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Fluvoxamine versus other anti-depressive agents for depression

  1. Ichiro M Omori1,*,
  2. Norio Watanabe2,
  3. Atsuo Nakagawa3,
  4. Andrea Cipriani4,
  5. Corrado Barbui4,
  6. Hugh McGuire5,
  7. Rachel Churchill6,
  8. Toshi A Furukawa7

Editorial Group: Cochrane Common Mental Disorders Group

Published Online: 17 MAR 2010

Assessed as up-to-date: 30 AUG 2008

DOI: 10.1002/14651858.CD006114.pub2


How to Cite

Omori IM, Watanabe N, Nakagawa A, Cipriani A, Barbui C, McGuire H, Churchill R, Furukawa TA. Fluvoxamine versus other anti-depressive agents for depression. Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD006114. DOI: 10.1002/14651858.CD006114.pub2.

Author Information

  1. 1

    Toyokawa City Hospital, Department of Psychiatry, Aichi, Japan

  2. 2

    Nagoya City University Graduate School of Medical Sciences, Department of Psychiatry & Cognitive-Behavioral Medicine, Nagoya, Aichi, Japan

  3. 3

    Keio University School of Medicine, Department of Psychiatry and the Center for Clinical Research, Tokyo, Japan

  4. 4

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

  5. 5

    National Collaborating Centre for Women's and Children's Health, London, UK

  6. 6

    University of Bristol, Centre for Mental Health, Addiction and Suicide Research, School of Social and Community Medicine, Bristol, UK

  7. 7

    Kyoto University Graduate School of Medicine / School of Public Health, Departments of Health Promotion and Behavior Change and of Clinical Epidemiology, Kyoto, Japan

*Ichiro M Omori, Department of Psychiatry, Toyokawa City Hospital, Koumei 1-19, Toyokawa, Aichi, 442-8561, Japan. ichiro.m.omori@gmail.com. mmds@sannet.ne.jp.

Publication History

  1. Publication Status: New
  2. Published Online: 17 MAR 2010

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Characteristics of included studies [ordered by study ID]
Amore 1989

MethodsFour-week double blind, randomised study.


ParticipantsPsychiatric inpatients meeting DSM-III for major depression without psychotic features, with a minimum baseline score of 21 on the HDRS-21.
Age range: 20-70 years old.
Exclusion criteria: during pregnancy, lactation, or being of childbearing potential, serious diseases, alcohol or drug abuse, or treatment with any medications that might interact with antidepressant drugs.


InterventionsFluvoxamine: 15 participants.
Imipramine: 15 participants.
Fluvoxamine dose range: 100-150 mg/day.
Imipramine dose range: 100-150 mg/day.

Benzodiazepine were allowed as additional medications.


OutcomesHamilton Rating Scale for Depression (HRSD) -21, Zung Self-Rating Depression Scale, Clinical Global Impression-severity (CGI-S) and Clinical Global Impression-improvement (CGI-I).

Total dropout, dropout due to inefficiency, due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "in a double blind fashion", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 5/15 missing from control group (4 due to adverse effects).

Selective reporting (reporting bias)High riskStandard deviations (SDs) of endpoint / change score for depression were not reported.

Ansseau 1991a

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPsychiatric inpatients meeting RDC for major depressive disorder, endogenous subtype, with a minimum baseline score of 25 on the Montgomery and Asberg Scale for Depression (MADRS).
Age range: 20-70 years old.
Exclusion criteria: patients presenting any evidence of contra-indications for a tricyclic antidepressant, or serious or uncontrolled medical illness.


InterventionsFluvoxamine: 41 participants.
Milnacipran: 42 participants.
Fluvoxamine dose: 200 mg/day.
Milnacipran dose: 300 mg/day for 2 weeks and 150mg/day during the 2 following weeks)

The active period was preceded by a washout period of 4-7 days on placebo and lorazepam (up to 10 mg/day) and nitrazepam (up to 10 mg/day) if needed. These associated drugs could be maintained during the treatment period if necessary.


OutcomesHRSD-24, CGI-I, CGI-S, CGI-efficacy index, Raskin Scale for Depression.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugAs a comparator drug.


Notes11/127 (8.7%) patients were with bipolar depression and 14/127 (11.0%) patients were with psychotic features.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskno details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskBoth participants and drug prescribing physicians were blinded. No further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 6/41 missing from fluvoxamine group (1 due to lack of efficacy, 5 due to adverse effects); 10/86 missing from control group (2 due to lack of efficacy, 7 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Ansseau 1991b

Methods=Ansseau 1991a


Participants=Ansseau 1991a


InterventionsFluvoxamine: 41 participants.
Milnacipran: 44 participants.
Fluvoxamine dose: 200 mg/day.
Milnacipran dose: 200 mg/day for 4 weeks. The active period was preceded by a washout period of 4-7 days on placebo and lorazepam (up to 10 mg/day) and nitrazepam (up to 10 mg/day) if needed. These associated drugs could be maintained during the treatment period if necessary.


Outcomes=Ansseau 1991a


Funded by pharmaceutical companies=Ansseau 1991a


Fluvoxamine as an investigational or comparator drug=Ansseau 1991a


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk=Ansseau 1991a

Allocation concealment (selection bias)Unclear risk=Ansseau 1991a

Blinding (performance bias and detection bias)
All outcomes
Unclear risk=Ansseau 1991a

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk=Ansseau 1991a

Selective reporting (reporting bias)High risk=Ansseau 1991a

Ansseau 1994

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric in- and outpatients meeting DSM-III-R for major depressive episode, with a minimum baseline score of 18 on the HRSD-21.
Age range: 18-65 years old.
Exclusion criteria: clinically significant co-existing diseases or other psychiatric disorders, history of alcohol or drug abuse, women of child bearing potential not employing adequate contraception, recent treatment with monoamine oxidase inhibitors, neuroleptics, or lithium, and current treatment with oral anticoagulants and type 1C antiarrythmic.


InterventionsFluvoxamine: 64 participants.
Paroxetine: 56 participants.
Fluvoxamine dose range: 50-200 mg/day.
Paroxetine dose range: 20-30 mg/day.

For patients who had received benzodiazepines for at least two weeks prior to continue these agents, providing the dose remained unchanged throughout the study period. In addition, low dose lormethazepam or chloral hydrate were permitted in case of severe insomnia.


OutcomesHRSD-21, CGI-S, Hamilton Rating Scale for Anxiety (HRSA).

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesPatients with major depressive episode (DSM-III-R) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "the trial used a double-blind design", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 23/64 missing from fluvoxamine group (5 due to lack of efficacy, 13 due to adverse effects); 16/56 missing from control group (2 due to lack of efficacy, 3 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Asakura 2005

MethodsFour-week double blind, single-centre, randomised study.


ParticipantsPsychiatric in- and outpatients meeting major depressive disorder or other affective disorder according to DSM-IV. Baseline HRSD score: 20.02 (SD 6.60).
Age: 20 years old or more, mean 41.3 years old (SD 13.7).
Exclusion criteria: treated with any antidepressants for the current depressive episode.


InterventionsFluvoxamine: 158 participants.
Imipramine: 161 participants.
Fluvoxamine dose range: 50-150 mg/day.
Imipramine dose range: 75-150 mg/day.


OutcomesHRSD-17, CGI.

Total dropout.


Funded by pharmaceutical companiesFunded by pharmaceutical companies market fluvoxamine and comparator drug.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesAlmost all the patients were drug naive outpatients.

17% (54/309) of participants were with dysthymic disorder, depressive disorder not otherwise specified, bipolar II disorder or major depressive disorder with psychotic features.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "patients were randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 9/158 missing from fluvoxamine group; 12/161 missing from control group.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Barge-Schaapveld 1995

MethodsSix-week open, multicentre, randomised study.


ParticipantsPrimary care outpatients meeting DSM-III-R for major depressive disorder, with a minimum baseline score of 18 on the HRSD-17.
Patients were recruited in five primary care practices.
Age range: 18-65 years old.
Exclusion criteria: other psychiatric or medical conditions.


InterventionsFluvoxamine: 13 participants.
Amitriptyline: 10 participants.
Fluvoxamine dose: 100 mg/day.
Amitriptyline dose: 150 mg/day.


OutcomesHRSD-17.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "patients were randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
High riskPatients were blinded. No blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 2/13 missing from fluvoxamine group.

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Barrelet 1991

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPsychiatric in- and outpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 17 on the HRSD-17.
Age: mean 54.2 years old (SD 14.6).
Exclusion criteria: organic brain disorders, alcohol dependence, risk of suicide, with schizophrenic symptoms, severe medical illness.


InterventionsFluvoxamine: 30 participants.
Moclobemide: 31 participants.
Fluvoxamine dose range: 100-200 mg/day.
Moclobemide dose range: 300-450 mg/day.

Benzodiazepine and lithium were allowed.


OutcomesHRSD-17, HRSA, Widlocher Psychomotor Retardation Scale, Hospital Anxiety and Depression Scale.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugAs a comparator drug.


NotesPatients with major affective disorder (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double aveugle", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 5/30 missing from fluvoxamine group (4 due to adverse effects); 5/30 missing from control group (4 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Bocksberger 1993

MethodsFour-week double blind, single-centre, randomised study.


ParticipantsPsychiatric inpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 20 on the MADRS.
Age range: 65 years old or more.
Exclusion criteria: marked suicidal tendency, symptoms of psychosis, severe organic disease, alcoholism, drug abuse.


InterventionsFluvoxamine: 20 participants.
Moclobemide: 20 participants.
Fluvoxamine dose range: 100-200 mg/day.
Moclobemide dose range: 300-450 mg/day.

Patients receiving lithium were enrolled in the study, providing treatment had been stabilized for at least four weeks prior to entry. The use of concomitant psychotropic medication was prohibited, with the exception of lithium for patients on a previously established lithium regimen, or one benzodiazepine or chloral hydrate, if judged necessary by the investigator. Drugs that had been given regularly for somatic complaints were allowed to continue if there were no psychotropic effects.


OutcomesMADRS, CGI-I, Widlocher Psychomotor Retardation Scale.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugAs a comparator drug.


NotesPatients with major affective disorder (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "two randomized parallel groups", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "a double blind study", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 2/20 missing from fluvoxamine group (1 due to adverse effects); 1/20 missing from control group.

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Bougerol 1992

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric in- and outpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 17 on the HRSD-17.
Age range: 18 years old or more.
Exclusion criteria: marked suicidal tendency, symptoms of psychosis; severe organic disease, patient undergoing electroshock therapy or structured psychotherapy, alcoholism, drug abuse.


InterventionsFluvoxamine: 63 participants.
Moclobemide: 67 participants.
Fluvoxamine dose range: 100-200 mg/day.
Moclobemide dose range: 300-450 mg/day.

Patients receiving lithium were enrolled in the study, providing treatment had been stabilized for at least 4 weeks prior to entry. The use of concomitant psychotropic medication was prohibited, with the exception of lithium for patients on a previously established lithium regimen, or one benzodiazepine, if judged necessary by the investigator. Drugs that had been given regularly for somatic complaints were allowed to continue if there were no psychotropic effects. During the study, patients were not required to avoid tyramine-rich food.


OutcomesHRSD-17, CGI-efficacy index, Widlocher Psychomotor Retardation Scale.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugAs a comparator drug.


NotesPatients with major affective disorder (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "two randomized parallel groups", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 19/63 missing from fluvoxamine group (3 due to lack of efficacy, 9 due to adverse effects); 15/67 missing from control group (5 due to lack of efficacy, 6 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Bramanti 1988

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPatients suffering major depressive disorder according to DSM-III, with a minimum baseline score of 18 on the HRSD-21.
Age range: 18 years old or more.
Exclusion criteria: pregnancy or a risk of pregnancy, lactating women, severe impairment of liver or renal function, treatment with lithium, other antidepressants or MAO inhibitors in the previous two weeks before the study.


InterventionsFluvoxamine: 30 participants.
Imipramine: 30 participants.
Fluvoxamine dose range: 100-150 mg/day.
Imipramine dose range: 100-150 mg/day.

Treatments with benzodiazepines was allowed, if necessary. No treatments with barbiturates, other antidepressants, or amphetamine were permitted.


OutcomesHRSD-21, CGI-I, CGI-S.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes5/60 (8%) patients were with psychotic features.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly allocated", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskStudy medicines were dispensed in identical pharmaceutical forms, no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 2/30 missing from fluvoxamine group (2 due to lack of efficacy); 1/30 missing from control group (1 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Brown 1986

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depression, with a minimum baseline score of 20 on the HRSD-21.
Age range: 21-60 years old.
Exclusion criteria: clinically significant physical illness or were taking medication, such as anticonvulsants.


