7.00]
1.2 versus clomipramine192Odds Ratio (M-H, Random, 95% CI)1.05 [0.14, 7.76]
1.3 versus dothiepin1271Odds Ratio (M-H, Random, 95% CI)0.14 [0.02, 1.12]
1.4 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)0.17 [0.01, 3.53]
1.5 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)0.57 [0.05, 6.42]
2 Paroxetine versus newer or non-conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus nefazodone140Odds Ratio (M-H, Random, 95% CI)4.75 [0.48, 46.91]
2.2 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)1.58 [0.20, 12.39]
Analysis 30.1.

Comparison 30 SE - Confusion, Outcome 1 Paroxetine versus older ADs.

Analysis 30.2.

Comparison 30 SE - Confusion, Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 31. SE - Constipation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs263934Odds Ratio (M-H, Random, 95% CI)0.49 [0.40, 0.60]
1.1 versus amitriptyline101146Odds Ratio (M-H, Random, 95% CI)0.61 [0.37, 0.99]
1.2 versus clomipramine21111Odds Ratio (M-H, Random, 95% CI)0.57 [0.38, 0.85]
1.3 versus dothiepin1271Odds Ratio (M-H, Random, 95% CI)0.57 [0.32, 0.99]
1.4 versus imipramine7633Odds Ratio (M-H, Random, 95% CI)0.40 [0.25, 0.63]
1.5 versus lofepramine2228Odds Ratio (M-H, Random, 95% CI)0.49 [0.20, 1.23]
1.6 versus maprolitine3429Odds Ratio (M-H, Random, 95% CI)0.31 [0.17, 0.55]
1.7 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)0.22 [0.01, 4.73]
2 Paroxetine versus other SSRIs7 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus escitalopram1454Odds Ratio (M-H, Random, 95% CI)2.52 [0.87, 7.29]
2.2 versus fluoxetine31001Odds Ratio (M-H, Random, 95% CI)2.71 [1.47, 5.01]
2.3 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)2.15 [0.36, 12.76]
2.4 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)3.26 [1.73, 6.14]
3 Paroxetine versus newer or non-conventional ADs16 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus bupropion2240Odds Ratio (M-H, Random, 95% CI)2.00 [0.59, 6.81]
3.2 versus duloxetine51573Odds Ratio (M-H, Random, 95% CI)0.74 [0.46, 1.18]
3.3 versus mirtazapine2529Odds Ratio (M-H, Random, 95% CI)0.93 [0.51, 1.69]
3.4 versus nefazodone140Odds Ratio (M-H, Random, 95% CI)3.35 [0.32, 35.36]
3.5 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.48 [0.36, 0.63]
3.6 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)7.10 [0.36, 138.80]
3.7 versus venlafaxine2466Odds Ratio (M-H, Random, 95% CI)1.16 [0.33, 4.12]
Analysis 31.1.

Comparison 31 SE - Constipation, Outcome 1 Paroxetine versus older ADs.

Analysis 31.2.

Comparison 31 SE - Constipation, Outcome 2 Paroxetine versus other SSRIs.

Analysis 31.3.

Comparison 31 SE - Constipation, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 32. SE - Cough
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.29]
2 Paroxetine versus newer or non-conventional ADs5 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus duloxetine2528Odds Ratio (M-H, Random, 95% CI)1.22 [0.43, 3.42]
2.2 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)1.32 [0.50, 3.48]
Analysis 32.1.

Comparison 32 SE - Cough, Outcome 1 Paroxetine versus older ADs.

Analysis 32.2.

Comparison 32 SE - Cough, Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 33. SE - Delirium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus fluoxetine190Odds Ratio (M-H, Random, 95% CI)3.07 [0.12, 77.32]
2 Paroxetine versus older ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus clomipramine192Odds Ratio (M-H, Random, 95% CI)0.2 [0.01, 4.28]
Analysis 33.1.

Comparison 33 SE - Delirium, Outcome 1 Paroxetine versus other SSRIs.

Analysis 33.2.

Comparison 33 SE - Delirium, Outcome 2 Paroxetine versus older ADs.

Comparison 34. SE - Depersonalization
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus amitriptyline121Odds Ratio (M-H, Random, 95% CI)5.53 [0.23, 130.34]
1.2 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)2.63 [0.10, 66.00]
2 Paroxetine versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine1176Odds Ratio (M-H, Random, 95% CI)2.97 [0.12, 73.81]
2.2 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)0.46 [0.08, 2.75]
3 Paroxetine versus newer or non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)3.0 [0.12, 74.28]
Analysis 34.1.