InterventionsFluvoxamine: 33 participants.
Imipramine: 17 participants.
Fluvoxamine dose range: 200-300 mg/day.
Imipramine dose range: 150-225 mg/day.


OutcomesHRSD-21.

Total dropout, dropout due to inefficiency, dropout due to side effects.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesStudy authors examined pituitary-adrenocortical status in relation to medication.

No clinical data were reported for imipramine group. No efficacy data could be entered in a meta-analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 8/33 missing from fluvoxamine group (8 due to adverse effects); 4/17 missing from control group (4 due to adverse effects).

Selective reporting (reporting bias)High riskNo clinical data were reported for imipramine group.

Brunner 1994

MethodsFour-week open, randomised study.


ParticipantsPsychiatric inpatients suffering from depression according to Feighner criteria, with a minimum baseline score of 17 on the HRSD-17.
Age range: 18-70 years old.
Exclusion criteria: Woman who were pregnant or not taking adequate contraceptive measures, an initial depressive episode of less than two weeks' duration, depression secondary to another psychiatric condition, severe physical illness, or who had received lithium or shock therapy in the previous four weeks.


InterventionsFluvoxamine: 20 participants.
Amineptine: 20 participants.
Fluvoxamine dose range: 100-300 mg/day.
Amineptine dose range: 100-200 mg/day.

Diazepam (sedative), flunitrazepam (hypnotic) and cymemazine (sedative neuroleptic) were allowed.


OutcomesHRSD-17, CGI-I, CGI-S.

Total dropout, dropout due to inefficiency, dropout due to side effects.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with depression (Feighner criteria) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized study", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "open study".

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 2/20 missing from fluvoxamine group (1 due to adverse effects); 3/20 missing from control group (4 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Cassano 1986

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPsychiatric in- and outpatients meeting DSM-III for major affective disorder, with a minimum baseline score of 15 on the HDRS-17.
Age range: 19-70 years old.
Exclusion criteria: child bearing potential or pregnant women; antidepressant therapy in the past 2 weeks; ECT within the last month; depressive symptoms secondary to other psychiatric illness; dependence upon licit or illicit drugs; serious organic diseases; need for concurrent medications which could interact with the study drugs or obscure their effects; patients unwilling or unable to cooperate with the study.


InterventionsFluvoxamine: 169 participants.
Imipramine: 161 participants.
Placebo: 151 participants.
Fluvoxamine dose range: 50-300 mg/day.
Imipramine dose range: 50-300 mg/day.

Chloral hydrate or flurazepam as hypnotics were allowed during the trial.


OutcomesHDRS-17, CGI-I, CGI-severity, BPRS, SCL-90, SDS.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with major affective disorder (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized". no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double-blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 67/169 missing from fluvoxamine group (12 due to lack of efficacy, 19 due to adverse effects); 57/161 missing from control group (10 due to lack of efficacy, 17 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Claghorn 1996

MethodsSix-week double blind, single-centre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depressive disorder (single or recurrent episode without psychotic features or only mood-congruent psychotic features). Baseline symptom severity (mean (SD) for HRSD-21) was 26.1 (3.6).
Age range: 18-65years old.
Exclusion criteria: any significant health problems, as determined by a physical examination and clinical laboratory tests (blood chemistry, hematology, urinalysis, serum pregnancy test) and electrocardiograms.


InterventionsFluvoxamine: 50 participants.
Imipramine: 50 participants.
Placebo: 50 participants.
Fluvoxamine dose range: 50-150 mg/day.
Imipramine dose range: 80-240 mg/day.


OutcomesHRSD-21, MADRS, CGI-I, Raskin Depression Scale and Covi Anxiety Scale, SCL-56.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 30/50 missing from fluvoxamine group (4 due to lack of efficacy, 12 due to adverse effects); 29/50 missing from control group (3 due to lack of efficacy, 13 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Clerc 2001

MethodsSix-week, multicentre, randomised study.


ParticipantsPsychiatric in- and outpatients suffering from major depression according to DSM-III-R, with a minimum baseline score of 25 on the MADRS.
Age range: 18-70 years old.
Exclusion criteria: depression was associated with other conditions such as dysthymic disorder or schizophrenia, suicidal ideas or extreme anxiety, bipolar depression treated with lithium within the 3 months prior to the study, pregnancy or breastfeeding, serious medical conditions or treatment with drugs known to interact with fluvoxamine or milnacipran.


InterventionsFluvoxamine: 56 participants.
Milnacipran: 57 participants.
Fluvoxamine dose: 200 mg/day.
Milnacipran dose: 100 mg/day.

No other psychotropic drugs were permitted during the trial and any such drugs were withdrawn during the run-in period. Tranquilizers or hypnotics (other than nitrazepam or lorazepam) were withdrawn at least 3 days before starting medication, and antidepressants were withdrawn 7 days before the study (15 days for monoamine oxidase inhibitor). Intermediate-acting neuroleptic agents were withdrawn 7 days before the trial, and long-acting agents were withdrawn 1 month before. Nitrazepam or lorazepam, at daily doses up to 5 and 10 mg, respectively, or chloral hydrate syrup, could be given as necessary during the run-in and subsequent phases.


OutcomesHRSD-17, HRSD-24, MADRS, CGI-I.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugAs a comparator drug.


Notes2/113 (1.8%) patients were with psychotic features.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskPatients were blinded, no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 17/56 missing from fluvoxamine group (7 due to lack of efficacy, 4 due to adverse effects); 15/57 missing from control group (10 due to lack of efficacy, 1 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Coleman 1982

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPsychiatric inpatients suffering from both unipolar and bipolar depression, with the dysphoric mood accompanied by at least five of Feighner criteria.
Age range: not stated.
Exclusion criteria: not stated.


InterventionsFluvoxamine: 50 participants.
Clomipramine: 48 participants.
Fluvoxamine dose range: 150-300 mg/day.
Clomipramine dose range: 150-300mg/day.


OutcomesHRSD, CGI-I, CGI-S.

Total dropout, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with bipolar depression were included, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 9/50 missing from fluvoxamine group; 5/48 missing from control group (due to lack of efficacy, due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Dalery 2003

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depressive episode, with a minimum baseline score of 17 on the HRSD-17.
Age range: 18-70 years old.
Exclusion criteria: acute suicidal ideation or a serious suicide attempt in the previous 6 months; dementia; a history of epilepsy or seizures; concurrent or recent (6 months) alcoholism, other psychoactive substance abuse or drug-induced psychosis, were pregnant, lactating or of childbearing potential and not taking adequate contraceptive measures, or if they had clinically uncontrolled hepatic, renal, pulmonary, endocrine or collagen disease. Also excluded were patients who had previously failed SSRI therapy or who required concomitant lithium, warfarin, hepatically metabolised antivitamine K agents, carbamazepine, theophyline, insulin or hypoglycaemic agents. Patients were required not to receive monoamine oxidase inhibitors or ECT in the 2 weeks prior to the study.


InterventionsFluvoxamine: 90 participants.
Fluoxetine: 94 participants.
Fluvoxamine dose: 100 mg/day.
Fluoxetine dose: 20 mg/day.

Oxazepam or nitrazepam were permitted as necessary for night time sedation; no other psychotherapeutic treatments or ECT were permitted during the study.


OutcomesHRSD-17, CGI-I, CGI-S, Clinical Anxiety Scale, Irritability, Depression and Anxiety scale, Beck's scale for suicide ideation score.

Total dropout, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesPatients with major depressive episode (DSM-III-R) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomised", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 24/90 missing from fluvoxamine group; 20/94 missing from control group (due to lack of efficacy, due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

de Wilde 1983

MethodsSix-week double blind, randomised study.


ParticipantsPsychiatric outpatients meeting Feighner criteria for depression, with a minimum baseline score of 16 on the HRSD-17.
Age range: 18-70 years old.
Exclusion criteria: significant concurrent organic disease, depression as a secondary manifestation of other psychiatric illnesses, pregnant or lactating women, patients who had received ECT or lithium within the last 4 weeks, patients with a high suicide risk and those with a history of drug allergy.


InterventionsFluvoxamine: 22 participants.
Clomipramine: 51 participants.
Fluvoxamine dose range: 100-300 mg/day.
Clomipramine dose range: 50-150 mg/day.

During the treatment free period and the study period the following concurrent medication was allowed: benzodiazepines as hypnotics, sedatives or tranquillizers, chloral hydrate as a hypnotic, antibiotics, non-narcotic analgesics, antacids and laxatives. Antihypertensive agents, anticoagulants and alcohol were not allowed. Psychotropic medication other than the benzodiazepines or chloral hydrate were forbidden.


OutcomesHRSD-17, CGI-S.

Total dropout, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes2/43 (4.7%) patients were with bipolar depression.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.

Selective reporting (reporting bias)High riskSDs for endpoint score and change score were not reported.

Dick 1983

MethodsFour-week double blind, randomised study.


ParticipantsPsychiatric inpatients suffering from persistent alteration of mood (depressed mood), had to be accompanied by at least 5 characteristics as mentioned in the Feighner criteria, with a minimum baseline score of 16 on the HRSD-17.
Age range: 34-64 years old.
Exclusion criteria: not stated.


InterventionsFluvoxamine: 17 participants.
Clomipramine: 15 participants.
Fluvoxamine dose: 150 mg/day.
Clomipramine dose: 150 mg/day.

The protocol did not allow drugs other than the study medication during the study period except, if necessary, limited use of diazepam, levomepromazine (methotrimeprazine) and flunitrazepam.


OutcomesHRSD-17, CGI-S, CGI-change in condition score and a self rating scale.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with depression (Feighner criteria) were included, so there might be some bipolar depression, but correct number was not reported.
*The HRSD-17 items 'genital symptoms' and 'loss of weight' were not recorded, study authors analysed left 15 items only.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 4/17 missing from fluvoxamine group (2 due to adverse effects); 4/15 missing from control group (1 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Fabre 1996

MethodsSix-week double blind, single-centre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depressive disorder, with a minimum baseline score of 20 on the HRSD-21.
Age range: 18-65 years old.
Exclusion criteria: any other primary psychiatric diagnosis, unstable medical conditions, clinically significant abnormal laboratory findings.


InterventionsFluvoxamine: 50 participants.
Imipramine: 50 participants.
Placebo: 50 participants.
Fluvoxamine dose range: 50-150 mg/day.
Imipramine dose range: 80-240 mg/day.

101 received at least one concomitant medication during the double blind portion of the trial. Concomitant medication was limited, only chloral hydrate was allowed as a hypnotic during the first two weeks of therapy. No sedative hypnotic was permitted after week 2. The most frequently prescribed medications were acetaminophen, aspirin, and other non-steroidal anti-inflammatory agents or non-sedating antihistamines, which should not have influenced the safety or efficacy outcome measures used in this study.


OutcomesHRSD-21, MADRS, CGI-S, Raskin-Covi, SCL-56.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 28/50 missing from fluvoxamine group (7 due to lack of efficacy, 7 due to adverse effects); 25/50 missing from control group (2 due to lack of efficacy, 9 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Feighner 1989

MethodsSix-week double blind, randomised study.


ParticipantsPsychiatric inpatients meeting DSM-III for major depression. All but one also quantified for melancholic subtype.
Age range: 18-71 years old.
Exclusion criteria: not reported.


InterventionsFluvoxamine: 31 participants.
Imipramine: 36 participants.
Placebo: 19 participants.
Fluvoxamine dose range: 150-300 mg/day.
Imipramine dose range: 150-300 mg/day.


OutcomesHRSD, CGI-S, BPRS, Zung Depression Scale, SCL-90.

Total dropout, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 10/31 missing from fluvoxamine group (7 due to adverse effects); 13/36 missing from control group (13 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Gonul 1999

MethodsFour-week double blind, randomised study.


ParticipantsPatients with major depression (DSM-IV).
Age: mean 35.6 years old (SD 11.8).
Exclusion criteria: psychotic symptoms, catatonia.


InterventionsFluvoxamine: 40 participants.
Fluoxetine: 40 participants.
Paroxetine: 40 participants.
Sertraline: 40 participants.
Fluvoxamine dose: 150 mg/day.
Fluoxetine dose: 20 mg/day.
Paroxetine dose: 20 mg/day.
Sertraline dose: 50 mg/day.


OutcomesHRSD.

Total dropout, dropout due to side effects.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesPatients with "major depression" (DSM-IV) were included, so there might be some bipolar depression, but correct number was not reported.

No clinical efficacy data could be entered in a meta -analysis; study authors reported only as "When the number of patients responding therapy was taken into account for the efficacy to each SSRI, we could not find any significant difference among them".


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "single blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 3/40 missing from fluvoxamine group (3 due to adverse effects); 4/40 missing from fluoxetine group (4 due to adverse effects); 6/40 missing from paroxetine group (6 due to adverse effects); 4/40 missing from sertraline group (6 due to adverse effects).

Selective reporting (reporting bias)High riskResults of HRSD were not reported.

Guy 1984

MethodsSix-week double blind, randomised study.


ParticipantsPsychiatric inpatients meeting RDC for primary depression (unipolar or bipolar) and a persistent alteration of mood.
Age range: 18-60 years old.
Exclusion criteria: females not practicing contraception, significant medical illnesses, continuing alcohol/drug abuse, history of other psychiatric illness in which the depression was secondary.


InterventionsFluvoxamine: 17 participants.
Imipramine: 19 participants.
Fluvoxamine dose range: 150-225 mg/day.
Imipramine dose range: 150-225 mg/day.

Remedial medications were administered in at least one occasion to approximately 80 % of the patients in each treatment group. Flurazepam for sleep disturbance and acetaminophen for headache were the most frequently prescribed medications. In both instances, a higher percent of fluvoxamine-treated patients (64%) received these medications than patients in the imipramine group. Less frequently and non differentially prescribed were medications for constipation, diet supplementation, coughs and colds, and minor infections.


OutcomesHRSD-17, CGI-I, CGI-S, BPRS, NOSIE (Nurses' observation scale for independent evaluation), Zung self-rating depression scale.

Total dropout, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes7/36 (19.4%) bipolar patients were included.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "assigned by randomization list", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 1/17 missing from fluvoxamine group; 3/19 missing from control group.

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Hackett 1998a

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III for major depression, with a minimum pre-study and baseline score of 24 on the MADRS and no more than 20 % decrease in those score from pre-study to baseline.
Age range: not stated.
Exclusion criteria: not stated.


InterventionsFluvoxamine: 34 participants.
Venlafaxine (twice a day): 37 participants.
Fluvoxamine dose: 200 mg/day.
Venlafaxine dose (twice a day): 100 mg/day.


OutcomesHRSD, MADRS, CGI-I.

Total dropout.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugAs a comparator drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 13/34 missing from fluvoxamine group; 9/37 missing from venlafaxine (twice a day) group; 9/40 missing from venlafaxine (three times a day) group.

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Hackett 1998b

Methods=Hackett 1998a


Participants=Hackett 1998a


InterventionsFluvoxamine: 34 participants.
Venlafaxine (three times a day): 40 participants.
Fluvoxamine dose: 200 mg/day.
Venlafaxine dose (three times a day): 100 mg/day.


Outcomes=Hackett 1998a


Funded by pharmaceutical companies=Hackett 1998a


Fluvoxamine as an investigational or comparator drug=Hackett 1998a


Notes=Hackett 1998a


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk=Hackett 1998a

Allocation concealment (selection bias)Unclear risk=Hackett 1998a

Blinding (performance bias and detection bias)
All outcomes
Unclear risk=Hackett 1998a

Incomplete outcome data (attrition bias)
All outcomes
High risk=Hackett 1998a

Selective reporting (reporting bias)High risk=Hackett 1998a

Haffmans 1996

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depression, with a minimum baseline score of 16 on the HRSD-17.
Age range: 18-70 years old.
Exclusion criteria: patients who had been treated with MAO-I or fluoxetine within the last 3 weeks or with other psychotropic drugs within the last week, with the exception of benzodiazepines; primary psychiatric diagnosis; a history of epilepsy, alcohol and/or drug abuse; pregnant or lactating women and women of childbearing potential failing to use standard birth control methods; renal, hepatic, cardiovascular, neurological or somatic disorders and/or significant abnormal laboratory findings; mental retardation.


InterventionsFluvoxamine: 109 participants.
Citalopram: 108 participants.
Fluvoxamine dose range: 150-200 mg/day.
Citalopram dose range: 30-40 mg/day.

Selected benzodiazepines as permitted concomitant medication at baseline could be continued during the study. Patients who were receiving other benzodiazepines were switched to one of the following permitted drugs. The maximum dose of the benzodiazepines which could be given during the study were; oxazepam at 50 mg daily, lormethazepam at 4 mg daily, temazepam at 20 mg daily, lorazepam at 4 mg daily, flurazepam at 15 mg daily. Preferably, the daily dose was stable during the study period. All non psychotropic medication was allowed but the regime was to be kept stable. In case of severe nausea and/or vomiting, domperidone could be given.


OutcomesHRSD-17, CGI-S, Zung Self-Rating Depression scale.

Total dropout, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes6/217 (2.8%) patients were with bipolar depression and 4/217 (1.8%) patients with psychotic features.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 29/109 missing from fluvoxamine group (26 due to adverse effects); 22/108 missing from control group (16 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Harris 1991a

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 17 on the HRSD-17.
Age range: 18-65 years old.
Exclusion criteria: pregnant or at risk of pregnancy or breast feeding, epilepsy; patients receiving other antidepressants therapy, adrenergic neuron blockers, clonidine, sympathomimetic or anticholinergic drugs; severe impairment of renal or cardiovascular function, prostatic hypertrophy, urinary retention, narrow angle glaucoma, increased intraocular pressure, hyperthyroidism; severe suicidal risk.


InterventionsFluvoxamine: 35 participants.
Amitriptyline: 34 participants.
Fluvoxamine dose range: 50-150 mg/day.
Amitriptyline dose range: 50-150 mg/day.

The use of other antidepressants was prohibited, but benzodiazepine previously described as hypnotics or anxiolytics were permitted. Other concurrent medication had to been kept to a minimum and be fully documented.


OutcomesHRSD-17, CGI-I.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with major depressive episode (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly allocated", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 12/35 missing from fluvoxamine group (1 due to lack of efficacy, 5 due to adverse effects); 10/34 missing from control group (4 due to lack of efficacy, 6 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint score for depression were not reported.

Itil 1983

MethodsSix-week double blind, randomised study.


ParticipantsPsychiatric outpatients meeting RDC for depression, with a minimum baseline score of 15 on the HRSD-17.
Age range: 18-65 years old.
Exclusion criteria: Pregnant women and women of childbearing potential; patients whose depression was secondary to another illness; patients receiving imipramine, MAO inhibitors within 2 weeks of study commencement, ECT within 4 weeks of study commencement, lithium carbonate, or any short or long term medication which might interact with study drug.


InterventionsFluvoxamine: 22 participants.
Imipramine: 25 participants.
Placebo: 22 participants.
Fluvoxamine dose range: 50-300 mg/day
Imipramine dose range: 50-300 mg/day.


OutcomesHRSD-16, CGI-I, CGI-S, SCL-90, Beck depression inventory (BDI).

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes3/69 (4.3%) were with bipolar depression.
* Study authors stated the using 'HRSD-16'.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 12/22 missing from fluvoxamine group (9 due to adverse effects); 12/25 missing from control group (1 due to lack of efficacy, 7 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Kasper 1990

MethodsSix-week double blind, randomised study.


ParticipantsPsychiatric inpatients meeting RDC for major depression, with a minimum baseline score of 18 on the HRSD-21.
Age range: 28-71 years old.
Exclusion criteria: medical illness examined by complete medical and neurological evaluations; alcohol and drug abuse; pathological signs of EEG, ECG, and laboratory examinations.


InterventionsFluvoxamine: 21 participants.
Maprotiline: 21 participants.
Fluvoxamine dose range: 100-300 mg/day.
Maprotiline dose range: 100-300 mg/day.

Following admission to the study, all psychotropic drugs were discontinued (wash out phase: 7 days) and patients remained drug free except for chlor-hydrate, which was given for agitation or insomnia. Patients underwent a TSD (total sleep deprivation) at day 0 and day 8. All patients were deprived of sleep for one total night (40 hours).


OutcomesHRSD-21, CGI.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes2/42 (5%) patients were with bipolar depression and 2/42 (5%) patients were with psychotic features.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", "capsules of either fluvoxamine or maprotiline in identical presentation", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 1/21 missing from control group (due to lack of efficacy, due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Kato 2006

MethodsSix-week open, single-centre, randomised study.


ParticipantsPatients meeting DSM-IV for major depressive disorder.
Age: mean 44.8 years old (SD 14.9).
Exclusion criteria: additional diagnoses on Axis I and Axis II, pregnancy, and medical and neurological disorders.


InterventionsFluvoxamine: 49 participants.
Paroxetine: 52 participants.
Fluvoxamine dose range: 50-150 mg/day.
Paroxetine dose range: 20-40 mg/day.

Patients who had been receiving benzodiazepines for at least 10 days before entering the study were permitted to continue these agents, providing that dose remained unchanged throughout the study period. A low dose sleep inducing hypnotic agent, either brotizolam or triazolam, was permitted for severe insomnia as an additional medication.


OutcomesHRSD-21.

Total dropout, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical companies market fluvoxamine and comparator drug.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesStudy authors examined the association between 5HTT gene-linked polymorphic region genotype and SSRI treatment response.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "open-label study", "HRSD score evaluations were administered at weekly intervals by trained raters, who were blind to genotyping".

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 8/49 missing from fluvoxamine group (4 due to adverse effects); 13/52 missing from control group (6 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint score for depression were not reported.

Kavoussi 1999

MethodsEight-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-IV for major depressive disorder, with a minimum baseline score of 20 on the HRSD-21.
Age (mean (SD)): 35.4 (7.7).
Exclusion criteria: other Axis I disorders (current or past), any Axis II disorder; had ever been actively suicidal, or had a history of substance dependence within 6 months of the study; had been previously treated with fluoxetine or fluvoxamine.


InterventionsFluvoxamine: number of participants not stated.
Fluoxetine: number of participants not stated.
Fluvoxamine dose range: 100-150 mg/day
Fluoxetine dose range: 20-80 mg/day.


OutcomesNo efficacy and tolerability data could be entered in a meta-analysis were reported.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesStudy authors examined prolactin response to d-fenfluramine challenge before and after antidepressant treatment.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", "the medications were blindly titrated", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details.

Selective reporting (reporting bias)High riskNo clinical outcome data were reported.

Kiev 1997

MethodsSeven-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for recurrent major depressive disorder, with a minimum baseline score of 20 on the HRSD-21.
Age range: 18-65 years old.
Exclusion criteria: woman of childbearing potential were required to use appropriate birth control methods, and no pregnant or nursing patients were included the study; patients who were not fluent in written or oral English; had a history of medication noncompliance or substance abuse within the previous 6 months (other than nicotine); had been treated within 30 days with a drug with anticipated major organ toxicity; had a severe risk of suicide or displayed auto-aggressive behavior during the current depressive episode; hypersensitivity to SSRIs; participation in previous fluvoxamine studies; significant organic disease; clinically significant laboratory abnormalities; other primary psychiatric diagnoses; patients who would not be able to return for assessment due to transportation difficulties.


InterventionsFluvoxamine: 30 participants.
Paroxetine: 30 participants.
Fluvoxamine dose range: 50-150 mg/day.
Paroxetine dose range: 20-50 mg/day.

Sufficient washout from other investigational drugs prior psychotropic drugs, and ECT was assured, and concomitant use of any psychotropic medication was prohibited. While medications to treat gastrointestinal disturbances (antacids, laxatives), and headache (acetaminophen, aspirin, ibuprofen) and to provide nighttime sedation (chloral hydrate only) were permitted, all other medication use was prohibited unless approved by the study physician.


OutcomesHRSD-21, CGI-I, CGI-S, HRSA, SCL-56.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 11/30 missing from fluvoxamine group (1 due to lack of efficacy, 2 due to adverse effects); 9/30 missing from control group (3 due to lack of efficacy, 5 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint score for depression were not reported.

Koetsier 2002

MethodsFour-week double blind, single-centre, randomised study.


ParticipantsPsychiatric inpatients suffering from major depressive disorder according to DSM-IV, with a minimum baseline score of 14 on the HRSD-17.
Age range: 32-65 years old.
Exclusion criteria: history of a treatment with a TCA with adequate plasma levels during 4 weeks.


InterventionsFluvoxamine: 27 participants.
Imipramine: 25 participants.
Fluvoxamine dose range: not stated.
Imipramine dose range: not stated.

During the treatment period no psychotropic drugs were allowed besides the study medication.


OutcomesHRSD-17, SPRS (Salpetriere retardation rating scale), shortened version of POMS (Profile of mood state).

Total dropout, dropout due to inefficiency, dropout due to side effects.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 3/27 missing from fluvoxamine group (2 due to adverse effects); 3/25 missing from control group (2 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Kostiukova 2003

MethodsSix-week, single-centre, randomised study.