Comparison 34 SE - Depersonalization, Outcome 1 Paroxetine versus older ADs.

Analysis 34.2.

Comparison 34 SE - Depersonalization, Outcome 2 Paroxetine versus other SSRIs.

Analysis 34.3.

Comparison 34 SE - Depersonalization, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 35. SE - Depression
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs2323Odds Ratio (M-H, Random, 95% CI)0.92 [0.09, 9.38]
1.1 versus amitriptyline1217Odds Ratio (M-H, Random, 95% CI)3.0 [0.12, 74.46]
1.2 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)0.28 [0.01, 7.06]
2 Paroxetine versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine41128Odds Ratio (M-H, Random, 95% CI)0.97 [0.45, 2.09]
3 Paroxetine versus newer or non-conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)1.41 [0.39, 5.13]
3.2 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)0.76 [0.23, 2.46]
Analysis 35.1.

Comparison 35 SE - Depression, Outcome 1 Paroxetine versus older ADs.

Analysis 35.2.

Comparison 35 SE - Depression, Outcome 2 Paroxetine versus other SSRIs.

Analysis 35.3.

Comparison 35 SE - Depression, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 36. SE - Diarrhoea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs131743Odds Ratio (M-H, Random, 95% CI)2.41 [1.56, 3.73]
1.1 versus amitriptyline5653Odds Ratio (M-H, Random, 95% CI)1.91 [0.88, 4.14]
1.2 versus dothiepin1271Odds Ratio (M-H, Random, 95% CI)3.47 [1.23, 9.75]
1.3 versus imipramine2159Odds Ratio (M-H, Random, 95% CI)1.88 [0.58, 6.02]
1.4 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)6.36 [0.32, 126.19]
1.5 versus maprolitine2358Odds Ratio (M-H, Random, 95% CI)2.94 [1.34, 6.47]
1.6 versus nortriptyline180Odds Ratio (M-H, Random, 95% CI)4.52 [0.21, 97.16]
1.7 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)0.22 [0.01, 4.73]
2 Paroxetine versus other SSRIs12 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)1.36 [0.76, 2.45]
2.2 versus escitalopram1454Odds Ratio (M-H, Random, 95% CI)1.62 [0.82, 3.20]
2.3 versus fluoxetine71940Odds Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]
2.4 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)2.79 [0.75, 10.33]
2.5 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)0.40 [0.26, 0.60]
3 Paroxetine versus newer or non-conventional ADs19 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)1.12 [0.33, 3.77]
3.2 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)1.27 [0.47, 3.43]
3.3 versus bupropion2240Odds Ratio (M-H, Random, 95% CI)3.03 [1.35, 6.84]
3.4 versus duloxetine51573Odds Ratio (M-H, Random, 95% CI)1.38 [0.68, 2.77]
3.5 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)2.10 [1.00, 4.44]
3.6 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)1.12 [0.69, 1.83]
3.7 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)3.45 [2.31, 5.15]
3.8 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)7.10 [0.36, 138.80]
3.9 versus venlafaxine1361Odds Ratio (M-H, Random, 95% CI)1.16 [0.44, 3.09]
3.10 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)3.17 [0.13, 79.60]
Analysis 36.1.

Comparison 36 SE - Diarrhoea, Outcome 1 Paroxetine versus older ADs.

Analysis 36.2.

Comparison 36 SE - Diarrhoea, Outcome 2 Paroxetine versus other SSRIs.

Analysis 36.3.