ParticipantsPsychiatric inpatients meeting ICD-10 for recurrent depressive disorder without psychotic features, with a minimum baseline score of 19 on the HRSD-17. Age range: 18-65 years old.
Exclusion criteria: not stated.


InterventionsFluvoxamine: 30 participants.
Amitriptyline: 30 participants.
Fluvoxamine dose range: 50-300 mg/day.
Amitriptyline dose range: 50-250 mg/day.


OutcomesHRSD-17.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 7/30 missing from fluvoxamine group (4 due to lack of efficacy, 3 due to adverse effects); 8/30 missing from control group (3 due to lack of efficacy, 5 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Lydiard 1989

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III for major depressive disorder, with a minimum baseline score of 22 on the HRSD-17.
Age range: 23-80 years old.
Exclusion criteria: not physically healthy, were psychotic or had organic brain syndrome, had a history of bipolar affective disorder, exhibited current depressive symptomatology of less than 1 month and greater than 18 month in duration, were currently taking any psychotropic medication, were substance abusers, or exhibited a clear suicidal intent.


InterventionsFluvoxamine: 18 participants.
Imipramine: 18 participants.
Placebo: 18 participants.
Fluvoxamine dose range: 100-300 mg/day.
Imipramine dose range: 100-300 mg/day.


OutcomesHRSD-17, MADRS, CGI-I.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 1/18 missing from fluvoxamine group (1 due to adverse effects); 2/18 missing from control group (2 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

March 1990

MethodsSix-week double blind, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III for major affective disorder, with a minimum baseline score of 22 on the HRSD-17.
Age range: 18-67 years old.
Exclusion criteria: pregnant women, lactating women, or women of childbearing potential who were taking inadequate contraceptive measures; patients with schizophrenia, psychotic symptoms, organic dementias, or a diagnosis within 1 year of substance abuse or alcoholism; patients with cardiovascular, hepatic, renal, gastrointestinal, pulmonary, metabolic, or other systematic diseases that could interfere with the diagnosis, treatment, or assessment of depression; patients who required treatment with any concurrent medication that might interact with or obscure the action of the study medications; patients with clinically significant abnormalities in ECG or laboratory results; patients with multiple drug allergies; patients who had received monoamine oxidase inhibitors or lithium in the 2 weeks preceding study entry or who had received any other antidepressant drugs in the preceding 1 week; patients who had received any investigational drug or ECT in the previous 4 weeks.


InterventionsFluvoxamine: 18 participants.
Imipramine: 18 participants.
Placebo: 18 participants.
Fluvoxamine dose range: 100-300 mg/day.
Imipramine dose range: 100-300 mg/day.


OutcomesHRSD-17. MADRS, CGI-I, 58 items Hopkins symptom checklist (HSCL).

Total dropout, dropout due to inefficiency, dropout due to side effects.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes1/54 (2%) patients were with bipolar depression.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomization", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", "fluvoxamine, imipramine, and placebo were provided in identical gray capsules, "no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 5/18 missing from fluvoxamine group (5 due to adverse effects); 3/18 missing from control group (3 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Mendonca Lima 1997

MethodsFour-week open, single-centre, randomised study.


ParticipantsPatients meeting DSM-III-R for major depression or dysthymia, with a minimum baseline score of 25 on the MADRS.
Age: mean 35.6 years old (SD 8.3).
Exclusion criteria: hepatic, renal, endocrine, cardiac disease; taking any medication that could affect thyroid function.


InterventionsFluvoxamine: 20 participants.
Maprotiline: 20 participants.
Fluvoxamine dose: 100 mg/day
Maprotiline dose: 75 mg/day.

Only bromazepam (at most 18 mg/day) were allowed.


OutcomesMADRS, Newcastle Diagnostic Scale.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesThere were some patients with dysthymia, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "en ouvert" (open study), no further details.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.

Selective reporting (reporting bias)High riskSDs of endpoint score for depression were not reported.

Miller 2001

MethodsSix-week double blind, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III for major depression.
Age range: not reported.
Exclusion criteria: not reported.


InterventionsFluvoxamine: 13 participants.
Imipramine: 11 participants.
Placebo: 13 participants.
Fluvoxamine dose range: not stated.
Imipramine dose range: not stated.


OutcomesHRSD (change score only). No tolerability data could be entered in a meta-analysis were reported.


Funded by pharmaceutical companiesNo funding by pharmaceutical companies.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double blind", "HRSD score were obtained by a research clinician unaware of treatment assignment".

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Moon 1991

MethodsSix-week double blind, single-centre, randomised study.


ParticipantsPrimary care outpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 24 on the MADRS.
Age range: 18-65 years old.
Exclusion criteria: clinically important impairment of hepatic or renal function; history of epilepsy; severe suicide risk; pregnant females or those at risk of becoming pregnant.


InterventionsFluvoxamine: 31 participants.
Mianserin: 31 participants.
Fluvoxamine dose range: 100-300 mg/day.
Mianserin dose range: 60-180 mg/day.

During the study, from entry into the placebo period onwards, no other psychotropic medication (antidepressant, tranquillisers or hypnotics) were allowed, Patients were asked to keep other concurrent drugs to a minimum and to abstain from alcohol.


OutcomesMADRS, CGI-I.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with major depressive episode (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 3/31 missing from fluvoxamine group (3 due to adverse effects); 10/31 missing from control group (7 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Mullin 1988

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric inpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 17 on the HRSD-17.
Age range: 20-69 years old.
Exclusion criteria: pregnant or breast feeding; receiving other anti-depressive therapy which could not be discontinued for the duration of the trial; severe impairment of liver or renal function; history of recent myocardial infarction, any degree of heart block or any other cardiac arrhythmia, as such conditions contraindicate the use of dothiepin; history of narrow angle glaucoma, prostatic hypertrophy or epilepsy, as dothiepin should be avoided in these patients.


InterventionsFluvoxamine: 37 participants.
Dothiepin: 36 participants.
Fluvoxamine dose range: 100-300 mg/day.
Dothiepin dose range: 75-225 mg/day.


OutcomesHRSD-17, CGI-I.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with major depressive episode (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomisation", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 11/37 missing from fluvoxamine group (2 due to lack of efficacy, 9 due to adverse effects); 12/36 missing from control group (4 due to lack of efficacy, 7 due to adverse effects).

Selective reporting (reporting bias)High riskSDs for endpoint score and change score were not reported.

Murasaki 1998a

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPsychiatric in- and outpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 16 on the HRSD-17. 186 out of 218 all allocated patients (85%) were with major depressive disorder.
Age range: 18-70 years old.
Exclusion criteria: schizophrenia; history of epilepsy; depressive state due to organic brain disorder; treatment with lithium or MAO inhibitors in the previous two weeks before the study; treatment with ECT in the previous three months before the study; dysuria, glaucoma, endocrine disorder including hypothyroidism; history of drug allergy; severe cardiac, hepatic, renal, hematological disorder; pregnant, at risk of pregnant, breastfeeding female.


InterventionsFluvoxamine: 113 participants.
Amitriptyline: 122 participants.
Fluvoxamine dose range: 50-150 mg/day.
Amitriptyline dose range: 50-150 mg/day.


OutcomesHRSD-21.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical companies market fluvoxamine and comparator drug.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes15/218 (6.9%) patients were with bipolar depression, 11/218 (5.0%) were with dysthymia and 6/218 (2.8%) with depressive disorder not otherwise specified.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 43/113 missing from fluvoxamine group (1 due to lack of efficacy, 17 due to adverse effects); 56 missing from control group (2 due to lack of efficacy, 28 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Nathan 1990

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPsychiatric inpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 15 on the HRSD-17.
Age: mean 39.7 years old (SD 13.7).
Exclusion criteria: history of bipolar disorder; evidence of psychosis; concurrent medical diseases.


InterventionsFluvoxamine: 20 participants.
Desipramine: 20 participants.
Fluvoxamine dose range: not stated.
Desipramine dose range: not stated.


OutcomesHRSD-17, Raskin, somatic symptoms scale, BDI.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", "patients were rated by an independent clinician", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 3/20 missing from fluvoxamine group (2 due to adverse effects); 2/20 missing from control group (2 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Nemeroff 1995

MethodsSeven-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depression, with a minimum baseline score of 20 on the HRSD-21.
Age range: 22-62 years old.
Exclusion criteria: pregnant or nursing female; did not have written and oral fluency in the English language; history of noncompliance; had been treated within 30 days with a drug having possible toxic effects on major organs; severe risk of suicide; intolerant to SSRI side effects; had participated in previous fluvoxamine studies; had other significant organic disease or other primary psychotic diagnoses.


InterventionsFluvoxamine: 49 participants.
Sertraline: 48 participants.
Fluvoxamine dose range: 50-150 mg/day
Sertraline dose range: 50-200 mg/day.

Concomitant use of any psychotropic medications, other than chloral hydrate for nighttime sedation, was prohibited. While medications to treat gastrointestinal disturbances and headache were permitted, all other medication use was prohibited unless approved by the study physician. Lactobacillus acidophilus was used to treat SSRI-induced diarrhoea.


OutcomesHRSD-21, CGI-I, HRSA, Raskin and Covi, SCL-56.

Total dropout, dropout due to inefficiency, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", study drugs were identical in appearance, no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 21/49 missing from fluvoxamine group (2 due to lack of efficacy, 9 due to adverse effects); 9/48 missing from control group (1 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint score for depression were not reported.

Otsubo 2005

MethodsEight-week open, single-centre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-IV for major depressive disorder.
Age range: 20-69 years old.
Exclusion criteria: patients who had failed to respond to 2 or more prior antidepressant trials in their current episode; medical contraindications to antidepressant therapy; significant hematologic, endocrine, or cardiovascular disease or conditions that might impair the study drug absorption, metabolism, or excretion; acute suicidal tendencies; history of a seizure disorder; history or presence of any psychotic disorder not associated with depression; history of drug or alcohol dependence within the past 2 years; experiences of receiving fluvoxamine or nortriptyline treatment.


InterventionsFluvoxamine: 36 participants.
Nortriptyline: 38 participants.
Fluvoxamine dose range: 25-150 mg/day.
Nortriptyline dose range: 25-150 mg/day.

Patients were allowed to take lormethazepam 1-2 mg/day at bedtime for sleep whenever necessary.


OutcomesHRSD-17, CGI-I, CGI-S.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesNo funding by pharmaceutical companies.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: ''the patients were able to identify the drugs prescribed from their distinct appearance", however. "the doctor in charge was blind to the medical settings", "the raters were completely blind to the medication settings".

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 11/36 missing from fluvoxamine group (4 due to lack of efficacy, 3 due to adverse effects); 17/38 missing from control group (2 due to lack of efficacy, 7 due to adverse effects).

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Ottevanger 1995

MethodsFour-week double blind, multicentre, randomised study.


ParticipantsPsychiatric inpatients meeting Feighner criteria for depression, with a minimum baseline score of 17 on the HRSD-17.
Age: mean 54.2 years old (SD 14.0).
Exclusion criteria: patients receiving lithium or had undergone shock therapy during the previous 4 weeks; symptoms of depression which were only secondary manifestation of some other psychiatric condition; already on monoamine oxidase inhibitors or other antidepressants.


InterventionsFluvoxamine: 20 participants.
Clomipramine: 20 participants.
Fluvoxamine dose range: 100-300 mg/day.
Clomipramine dose range: 50-150 mg/day.

The use of diazepam (5-35mg/day) for sedation, and flunitrazepam (2 -4 mg/day) for insomnia was permitted.


OutcomesHRSD-17, CGI-S.

Total dropout, dropout due to inefficiency, dropout due to side effects.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes1/40 (3%) patients were with bipolar depression.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 5/20 missing from fluvoxamine group (1 due to lack of efficacy, 2 due to adverse effects); 3/20 missing from control group (2 due to lack of efficacy, 1 due to adverse effects).

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Perez 1990

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III for major depressive episode, with a minimum baseline score of 30 on the MADRS.
Age range: 18 years old or more; mean 41.6 years old.
Exclusion criteria: pregnant or at risk of becoming pregnant, breast feeding; strong suicide potential; major physical disorders such as epilepsy, hepatic or renal disease.


InterventionsFluvoxamine: 30 participants.
Mianserin: 33 participants.
Fluvoxamine dose range: 100-300 mg/day
Mianserin dose range: 60-180 mg/day.

No other form of antidepressant medication was allowed during the trial period.


OutcomesMADRS, CGI-I, Leeds Sleep Evaluation Questionnaire.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesPatients with major depressive episode (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 9/30 missing from fluvoxamine group (1 due to lack of efficacy, 6 due to adverse effects); 9/33 missing from control group (2 due to lack of efficacy, 5 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Rahman 1991

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPatients meeting DSM-III for major depressive episode, with a minimum baseline score of 29 on the MADRS.
Age range: 61-86 years old.
Exclusion criteria: concurrent depressive delusions or stupor; depression secondary to other psychiatric illness, according to DSM-III; narrow angle glaucoma; symptoms suggestive of prostatic hypertrophy; history of epilepsy, myocardial infarct within 3 months of entry into the study or any degree of heart block or other clinically significant arrhythmia.


InterventionsFluvoxamine: 26 participants.
Dothiepin: 26 participants.
Fluvoxamine dose range: 100-200 mg/day.
Dothiepin dose range: 100-200 mg/day.

Hypnotic and anxiolytic medication was allowed during the study, but other antidepressants were not.


OutcomesMADRS, CGI-I, Newcastle Scale.

Total dropout, dropout due to side effects, number of patients experiencing at least one side effect.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesPatients with major depressive episode (DSM-III) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 9/26 missing from fluvoxamine group (2 due to adverse effects); 7/26 missing from control group (2 due to adverse effects).

Selective reporting (reporting bias)High riskSDs for endpoint score and change score were not reported.

Rapaport 1996

MethodsSeven-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depressive episode, with a minimum baseline score of 20 on the HRSD-21.
Age range: 22-61 years old.
Exclusion criteria: pregnant or nursing patients; unstable medical conditions; other axis I diagnoses; acute suicidality; history of substance dependence within 6 months of the study; history of a seizure disorder; had been treated with either fluvoxamine or fluoxetine before enrolment.


InterventionsFluvoxamine: 51 participants.
Fluoxetine: 49 participants.
Fluvoxamine dose range: 100-150 mg/day.
Fluoxetine dose range: 20-80 mg/day.

Only chloral hydrate (up to a maximum of 1000 mg/day) was allowed as adjuvant medication for insomnia during the study.


OutcomesHRSD-21, CGI-I, CGI-S, HRSA, Raskin-Covi scale, SCL-56.

Total dropout, dropout due to side effects, number of patients experiencing at least one side effect, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesPatients with major depressive episode (DSM-III-R) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", "study medication was provided in identical-appearing green capsules", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 7/51 missing from fluvoxamine group (2 due to adverse effects); 8/49 missing from control group (2 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Rechlin 1994

MethodsTwo-week, randomised study.


ParticipantsPsychiatric inpatients meeting DSM-III-R for major depression, with a minimum baseline score of 20 on the HRSD.
Age range: 24-75 years old.
Exclusion criteria: diabetes mellitus, polyneuropathy, alcoholism, cardiac diseases, neurologic diseases.


InterventionsFluvoxamine: 8 participants.
Amitriptyline: 8 participants.
Doxepine: 8 participants.
Paroxetine: 8 participants.
Fluvoxamine dose: 150 mg/day.
Amitriptyline dose: 150 mg/day.
Doxepine dose: 150 mg/day.
Paroxetine dose: 20 mg/day.

No other psychopharmacologic drugs were allowed except for the continuation of lithium prophylaxis.


OutcomesNo efficacy and tolerability data could be entered in a meta-analysis were reported.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesStudy authors examined whether or not the application of SSRI in therapeutic doses influence heart rate variability.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly allocated", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details.

Selective reporting (reporting bias)High riskNo clinical outcomes were reported.

Remick 1994

MethodsSeven-week double blind, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-III-R for major depressive disorder, with a minimum baseline score of 20 on the HRSD-17.
Age range: 18-65 years old.
Exclusion criteria: any significant abnormalities detected on physical and laboratory examinations (hematology, urinalysis, clinical chemistry, ECG); a diagnosis of schizophrenia, other psychiatric disorders, or a principal diagnosis of panic disorder; history of epilepsy or seizures; history of alcohol or drug abuse within 6 months of study start; a woman who were pregnant or lactating.


InterventionsFluvoxamine: 16 participants.
Amitriptyline: 17 participants.
Fluvoxamine dose range: 50-300 mg/day.
Amitriptyline dose range: 50-300 mg/day.


OutcomesHRSD-17, CGI-I, CGI-S, CGI-Efficacy, Patient Global Improvement Scale (PGI), HRSA, Raskin-Covi scale, BDI.

Total dropout, dropout due to inefficiency, dropout due to side effects.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 3/16 missing from fluvoxamine group (3 due to adverse effects); 8/17 missing from control group (2 due to lack of efficacy, 6 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Rossini 2005

MethodsSeven-week double blind, single-centre, randomised study.


ParticipantsPsychiatric inpatients suffering from major depressive episode according to DSM-IV, with a minimum baseline score of 22 on the HRSD-21.
Age range: 59 years old or more.
Exclusion criteria: presence of any concomitant axis I diagnosis; presence of psychotic features together with somatic or neurological illnesses impairing psychiatric evaluation; mini mental state examination score less than 23.


InterventionsFluvoxamine: 40 participants.
Sertraline: 48 participants.
Fluvoxamine dose: 200 mg/day.
Sertraline dose: 150 mg/day.

Subjects had not taken nonreversible monoamine oxidase inhibitors or slow release neuroleptics for at least 1 month before entering the study. All bipolar patients were under maintenance with mood stabilizers, the treatment remained unchanged during the present trial. No other psychotropic medication was allowed with the exception of flurazepam (up to 30 mg at bed time)


OutcomesHRSD-21.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes17/84 (17%) patients were with bipolar depression.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomization was performed by a computer originated schedule".

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double blind", outcome assessors were blind to the treatment option.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 1/40 missing from fluvoxamine group (1 due to adverse effects); 3/48 missing from control group (3 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of change score for depression were not reported.

Rota 2005

MethodsSix-week, randomised study.


ParticipantsPsychiatric inpatients suffering from major depressive episode according to DSM-IV, with a minimum baseline score of 17 on the HRSD-21.
Age range: 28-65 years old.
Exclusion criteria: comorbidity with other DSM-IV axis I disorder; endocrinopathy or major medical illness; ocular glaucoma; prostatic hypertrophy; recent ECT or surgical event; use of psychoactive drugs or hormonal therapies; suicidal ideations.


InterventionsFluvoxamine: number of participants not stated.
Amitriptyline: number of participants not stated.
Fluvoxamine dose: 200 mg/day.
Amitriptyline dose: 150 mg/day.


OutcomesHRSD-21, CGI, BDI.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugUnclear.


NotesPatients with major depressive episode (DSM-IV) were included, so there might be some bipolar depression, but correct number was not reported.
Study authors assessed the time course changes in basal hypothalamic-pituitary-adrenocortical axis activity during the trial. Clinical outcome were reported only as "no difference between the two drugs", so those data could not be entered in a meta-analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details.

Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of participants not stated.

Selective reporting (reporting bias)High riskClinical outcome were reported only as "no difference between the two drugs".

Schoemaker 2002

MethodsSix-week double blind, multicentre, randomised study.


ParticipantsPsychiatric outpatients meeting DSM-IV for major depressive disorder, with a minimum baseline score of 18 on the HRSD-17.
Age range: 20-73 years old.
Exclusion criteria: Patients were excluded from the study; if their current depressive episode was present for longer than one year; if they were pregnant or lactating or women of childbearing potential not practicing a reliable method of contraception; had an actual suicide risk; had a history or present condition of: bipolar disorder, schizophrenia or psychotic symptoms, schizotypal or borderline personality disorder, or organic mental disorders; had a present condition of anxiety disorders (according to DSM-IV), eating disorders, postpartum depression, epilepsy or a history of seizure disorder or ever received treatment with anticonvulsant medication for epilepsy or seizures; alcohol or substance abuse (according to DSM-IV) during the last 6 months; had any clinically meaningful non-stable renal, hepatic, cardiovascular respiratory, cerebrovascular disease or other serious, progressive physical disease; had any clinically meaningful abnormal finding uncovered during the physical examination, ECG and/or clinically significant abnormal laboratory results at screening; had participated in other clinical trials within the last three months, suffered from withdrawal symptoms at screening as a result of drug discontinuation; had a body mass index greater than 30 or less than 18, had a known allergy or hypersensitivity to mirtazapine or fluvoxamine; had been treated during the present episode with either mirtazapine or fluvoxamine; required treatment with terfenadine, astemizole, warfarin, theophylline, or cisapride.


InterventionsFluvoxamine: 207 participants.
Mirtazapine: 205 participants.
Fluvoxamine dose range: 50-150 mg/day.
Mirtazapine dose range: 15-45 mg/day.

Concomitant intake of psychotropic was prohibited with the exception of a low dose hypnotic or anxiolytic (10 mg diazepam or equivalent dosage). Previous antidepressant treatment, including electroconvulsive therapy (ECT), had to be discontinued well in advance of randomization, excluding interference with study observations.


OutcomesHRSD-17, HRSD-21, CGI-I,CGI-S.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets comparator drug.


Fluvoxamine as an investigational or comparator drugAs a comparator drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomized", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 41/207 missing from fluvoxamine group (8 due to lack of efficacy, 16 due to adverse effects); 47/205 missing from control group (4 due to lack of efficacy, 25 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint score for depression were not reported.

Tourigny-Rivard 1996

MethodsTen-week double blind, multicentre, randomised study.


ParticipantsPatients meeting DSM-III-R for major depression, with a minimum baseline score of 18 on the HRSD-17.
Age range: 60-82 years old.


InterventionsFluvoxamine: 22 participants.
Desipramine: 25 participants.
Fluvoxamine dose range: to 150 mg/day.
Desipramine dose range: to 150 mg/day.


OutcomesHRSD, Geriatric Depression Scale, CGI, Brief Symptom Inventory.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesUnclear.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomised", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

Ueda 2002

MethodsFour-week, randomised study.


ParticipantsPatients meeting DSM-IV for major depressive disorder, with a minimum baseline score of 17 on the HRSD-17.
Age range: 18-77 years old.
Exclusion criteria: history of alcohol or drug abuse or dependency; physical complications; manic state or psychotic features before study.


InterventionsFluvoxamine: 24 participants.
Sulpiride: 24 participants.
Fluvoxamine dose range: not stated.
Sulpiride dose range: not stated.

None had been administered any antidepressants for at least one month before participating in the study. No drugs were taken other than BZP hypnotics, and the dosages of BZP were kept constant throughout the study period.


OutcomesHRSD-17.

Total dropout.


Funded by pharmaceutical companiesNo funding by pharmaceutical companies.


Fluvoxamine as an investigational or comparator drugUnclear.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy endpoint: 4/24 missing from fluvoxamine group; 4/24 missing from control group.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Zohar 2003

MethodsEight-week double blind, multicentre, randomised study.


ParticipantsPsychiatric inpatients suffering from major depressive episode, with or without mood congruent psychotic features not requiring antipsychotic treatment according to DSM-IV, with a minimum baseline score of 25 on the HRSD-17.
Age range: 18-70 years old.
Exclusion criteria: psychosis, a history of other psychiatric diagnosis; epilepsy or seizures; severe suicide risk; pregnant, lactating or of childbearing potential and not taking adequate contraceptive measures; clinically relevant/unstable disease which could affect the diagnosis and/or treatment of depression; hepatic or renal disease, severe heart disease, glaucoma, adrenal tumor, micturition disturbances, prostate hypertrophy; clinically relevant laboratory test abnormalities; multiple drug allergies; had been treated unsuccessfully with 2 or more antidepressants during the current episode of depression; had been treated with fluvoxamine or clomipramine during the current episode of depression.


InterventionsFluvoxamine: 44 participants.
Clomipramine: 42 participants.
Fluvoxamine dose range: 100-250 mg/day.
Clomipramine dose range: 100-250 mg/day.

Patients were required not to have received any antidepressants in the week prior to active treatment (5 weeks in the case of fluoxetine) or lithium, monoamine oxidase inhibitors, antipsychotics or ECT in the 2 weeks prior to active treatment. With the exception of oxazepam, which could be given for night-time sedation or control of anxiety, no other psychopharmacological treatments or ECT were permitted during the study.


OutcomesHRSD-17, MADRS, CGI-I, CGI-S.

Total dropout, dropout due to inefficiency, dropout due to side effects, side effect profile.


Funded by pharmaceutical companiesFunded by pharmaceutical company markets fluvoxamine.


Fluvoxamine as an investigational or comparator drugAs an investigational drug.


NotesPatients with major depressive episode (DSM-III-R) were included, so there might be some bipolar depression, but correct number was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned", no further details.

Allocation concealment (selection bias)Unclear riskNo details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind", no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskStudy endpoint: 10/44 missing from fluvoxamine group (1 due to lack of efficacy, 5 due to adverse effects); 13/42 missing from control group (10 due to adverse effects).