Comparison 36 SE - Diarrhoea, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 37. SE - Dizziness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs212554Odds Ratio (M-H, Random, 95% CI)0.80 [0.62, 1.03]
1.1 versus amitriptyline7777Odds Ratio (M-H, Random, 95% CI)0.42 [0.25, 0.72]
1.2 versus clomipramine192Odds Ratio (M-H, Random, 95% CI)0.19 [0.02, 1.70]
1.3 versus dothiepin2405Odds Ratio (M-H, Random, 95% CI)1.73 [0.94, 3.18]
1.4 versus imipramine6558Odds Ratio (M-H, Random, 95% CI)0.80 [0.53, 1.22]
1.5 versus lofepramine2228Odds Ratio (M-H, Random, 95% CI)0.76 [0.32, 1.81]
1.6 versus maprotiline1298Odds Ratio (M-H, Random, 95% CI)1.08 [0.66, 1.78]
1.7 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)0.57 [0.05, 6.42]
1.8 versus nortriptyline180Odds Ratio (M-H, Random, 95% CI)0.28 [0.01, 7.08]
2 Paroxetine versus other SSRIs10 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus escitalopram1454Odds Ratio (M-H, Random, 95% CI)0.97 [0.51, 1.84]
2.2 versus fluoxetine61737Odds Ratio (M-H, Random, 95% CI)1.50 [1.11, 2.04]
2.3 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)1.45 [0.44, 4.86]
2.4 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)1.40 [0.61, 3.22]
3 Paroxetine versus newer or non-conventional ADs23 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)1.2 [0.35, 4.13]
3.2 versus bupropion2240Odds Ratio (M-H, Random, 95% CI)0.81 [0.37, 1.76]
3.3 versus duloxetine51573Odds Ratio (M-H, Random, 95% CI)0.83 [0.58, 1.18]
3.4 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)3.03 [1.35, 6.82]
3.5 versus milnacipran1302Odds Ratio (M-H, Random, 95% CI)9.00 [0.48, 168.64]
3.6 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)1.19 [0.66, 2.11]
3.7 versus nefazodone2246Odds Ratio (M-H, Random, 95% CI)0.48 [0.23, 1.03]
3.8 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.84 [0.59, 1.21]
3.9 versus tianeptine2604Odds Ratio (M-H, Random, 95% CI)7.02 [1.25, 39.32]
3.10 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)0.51 [0.04, 5.79]
3.11 versus venlafaxine2466Odds Ratio (M-H, Random, 95% CI)1.39 [0.18, 10.62]
Analysis 37.1.

Comparison 37 SE - Dizziness, Outcome 1 Paroxetine versus older ADs.

Analysis 37.2.

Comparison 37 SE - Dizziness, Outcome 2 Paroxetine versus other SSRIs.

Analysis 37.3.

Comparison 37 SE - Dizziness, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 38. SE - Dry mouth
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs294578Odds Ratio (M-H, Random, 95% CI)0.23 [0.18, 0.30]
1.1 versus amitriptyline121576Odds Ratio (M-H, Random, 95% CI)0.27 [0.17, 0.43]
1.2 versus clomipramine21111Odds Ratio (M-H, Random, 95% CI)0.35 [0.26, 0.48]
1.3 versus dothiepin2405Odds Ratio (M-H, Random, 95% CI)0.22 [0.10, 0.50]
1.4 versus imipramine8835Odds Ratio (M-H, Random, 95% CI)0.16 [0.10, 0.26]
1.5 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)1.16 [0.25, 5.44]
1.6 versus maprolitine3429Odds Ratio (M-H, Random, 95% CI)0.13 [0.08, 0.23]
1.7 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)0.76 [0.12, 4.70]
2 Paroxetine versus other SSRIs11 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus citalopram1406Odds Ratio (M-H, Random, 95% CI)0.97 [0.56, 1.68]
2.2 versus escitalopram1454Odds Ratio (M-H, Random, 95% CI)1.44 [0.74, 2.83]
2.3 versus fluoxetine61920Odds Ratio (M-H, Random, 95% CI)1.67 [1.17, 2.38]
2.4 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)0.63 [0.21, 1.88]
2.5 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)1.01 [0.52, 1.99]
3 Paroxetine versus newer or non-conventional ADs22 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus agomelatine1284Odds Ratio (M-H, Random, 95% CI)4.79 [0.55, 41.52]
3.2 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)0.98 [0.30, 3.21]
3.3 versus bupropion2240Odds Ratio (M-H, Random, 95% CI)0.71 [0.27, 1.87]
3.4 versus duloxetine51571Odds Ratio (M-H, Random, 95% CI)0.78 [0.55, 1.10]
3.5 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)2.62 [1.36, 5.04]
3.6 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)0.58 [0.27, 1.24]
3.7 versus nefazodone2246Odds Ratio (M-H, Random, 95% CI)0.80 [0.35, 1.82]
3.8 versus reboxetine31375Odds Ratio (M-H, Random, 95% CI)0.35 [0.27, 0.45]
3.9 versus tianeptine1277Odds Ratio (M-H, Random, 95% CI)0.70 [0.22, 2.26]
3.10 versus trazodone1108Odds Ratio (M-H, Random, 95% CI)10.09 [0.53, 192.17]
3.11 versus venlafaxine2466Odds Ratio (M-H, Random, 95% CI)1.16 [0.44, 3.06]
Analysis 38.1.