Selective reporting (reporting bias)High riskSDs of endpoint/change score for depression were not reported.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Baischer 1991Allocation: randomised.
Interventions: fluvoxamine versus placebo

Belliini 1992Participants: those with bipolar disorder and major depression with psychotic features.

Blier 1997Allocation: not randomised.

Davis 1991Interventions: amitriptyline versus fluoxetine.

de Jonghe 1991Participants: those with major depression (n=22) and dysthymic disorder (n=26).

de Kemp 2002Participants: those with primary depression (n=40) and primary anxiety disorder (n=38).

de Wilde 1982Participants: those with unipolar depression (n=21) and bipolar depression (n=9).

Emrich 1987Allocation: randomised, crossover.
Participants: those with major depressive disorder.
Interventions: fluvoxamine versus oxaprotilene.
Outcome: clinical data not presented for first phase of crossover.

Entsuah 2002aAllocation: not randomised. meta-analysis.

Franchini 1997Allocation: randomised.
Participants: those with major depression in remission state (not acute phase).

Gasperini 1992Allocation: randomised.
Participants: those with major depression (n=38) and those with bipolar depression (n=18).

Gonella 1990Allocation: randomised.
Participants: those with major depression (n=13), bipolar depressive disorder (n=1) and dysthymia (n=6).

Goto 2006Allocation: not randomised.

Guelfi 1983Allocation: randomised.
Participants: depressed patients. not presented operational diagnostic criteria.

Harris 1991bAllocation: not randomised.

Hewer 1994Allocation: not randomised.

Hochberg 1995Allocation: randomised.
Participants: depressed outpatients.
Interventions: fluvoxamine versus TCAs versus placebo.
Outcomes: clinical data reported for maintenance phase only; no data presented for acute phase.

Khan 1989Allocation: randomised.
Participants: those with major depression.
Interventions: fluvoxamine versus imipramine versus placebo.
Outcomes: clinical data presented only for the comparison between antidepressants and placebo, no data presented between fluvoxamine and imipramine.

Klok 1981Allocation: randomised.
Participants: those with vital depressive syndromes; not presented operational diagnostic criteria.

Lara-Munoz 1996Allocation: not randomised.

Manfredonia 1992Allocation: randomised.
Participants: those with major depression (n=32) and bipolar disorder (n=16).

Muck-Seler 1991Allocation: not randomised.

Murasaki 1998bAllocation: not randomised.
Participants: those with major depressive disorder (n=129) and those with bipolar disorder (n=15), dysthymic disorder (n=17) and depressive disorder not otherwise specified (n=5).

Namiki 1996Allocation: not randomised.
Participants: those with major depressive disorder (n=101) and those with bipolar disorder (n=8), dysthymic disorder (n=58) cyclothymic disorder (n=1) and depressive disorder not otherwise specified (n=39).

Nicolini 1996Allocation: not randomised.

Nolen 1988Allocation: not randomised.
Participants: those with major depressive episode without psychotic features (n=51) and those with psychotic features (n=20).

Phanjoo 1991Allocation: not randomised.

Poldinger 1991Allocation: randomised.
Participants: those with any form of depression as diagnosed by the investigator, not presented any diagnostic criteria.

Price 1986Allocation: not randomised.

Ravindran 1995Allocation: randomised.
Participants: those with major depression (n=17), dysthymia (n=18) and healthy controls (n=18).

Sacchetti 1994Allocation: not randomised.

Sacchetti 1997Allocation: randomised.
Participants: those with major depression with mood congruent psychotic features.

Schanda 1979Allocation: not randomised.
Participants: those with depression; not presented operational diagnostic criteria.

Serretti 2004Allocation: not randomised.

Sheline 1997Allocation: not randomised.

van den Broek 2004Allocation: randomised.
Participants: those with major depression without psychotic features (n=90), with psychotic features (n=48).

Vandel 1995Allocation: not randomised.

White 1990Allocation: randomised, crossover.
Participants: those with major depression.
Interventions: fluvoxamine versus desipramine versus placebo.
Outcome: clinical data not presented for first phase of crossover.

Yu 2001Allocation: quasi randomised (sequence generated by odd or even hospital record number)
Participants: those with major depressive disorder (n=33) and those depressive neurosis (n=27).

Zanardi 2000Allocation: randomised.
Participants: those with major depressive episode with psychotic features.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Berlin 1998

MethodsAwaiting assessment.

Participants

Interventions

Outcomes

Notes

Coleman 1981a

MethodsUnpublished.

Participants

Interventions

Outcomes

Notes

Coleman 1981b

MethodsUnpublished.

Participants

Interventions

Outcomes

Notes

Coleman 1983

MethodsUnpublished.

Participants

Interventions

Outcomes

Notes

Donovan 1993

MethodsAwaiting assessment.

Participants

Interventions

Outcomes

Notes

Doogan 1981

MethodsUnpublished.

Participants

Interventions

Outcomes

Notes

Entsuah 2002b

MethodsAwaiting assessment.

Participants

Interventions

Outcomes

Notes

Faludi 1989

MethodsPaper is not yet available.

Participants

Interventions

Outcomes

Notes

Mallick 2003

MethodsAwaiting assessment.

Participants

Interventions

Outcomes

Notes

Naito 2007

MethodsAwaiting assessment.

Participants

Interventions

Outcomes

Notes

Ushiroyama 2004

MethodsAwaiting assessment.

Participants

Interventions

Outcomes

Notes

van Beek 1981

MethodsUnpublished.

Participants

Interventions

Outcomes

Notes

 
Comparison 1. Fluvoxamine versus TCAs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response (acute phase): Primary outcome16935Odds Ratio (M-H, Random, 95% CI)0.97 [0.73, 1.29]

    1.1 vs Imipramine
6375Odds Ratio (M-H, Random, 95% CI)0.97 [0.59, 1.58]

    1.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.84 [0.38, 1.85]

    1.3 vs Amitriptyline
4185Odds Ratio (M-H, Random, 95% CI)0.79 [0.35, 1.75]

    1.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    1.5 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.11 [0.55, 2.24]

    1.6 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 2 Response (early phase)252148Odds Ratio (M-H, Random, 95% CI)0.95 [0.78, 1.15]

    2.1 vs Imipramine
121213Odds Ratio (M-H, Random, 95% CI)1.00 [0.78, 1.29]

    2.2 vs Clomipramine
5299Odds Ratio (M-H, Random, 95% CI)1.04 [0.63, 1.71]

    2.3 vs Amitriptyline
4397Odds Ratio (M-H, Random, 95% CI)0.40 [0.13, 1.19]

    2.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)1.65 [0.58, 4.73]

    2.5 vs Desipramine
140Odds Ratio (M-H, Random, 95% CI)0.78 [0.19, 3.13]

    2.6 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)0.97 [0.35, 2.68]

 3 Remission (early phase)252148Odds Ratio (M-H, Random, 95% CI)0.95 [0.73, 1.22]

    3.1 vs Imipramine
121213Odds Ratio (M-H, Random, 95% CI)1.00 [0.71, 1.42]

    3.2 vs Clomipramine
5299Odds Ratio (M-H, Random, 95% CI)0.75 [0.40, 1.41]

    3.3 vs Amitriptyline
4397Odds Ratio (M-H, Random, 95% CI)0.41 [0.10, 1.76]

    3.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)2.33 [0.54, 10.14]

    3.5 vs Desipramine
140Odds Ratio (M-H, Random, 95% CI)1.0 [0.13, 7.89]

    3.6 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)0.97 [0.18, 5.16]

 4 Remission (acute phase)16935Odds Ratio (M-H, Random, 95% CI)1.00 [0.69, 1.45]

    4.1 vs Imipramine
6375Odds Ratio (M-H, Random, 95% CI)1.07 [0.59, 1.94]

    4.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.64 [0.28, 1.49]

    4.3 vs Amitriptyline
4185Odds Ratio (M-H, Random, 95% CI)0.61 [0.28, 1.31]

    4.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)1.78 [0.67, 4.77]

    4.5 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.06 [0.48, 2.35]

    4.6 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.5 [1.31, 15.42]

 5 Depression scale - Endpoint score: low=good (early phase)5186Std. Mean Difference (IV, Random, 95% CI)0.28 [-0.01, 0.57]

    5.1 vs Imipramine
158Std. Mean Difference (IV, Random, 95% CI)0.52 [-0.00, 1.05]

    5.2 vs Amitriptyline
253Std. Mean Difference (IV, Random, 95% CI)0.47 [-0.08, 1.02]

    5.3 vs Desipramine
135Std. Mean Difference (IV, Random, 95% CI)0.18 [-0.49, 0.84]

    5.4 vs Dothiepin
140Std. Mean Difference (IV, Random, 95% CI)-0.21 [-0.83, 0.41]

 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed dataOther dataNo numeric data

    6.1 vs Imipramine
Other dataNo numeric data

    6.2 vs Clomipramine
Other dataNo numeric data

    6.3 vs Amitriptyline
Other dataNo numeric data

    6.4 vs Nortriptyline
Other dataNo numeric data

 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed dataOther dataNo numeric data

    7.1 vs Imipramine
Other dataNo numeric data

    7.2 vs Clomipramine
Other dataNo numeric data

    7.3 vs Amitriptyline
Other dataNo numeric data

    7.4 vs Nortriptyline
Other dataNo numeric data

    7.5 vs Dothiepin
Other dataNo numeric data

    7.6 vs Desipramine
Other dataNo numeric data

 8 Depression scale - Change score: decrease=good (early phase)2119Std. Mean Difference (IV, Random, 95% CI)0.66 [-0.33, 1.64]

    8.1 vs Amitriptyline
158Std. Mean Difference (IV, Random, 95% CI)1.17 [0.61, 1.73]

    8.2 vs Nortriptyline
161Std. Mean Difference (IV, Random, 95% CI)0.16 [-0.34, 0.66]

 9 Depression scale - Change score: decrease=good (early phase) - missing SDsOther dataNo numeric data

    9.1 vs Imipramine
Other dataNo numeric data

    9.2 vs Clomipramine
Other dataNo numeric data

    9.3 vs Amitriptyline
Other dataNo numeric data

    9.4 vs Desipramine
Other dataNo numeric data

    9.5 vs Dothiepine
Other dataNo numeric data

 10 Depression scale - Change score: decrease=good (acute phase)3372Std. Mean Difference (IV, Random, 95% CI)0.28 [-0.22, 0.79]

    10.1 vs Imipramine
2322Std. Mean Difference (IV, Random, 95% CI)0.17 [-0.46, 0.81]

    10.2 vs Amitriptyline
150Std. Mean Difference (IV, Random, 95% CI)0.55 [-0.01, 1.12]

 11 Depression scale - Change score: decrease=good (acute phase) - missing SDsOther dataNo numeric data

    11.1 vs Imipramine
Other dataNo numeric data

    11.2 vs Clomipramine
Other dataNo numeric data

    11.3 vs Amitriptyline
Other dataNo numeric data

    11.4 vs Desipramine
Other dataNo numeric data

    11.5 vs Dothiepine
Other dataNo numeric data

 12 Total Dropout282268Odds Ratio (M-H, Random, 95% CI)0.96 [0.79, 1.18]

    12.1 vs Imipramine
131263Odds Ratio (M-H, Random, 95% CI)1.07 [0.81, 1.41]

    12.2 vs Clomipramine
5299Odds Ratio (M-H, Random, 95% CI)1.08 [0.58, 2.00]

    12.3 vs Amitriptyline
5420Odds Ratio (M-H, Random, 95% CI)0.78 [0.51, 1.17]

    12.4 vs Nortriptiyline
174Odds Ratio (M-H, Random, 95% CI)0.54 [0.21, 1.41]

    12.5 vs Desipramine
287Odds Ratio (M-H, Random, 95% CI)1.59 [0.24, 10.70]

    12.6 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.05 [0.49, 2.25]

 13 Dropout due to inefficacy221651Odds Ratio (M-H, Random, 95% CI)1.12 [0.68, 1.83]

    13.1 vs Imipramine
10841Odds Ratio (M-H, Random, 95% CI)1.48 [0.77, 2.86]

    13.2 vs Clomipramine
3158Odds Ratio (M-H, Random, 95% CI)0.93 [0.13, 6.69]

    13.3 vs Amitriptyline
5420Odds Ratio (M-H, Random, 95% CI)0.60 [0.20, 1.74]

    13.4 vs Nortriptiyline
174Odds Ratio (M-H, Random, 95% CI)2.25 [0.39, 13.12]

    13.5 vs Desipramine
285Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    13.6 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.46 [0.08, 2.67]

 14 Dropout due to side effects241772Odds Ratio (M-H, Random, 95% CI)0.79 [0.60, 1.04]

    14.1 vs Imipramine
11908Odds Ratio (M-H, Random, 95% CI)0.91 [0.63, 1.32]

    14.2 vs Clomipramine
3158Odds Ratio (M-H, Random, 95% CI)0.70 [0.24, 1.98]

    14.3 vs Amitriptyline
5420Odds Ratio (M-H, Random, 95% CI)0.59 [0.35, 1.00]

    14.4 vs Nortriptiyline
174Odds Ratio (M-H, Random, 95% CI)0.40 [0.10, 1.70]

    14.5 vs Desipramine
287Odds Ratio (M-H, Random, 95% CI)1.0 [0.13, 7.89]

    14.6 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.47, 3.32]

 15 Number of patients experiencing at least one side effect9663Odds Ratio (M-H, Random, 95% CI)0.70 [0.49, 0.98]

    15.1 vs Imipramine
2136Odds Ratio (M-H, Random, 95% CI)0.55 [0.18, 1.64]

    15.2 vs Clomipramine
275Odds Ratio (M-H, Random, 95% CI)0.45 [0.14, 1.43]

    15.3 vs Amitriptyline
3327Odds Ratio (M-H, Random, 95% CI)0.66 [0.42, 1.04]

    15.4 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.10 [0.51, 2.37]

 16 Subgroup analysis - Response (acute phase) 1. Fluvoxamine dosing - Standard dosage6413Odds Ratio (M-H, Random, 95% CI)0.88 [0.53, 1.46]

    16.1 vs Imipramine
2200Odds Ratio (M-H, Random, 95% CI)0.92 [0.51, 1.64]

    16.2 vs Amitriptyline
169Odds Ratio (M-H, Random, 95% CI)0.41 [0.16, 1.09]

    16.3 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    16.4 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

    16.5 vs Amitriptyline
123Odds Ratio (M-H, Random, 95% CI)0.5 [0.09, 2.84]

 17 Subgroup analysis - Response (acute phase) 1. Fluvoxamine dosing - High dosage10522Odds Ratio (M-H, Random, 95% CI)1.07 [0.74, 1.55]

    17.1 vs Imipramine
4175Odds Ratio (M-H, Random, 95% CI)0.95 [0.38, 2.40]

    17.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.84 [0.38, 1.85]

    17.3 vs Amitriptyline
293Odds Ratio (M-H, Random, 95% CI)1.51 [0.57, 4.02]

    17.4 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.11 [0.55, 2.24]

 18 Subgroup analysis - Response (acute phase) 2. Comparator dosing - Standard dosage4215Odds Ratio (M-H, Random, 95% CI)1.27 [0.64, 2.50]

    18.1 vs Clomipramine
143Odds Ratio (M-H, Random, 95% CI)0.57 [0.12, 2.74]

    18.2 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.11 [0.55, 2.24]

    18.3 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 19 Subgroup analysis - Response (acute phase) 2. Comparator dosing - High dosage15892Odds Ratio (M-H, Random, 95% CI)0.99 [0.74, 1.33]

    19.1 vs Imipramine
6375Odds Ratio (M-H, Random, 95% CI)0.97 [0.59, 1.58]

    19.2 vs Clomipramine
186Odds Ratio (M-H, Random, 95% CI)0.96 [0.39, 2.39]

    19.3 vs Amitriptyline
4185Odds Ratio (M-H, Random, 95% CI)0.79 [0.35, 1.75]

    19.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    19.5 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.11 [0.55, 2.24]

    19.6 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 20 Subgroup analysis - Response (acute phase) 4. Treatment settings - Inpatient5301Odds Ratio (M-H, Random, 95% CI)1.17 [0.71, 1.92]

    20.1 vs Imipramine
2103Odds Ratio (M-H, Random, 95% CI)1.59 [0.70, 3.61]

    20.2 vs Clomipramine
186Odds Ratio (M-H, Random, 95% CI)0.96 [0.39, 2.39]

    20.3 vs Amitriptyline
160Odds Ratio (M-H, Random, 95% CI)1.0 [0.26, 3.89]

    20.4 vs Dothiepin
152Odds Ratio (M-H, Random, 95% CI)1.0 [0.34, 2.98]

 21 Subgroup analysis - Response (acute phase) 4. Treatment settings - Outpatients9564Odds Ratio (M-H, Random, 95% CI)0.84 [0.58, 1.20]

    21.1 vs Imipramine
4272Odds Ratio (M-H, Random, 95% CI)0.80 [0.46, 1.39]

    21.2 vs Clomipramine
143Odds Ratio (M-H, Random, 95% CI)0.57 [0.12, 2.74]

    21.3 vs Amitriptyline
2102Odds Ratio (M-H, Random, 95% CI)0.91 [0.17, 5.00]

    21.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    21.5 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)1.19 [0.47, 3.00]

 22 Sensitivity analysis - Response (acute phase) 2. Excluding trials dropout rate >20%5185Odds Ratio (M-H, Random, 95% CI)0.78 [0.30, 2.07]

    22.1 vs Imipramine
272Odds Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.98]

    22.2 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

    22.3 vs Clomipramine
143Odds Ratio (M-H, Random, 95% CI)0.57 [0.12, 2.74]

    22.4 vs Amitriptyline
123Odds Ratio (M-H, Random, 95% CI)0.5 [0.09, 2.84]

 23 Sensitivity analysis - Response (acute phase) 3. Worst case scenario ITT16935Odds Ratio (M-H, Random, 95% CI)0.57 [0.40, 0.81]

    23.1 vs Imipramine
6375Odds Ratio (M-H, Random, 95% CI)0.60 [0.39, 0.90]

    23.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.84 [0.38, 1.85]

    23.3 vs Amitriptyline
4185Odds Ratio (M-H, Random, 95% CI)0.34 [0.13, 0.90]

    23.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    23.5 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)0.34 [0.16, 0.72]

    23.6 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 24 Sensitivity analysis - Response (acute phase) 4. Best case scenario ITT16935Odds Ratio (M-H, Random, 95% CI)1.78 [1.18, 2.69]

    24.1 vs Imipramine
6375Odds Ratio (M-H, Random, 95% CI)1.75 [0.78, 3.92]

    24.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.99 [0.44, 2.20]

    24.3 vs Amitriptyline
4185Odds Ratio (M-H, Random, 95% CI)1.67 [0.82, 3.37]

    24.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    24.5 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)4.04 [1.85, 8.81]

    24.6 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 25 Sensitivity analysis - Response (acute phase) 5. Excluding trials with imputation methods for calculating response5343Odds Ratio (M-H, Random, 95% CI)0.90 [0.57, 1.41]

    25.1 vs Imipramine
1100Odds Ratio (M-H, Random, 95% CI)0.92 [0.42, 2.02]

    25.2 vs Clomipramine
186Odds Ratio (M-H, Random, 95% CI)0.96 [0.39, 2.39]

    25.3 vs Amitriptyline
283Odds Ratio (M-H, Random, 95% CI)0.77 [0.26, 2.24]

    25.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

 26 Sensitivity analysis - Mean change from baseline (acute phase) 5. Excluding trials for which the SD had to be borrowed from other trials3148Std. Mean Difference (IV, Random, 95% CI)0.39 [0.07, 0.72]

    26.1 vs Imipramine
124Std. Mean Difference (IV, Random, 95% CI)0.64 [-0.19, 1.47]

    26.2 vs Amitriptyline
150Std. Mean Difference (IV, Random, 95% CI)0.55 [-0.01, 1.12]

    26.3 vs Nortriptyline
174Std. Mean Difference (IV, Random, 95% CI)0.22 [-0.24, 0.67]

 27 Sensitivity analysis - Response (acute phase) 6. Wish bias - Fluvoxamine as an investigational drug14860Odds Ratio (M-H, Random, 95% CI)0.99 [0.72, 1.36]

    27.1 vs Imipramine
6375Odds Ratio (M-H, Random, 95% CI)0.97 [0.59, 1.58]

    27.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.84 [0.38, 1.85]

    27.3 vs Amitriptyline
3162Odds Ratio (M-H, Random, 95% CI)0.90 [0.32, 2.50]

    27.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    27.5 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)1.19 [0.47, 3.00]

    27.6 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 28 Sensitivity analysis - Response (acute phase) 7. Funding - Excluding trials funded by the fluvoxamine marketing company5284Odds Ratio (M-H, Random, 95% CI)1.42 [0.82, 2.43]

    28.1 vs Imipramine
2103Odds Ratio (M-H, Random, 95% CI)1.59 [0.70, 3.61]

    28.2 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

    28.3 vs Amitriptyline
160Odds Ratio (M-H, Random, 95% CI)1.0 [0.26, 3.89]

    28.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

 29 Sensitivity analysis - Response (acute phase) 7. Funding - Trials funded by the fluvoxamine marketing company11651Odds Ratio (M-H, Random, 95% CI)0.84 [0.61, 1.16]

    29.1 vs Imipramine
4272Odds Ratio (M-H, Random, 95% CI)0.80 [0.46, 1.39]

    29.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.84 [0.38, 1.85]

    29.3 vs Amitriptyline
3125Odds Ratio (M-H, Random, 95% CI)0.75 [0.25, 2.29]

    29.4 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.11 [0.55, 2.24]

 30 Sensitivity analysis - Response (acute phase) 8. Excluding trials that might include patients with bipolar depression9540Odds Ratio (M-H, Random, 95% CI)1.09 [0.68, 1.73]

    30.1 vs Imipramine
4303Odds Ratio (M-H, Random, 95% CI)0.90 [0.44, 1.83]

    30.2 vs Amitriptyline
3116Odds Ratio (M-H, Random, 95% CI)1.16 [0.50, 2.72]

    30.3 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    30.4 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 31 Sensitivity analysis - Response (acute phase) 9. Excluding trials that included patients with psychotic features16935Odds Ratio (M-H, Random, 95% CI)0.97 [0.73, 1.29]

    31.1 vs Imipramine
6375Odds Ratio (M-H, Random, 95% CI)0.97 [0.59, 1.58]

    31.2 vs Clomipramine
2129Odds Ratio (M-H, Random, 95% CI)0.84 [0.38, 1.85]

    31.3 vs Amitriptyline
4185Odds Ratio (M-H, Random, 95% CI)0.79 [0.35, 1.75]

    31.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.91 [0.36, 2.28]

    31.5 vs Dothiepin
2125Odds Ratio (M-H, Random, 95% CI)1.11 [0.55, 2.24]

    31.6 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)4.22 [0.98, 18.13]

 
Analysis 1.6 Comparison 1 Fluvoxamine versus TCAs, Outcome 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Imipramine

Amore 1989HRSD-2122.6missing1525.4missing11

Asakura 2005HRSD-1710.77.014910.67.1149skewed.

Cassano 1986HRSD-1713.4missing12013.7missing119

Claghorn 1996HRSD-2121.1missing4421.3missing44

Fabre 1996HRSD-2119missing4618.3missing48

Feighner 1989HRSD-1712.5missing2116.6missing27

Guy 1984HRSD-1714.2missing1713missing16

Itil 1983HRSD-1612.78.2910.46.814skewed.

Koetsier 2002HRSD-1719.49.72715.58.025skewed.

Lydiard 1989HRSD-1718.6missing1717.2missing18

March 1990HRSD-1715.9missing1317.1missing15

vs Clomipramine

Coleman 1982HRSD-178.8missing418.6missing43

Ottevanger 1995HRSD-1715.18.12013.97.420skewed.

vs Amitriptyline

Harris 1991aHRSD-1717.1missing2910.0missing29

Murasaki 1998aHRSD-1714.57.88016.17.683skewed.

vs Nortriptyline

Otsubo 2005HRSD-1713.57.73215.76.529skewed.

 
Analysis 1.7 Comparison 1 Fluvoxamine versus TCAs, Outcome 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Imipramine

Claghorn 1996HRSD-2116missing4415.5missing44

Fabre 1996HRSD-2114.2missing4614.3missing48

Feighner 1989HRSD-1710.5missing2116.4missing27

Guy 1984HRSD-1713.0missing1612.1missing16

Lydiard 1989HRSD-1712.8missing179.0missing18

March 1990HRSD-1712.5missing1313.8missing15

vs Clomipramine

de Wilde 1983HRSD-176.4missing215.1missing21

Zohar 2003HRSD-1713.4missing4212.3missing42

vs Amitriptyline

Barge-Schaapveld 1995HRSD-1710.05.2118.68.010skewed.