Comparison 38 SE - Dry mouth, Outcome 1 Paroxetine versus older ADs.

Analysis 38.2.

Comparison 38 SE - Dry mouth, Outcome 2 Paroxetine versus other SSRIs.

Analysis 38.3.

Comparison 38 SE - Dry mouth, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 39. SE - Dyspepsia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs5 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus amitriptyline3552Odds Ratio (M-H, Random, 95% CI)0.44 [0.05, 3.72]
1.2 versus dothiepin1271Odds Ratio (M-H, Random, 95% CI)0.68 [0.25, 1.84]
1.3 versus maprotiline1298Odds Ratio (M-H, Random, 95% CI)0.47 [0.20, 1.12]
2 Paroxetine versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine31371Odds Ratio (M-H, Random, 95% CI)0.77 [0.54, 1.09]
2.2 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)0.51 [0.13, 1.95]
3 Paroxetine versus newer or non-conventional ADs6 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus duloxetine3802Odds Ratio (M-H, Random, 95% CI)0.67 [0.28, 1.61]
3.2 versus mirtazapine1197Odds Ratio (M-H, Random, 95% CI)1.33 [0.47, 3.72]
3.3 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)1.12 [0.64, 1.96]
Analysis 39.1.

Comparison 39 SE - Dyspepsia, Outcome 1 Paroxetine versus older ADs.

Analysis 39.2.

Comparison 39 SE - Dyspepsia, Outcome 2 Paroxetine versus other SSRIs.

Analysis 39.3.

Comparison 39 SE - Dyspepsia, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 40. SE - Dyspnea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus imipramine175Odds Ratio (M-H, Random, 95% CI)0.25 [0.07, 0.85]
2 Paroxetine versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine1203Odds Ratio (M-H, Random, 95% CI)2.31 [0.84, 6.35]
3 Paroxetine versus newer or non-conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus duloxetine1274Odds Ratio (M-H, Random, 95% CI)0.43 [0.02, 9.08]
3.2 versus reboxetine2845Odds Ratio (M-H, Random, 95% CI)4.30 [1.21, 15.26]
Analysis 40.1.

Comparison 40 SE - Dyspnea, Outcome 1 Paroxetine versus older ADs.

Analysis 40.2.

Comparison 40 SE - Dyspnea, Outcome 2 Paroxetine versus other SSRIs.

Analysis 40.3.

Comparison 40 SE - Dyspnea, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 41. SE - ECG abnormailities
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs3382Odds Ratio (M-H, Random, 95% CI)0.33 [0.08, 1.40]
1.1 versus amitriptyline1231Odds Ratio (M-H, Random, 95% CI)0.25 [0.05, 1.19]
1.2 versus maprolitine171Odds Ratio (M-H, Random, 95% CI)2.84 [0.11, 71.99]
1.3 versus nortriptyline180Odds Ratio (M-H, Random, 95% CI)0.11 [0.01, 2.27]
Analysis 41.1.

Comparison 41 SE - ECG abnormailities, Outcome 1 Paroxetine versus older ADs.

Comparison 42. SE - Emotional lability
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs7953Odds Ratio (M-H, Random, 95% CI)1.18 [0.54, 2.57]
1.1 versus amitriptyline4503Odds Ratio (M-H, Random, 95% CI)1.66 [0.65, 4.20]
1.2 versus clomipramine192Odds Ratio (M-H, Random, 95% CI)0.34 [0.01, 8.58]
1.3 versus maprolitine2358Odds Ratio (M-H, Random, 95% CI)0.60 [0.12, 2.91]
2 Paroxetine versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine41139Odds Ratio (M-H, Random, 95% CI)0.83 [0.31, 2.22]
3 Paroxetine versus newer or non-conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)0.62 [0.08, 5.05]
Analysis 42.1.

Comparison 42 SE - Emotional lability, Outcome 1 Paroxetine versus older ADs.

Analysis 42.2.

Comparison 42 SE - Emotional lability, Outcome 2 Paroxetine versus other SSRIs.

Analysis 42.3.

Comparison 42 SE - Emotional lability, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 43. SE - Fatigue
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)0.17 [0.01, 3.53]
1.2 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)3.50 [0.14, 87.83]
2 Paroxetine versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine1138Odds Ratio (M-H, Random, 95% CI)0.21 [0.04, 0.99]
2.2 versus sertraline2545Odds Ratio (M-H, Random, 95% CI)2.41 [1.21, 4.77]
3 Paroxetine versus newer or non-conventional ADs8 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus duloxetine31045Odds Ratio (M-H, Random, 95% CI)1.19 [0.60, 2.39]
3.2 versus hypericum1251Odds Ratio (M-H, Random, 95% CI)1.15 [0.54, 2.48]
3.3 versus mirtazapine3726Odds Ratio (M-H, Random, 95% CI)0.58 [0.32, 1.06]
3.4 versus reboxetine1325Odds Ratio (M-H, Random, 95% CI)4.91 [0.57, 42.47]
Analysis 43.1.

Comparison 43 SE - Fatigue, Outcome 1 Paroxetine versus older ADs.

Analysis 43.2.

Comparison 43 SE - Fatigue, Outcome 2 Paroxetine versus other SSRIs.

Analysis 43.3.

Comparison 43 SE - Fatigue, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 44. SE - Fever
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus imipramine180Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.22]
1.2 versus mianserin1116Odds Ratio (M-H, Random, 95% CI)3.50 [0.14, 87.83]
2 Paroxetine versus newer or non-conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)0.99 [0.28, 3.54]
Analysis 44.1.

Comparison 44 SE - Fever, Outcome 1 Paroxetine versus older ADs.

Analysis 44.2.

Comparison 44 SE - Fever, Outcome 2 Paroxetine versus newer or non-conventional ADs.

Comparison 45. SE - Flatulence
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Paroxetine versus older ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus amitriptyline121Odds Ratio (M-H, Random, 95% CI)3.0 [0.11, 82.40]
2 Paroxetine versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus fluoxetine1573Odds Ratio (M-H, Random, 95% CI)1.69 [0.87, 3.29]
2.2 versus fluvoxamine160Odds Ratio (M-H, Random, 95% CI)0.22 [0.02, 2.14]
3 Paroxetine versus newer or non-conventional ADs6 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus aprepitant (MK-869)1143Odds Ratio (M-H, Random, 95% CI)0.38 [0.07, 2.01]
3.2 versus mirtazapine1254Odds Ratio (M-H, Random, 95% CI)4.19 [1.35, 13.00]
3.3 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)1.84 [0.87, 3.87]
3.4 versus duloxetine2528Odds Ratio (M-H, Random, 95% CI)2.34 [0.83, 6.59]
Analysis 45.1.

Comparison 45 SE - Flatulence, Outcome 1 Paroxetine versus older ADs.

Analysis 45.2.

Comparison 45 SE - Flatulence, Outcome 2 Paroxetine versus other SSRIs.

Analysis 45.3.

Comparison 45 SE - Flatulence, Outcome 3 Paroxetine versus newer or non-conventional ADs.

Comparison 46. SE - Gastrointestinal disorder
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Appendicitis1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus fluoxetine1138Odds Ratio (M-H, Random, 95% CI)3.13 [0.13, 78.26]
2 Cholelithiasis1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus imipramine1202Odds Ratio (M-H, Random, 95% CI)0.17 [0.01, 4.16]
3 Colitis1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus fluoxetine1122Odds Ratio (M-H, Random, 95% CI)7.61 [0.38, 150.51]
4 Eructation1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus reboxetine1520Odds Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.71]
5 Melena1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus maprolitine160Odds Ratio (M-H, Random, 95% CI)3.55 [0.14, 90.59]
6 Gastritis1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
6.1 versus imipramine1202Odds Ratio (M-H, Random, 95% CI)1.53 [0.16, 15.03]
7 Gastroenteritis2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
7.1 versus reboxetine21050Odds Ratio (M-H, Random, 95% CI)1.13 [0.42, 2.98]
8 Intestinal obstruction1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
8.1 versus fluoxetine1138Odds Ratio (M-H, Random, 95% CI)3.13 [0.13, 78.26]
9 Intestinal perforation1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
9.1 versus lofepramine1106Odds Ratio (M-H, Random, 95% CI)0.28 [0.01, 7.06]
10 Peptic ulcer hemorrhage1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
10.1 versus fluoxetine1573Odds Ratio (M-H, Random, 95% CI)3.06 [0.12, 75.52]
11 NOS18 Odds Ratio (M-H, Random, 95% CI)Subtotals only
11.1 versus amisulpride2298Odds Ratio (M-H, Random, 95% CI)1.77 [0.14, 21.98]
11.2 versus amitriptyline4478Odds Ratio (M-H, Random, 95% CI)0.68 [0.35, 1.33]
11.3 versus clomipramine183Odds Ratio (M-H, Random, 95% CI)0.56 [0.23, 1.38]