Harris 1991aHRSD-1710.4missing6.6missing26

Kostiukova 2003HRSD-177.4missing306.7missing30

Remick 1994HRSD-178.77.21310.36.010skewed.

vs Nortriptyline

Otsubo 2005HRSD-1711.98.93612.15.938skewed.

vs Dothiepin

Mullin 1988HRSD-178.3missing268.5missing24

Rahman 1991MADRS13.5missing1914.4missing21

vs Desipramine

Tourigny-Rivard 1996HRSD-174.9missing2210.8missing25

 
Analysis 1.9 Comparison 1 Fluvoxamine versus TCAs, Outcome 9 Depression scale - Change score: decrease=good (early phase) - missing SDs.
Depression scale - Change score: decrease=good (early phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Imipramine

Amore 1989HRSD-21-3.1missing15-3.4missing11

Bramanti 1988HRSD-21-11.1missing28-10.4missing30

Cassano 1986HRSD-17-12.2missing120-12.2missing119

Claghorn 1996HRSD-21-5missing44-4.6missing44

Fabre 1996HRSD-21-8.7missing46-8.2missing48

Feighner 1989HRSD-17-12.5missing21-10.6missing27

Guy 1984HRSD-17-10.4missing17-12.1missing16

Itil 1983HRSD-17-7.6missing9-11.5missing14

Koetsier 2002HRSD-17-7.6missing27-12.2missing25

Lydiard 1989HRSD-17-5.9missing17-8.2missing18

March 1990HRSD-17-9.1missing13-8.4missing15

vs Clomipramine

Coleman 1982HRSD-17-16.6missing41-16missing43

de Wilde 1983HRSD-17-6.9missing22-6.5missing21

Dick 1983HRSD-17-11.7missing15-8.6missing13

Ottevanger 1995HRSD-17-11.3missing20-11.8missing20

Zohar 2003HRSD-17-10.8missing42-9.8missing42

vs Amitriptyline

Barge-Schaapveld 1995HRSD-17-6.6missing12-8.2missing10

Kostiukova 2003HRSD-17-5.3missing30-8.6missing30

Murasaki 1998aHRSD-17-8.4missing80-7.5missing83

Remick 1994HRSD-17-6.6missing13-6.9missing9

vs Desipramine

Nathan 1990HRSD-17-8.4missing17-9.3missing18

vs Dothiepine

Mullin 1988HRSD-17-6.5missing26-7.2missing24

Rahman 1991MADRS-10.2missing19-7.9missing21

 
Analysis 1.11 Comparison 1 Fluvoxamine versus TCAs, Outcome 11 Depression scale - Change score: decrease=good (acute phase) - missing SDs.
Depression scale - Change score: decrease=good (acute phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Imipramine

Claghorn 1996HRSD-21-10.1missing44-10.4missing44

Fabre 1996HRSD-21-13.5missing46-12.2missing48

Feighner 1989HRSD-17-14.5missing21-10.8missing27

Guy 1984HRSD-17-11.6missing16-13missing16

Lydiard 1989HRSD-17-11.7missing17-17.4missing18

March 1990HRSD-17-12.5missing13-11.7missing15

vs Clomipramine

de Wilde 1983HRSD-17-17missing21-19.1missing21

Zohar 2003HRSD-17-17.2missing42-18.2missing42

vs Amitriptyline

Barge-Schaapveld 1995HRSD-17-15.7missing11-15.8missing10

Kostiukova 2003HRSD-17-18.9missing30-19missing30

Remick 1994HRSD-17-16.3missing13-14.3missing9

vs Desipramine

Nathan 1990HRSD-17-19.2missing22-13.5missing25

vs Dothiepine

Mullin 1988HRSD-17-13missing26-12.7missing24

Rahman 1991MADRS-22.1missing19-20.5missing21

 
Comparison 2. Fluvoxamine versus Heterocyclics

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response (acute phase): Primary outcome2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

    1.1 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

 2 Response (early phase)3122Odds Ratio (M-H, Random, 95% CI)0.93 [0.45, 1.94]

    2.1 vs Amineptine
140Odds Ratio (M-H, Random, 95% CI)1.0 [0.26, 3.87]

    2.2 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)0.91 [0.38, 2.17]

 3 Remission (early phase)3122Odds Ratio (M-H, Random, 95% CI)1.25 [0.50, 3.13]

    3.1 vs Amineptine
140Odds Ratio (M-H, Random, 95% CI)1.0 [0.13, 7.89]

    3.2 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)1.32 [0.47, 3.69]

 4 Remission (acute phase)2125Odds Ratio (M-H, Random, 95% CI)2.02 [0.55, 7.39]

    4.1 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)2.02 [0.55, 7.39]

 5 Depression scale - Endpoint score: low=good (early phase)280Std. Mean Difference (IV, Random, 95% CI)-0.10 [-0.54, 0.34]

    5.1 vs Amineptine
139Std. Mean Difference (IV, Random, 95% CI)-0.27 [-0.90, 0.36]

    5.2 vs Maprotiline
141Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.56, 0.66]

 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed dataOther dataNo numeric data

    6.1 vs Maprotiline
Other dataNo numeric data

 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed dataOther dataNo numeric data

    7.1 vs Mianserin
Other dataNo numeric data

 8 Depression scale - Change score: decrease=good (early phase)140Std. Mean Difference (IV, Random, 95% CI)0.01 [-0.61, 0.63]

    8.1 vs Maprotiline
140Std. Mean Difference (IV, Random, 95% CI)0.01 [-0.61, 0.63]

 9 Depression scale - Change score: decrease=good (early phase) - missing SDsOther dataNo numeric data

    9.1 vs Amineptine
Other dataNo numeric data

    9.2 vs Maplotiline
Other dataNo numeric data

    9.3 vs Mianserin
Other dataNo numeric data

 10 Depression scale - Change score: decrease=good (acute phase) - missing SDsOther dataNo numeric data

    10.3 vs Mianserin
Other dataNo numeric data

 11 Total Dropout5247Odds Ratio (M-H, Random, 95% CI)0.58 [0.25, 1.34]

    11.1 vs Amineptine
140Odds Ratio (M-H, Random, 95% CI)0.63 [0.09, 4.24]

    11.2 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]

    11.3 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)0.54 [0.11, 2.65]

 12 Dropout due to inefficacy5247Odds Ratio (M-H, Random, 95% CI)0.44 [0.06, 3.14]

    12.1 vs Amineptine
140Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]

    12.2 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    12.3 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)0.53 [0.05, 6.21]

 13 Dropout due to side effects5247Odds Ratio (M-H, Random, 95% CI)0.80 [0.33, 1.97]

    13.1 vs Amineptine
140Odds Ratio (M-H, Random, 95% CI)3.15 [0.12, 82.16]

    13.2 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]

    13.3 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)0.75 [0.20, 2.77]

 14 Number of patients experiencing at least one side effect3144Odds Ratio (M-H, Random, 95% CI)1.24 [0.46, 3.31]

    14.1 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)1.01 [0.17, 6.00]

    14.2 vs Mianserin
162Odds Ratio (M-H, Random, 95% CI)1.77 [0.62, 5.06]

 15 Sensitivity analysis - Response (acute phase) 3. Worst case scenario ITT2125Odds Ratio (M-H, Random, 95% CI)0.76 [0.10, 5.62]

    15.1 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)0.76 [0.10, 5.62]

 16 Sensitivity analysis - Response (acute phase) 4. Best case scenario ITT2125Odds Ratio (M-H, Random, 95% CI)3.04 [1.20, 7.67]

    16.1 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)3.04 [1.20, 7.67]

 17 Sensitivity analysis - Response (acute phase) 5. Excluding trials with imputation methods for calculating response162Odds Ratio (M-H, Random, 95% CI)2.24 [0.51, 9.91]

    17.1 vs Mianserin
162Odds Ratio (M-H, Random, 95% CI)2.24 [0.51, 9.91]

 18 Sensitivity analysis - Response (acute phase) 6. Wish bias - Fluvoxamine as an investigational drug162Odds Ratio (M-H, Random, 95% CI)2.24 [0.51, 9.91]

    18.1 vs Mianserin
162Odds Ratio (M-H, Random, 95% CI)2.24 [0.51, 9.91]

 19 Sensitivity analysis - Response (acute phase) 7. Funding - Trials funded by the fluvoxamine marketing company2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

    19.1 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

 20 Sensitivity analysis - Response (acute phase) 8. Excluding trials that might include patients with bipolar depression2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

    20.1 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

 21 Sensitivity analysis - Response (acute phase) 9. Excluding trials that included patients with psychotic features2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

    21.1 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)1.25 [0.55, 2.87]

 
Analysis 2.6 Comparison 2 Fluvoxamine versus Heterocyclics, Outcome 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Maprotiline

Mendonca Lima 1997MADRS13.4missing2014.0missing20

 
Analysis 2.7 Comparison 2 Fluvoxamine versus Heterocyclics, Outcome 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Mianserin

Perez 1990MADRS11.97.52213.67.525skewed.

 
Analysis 2.9 Comparison 2 Fluvoxamine versus Heterocyclics, Outcome 9 Depression scale - Change score: decrease=good (early phase) - missing SDs.
Depression scale - Change score: decrease=good (early phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Amineptine

Brunner 1994HRSD-17-9.7missing19-8.5missing20

vs Maplotiline

Kasper 1990HRSD-21-12.5missing21-15.4missing20

vs Mianserin

Moon 1991MADRS-10missing28-11.5missing21

 
Analysis 2.10 Comparison 2 Fluvoxamine versus Heterocyclics, Outcome 10 Depression scale - Change score: decrease=good (acute phase) - missing SDs.
Depression scale - Change score: decrease=good (acute phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Mianserin

Moon 1991MADRS-22missing28-24.1missing21

Perez 1990MADRS-23.9missing22-23.6missing25

 
Comparison 3. Fluvoxamine versus other SSRIs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response (acute phase): Primary outcome8967Odds Ratio (M-H, Random, 95% CI)0.96 [0.74, 1.25]

    1.1 vs Paroxetine
3281Odds Ratio (M-H, Random, 95% CI)0.83 [0.51, 1.34]

    1.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.21 [0.53, 2.75]

    1.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)1.00 [0.62, 1.61]

    1.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]

 2 Response (early phase)8967Odds Ratio (M-H, Random, 95% CI)0.98 [0.68, 1.42]

    2.1 vs Paroxetine
3281Odds Ratio (M-H, Random, 95% CI)0.71 [0.41, 1.24]

    2.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.32 [0.58, 2.98]

    2.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)1.23 [0.45, 3.41]

    2.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.60 [0.19, 1.90]

 3 Remission (early phase)7783Odds Ratio (M-H, Random, 95% CI)0.76 [0.42, 1.38]

    3.1 vs Paroxetine
3281Odds Ratio (M-H, Random, 95% CI)0.65 [0.25, 1.67]

    3.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)0.87 [0.29, 2.55]

    3.3 vs Fluoxetine
1100Odds Ratio (M-H, Random, 95% CI)0.8 [0.25, 2.57]

    3.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.99 [0.06, 16.04]

 4 Remission (acute phase)8967Odds Ratio (M-H, Random, 95% CI)0.98 [0.71, 1.37]

    4.1 vs Paroxetine
3281Odds Ratio (M-H, Random, 95% CI)0.77 [0.45, 1.33]

    4.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.31 [0.48, 3.57]

    4.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)1.24 [0.74, 2.06]

    4.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.56 [0.23, 1.34]

 5 Depression scale - Endpoint score: low=good (early phase)2177Std. Mean Difference (IV, Random, 95% CI)-0.05 [-0.35, 0.24]

    5.1 vs Paroxetine
193Std. Mean Difference (IV, Random, 95% CI)-0.07 [-0.47, 0.34]

    5.2 vs Sertraline
184Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.46, 0.39]

 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed dataOther dataNo numeric data

    6.1 vs Paroxetine
Other dataNo numeric data

    6.2 vs Sertraline
Other dataNo numeric data

    6.3 vs Citalopram
Other dataNo numeric data

    6.4 vs Fluoxetine
Other dataNo numeric data

 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed dataOther dataNo numeric data

    7.1 vs Paroxetine
Other dataNo numeric data

    7.2 vs Sertraline
Other dataNo numeric data

    7.3 vs Fluoxetine
Other dataNo numeric data

    7.4 vs Citalopram
Other dataNo numeric data

 8 Depression scale - Change score: decrease=good (early phase)180Std. Mean Difference (IV, Random, 95% CI)0.20 [-0.24, 0.64]

    8.1 vs Paroxetine
180Std. Mean Difference (IV, Random, 95% CI)0.20 [-0.24, 0.64]

 9 Depression scale - Change score: decrease=good (early phase) - missing SDsOther dataNo numeric data

    9.1 vs Paroxetine
Other dataNo numeric data

    9.2 vs Sertraline
Other dataNo numeric data

    9.3 vs Citalopram
Other dataNo numeric data

    9.4 vs Fluoxetine
Other dataNo numeric data

 10 Depression scale - Change score: decrease=good (acute phase)3230Std. Mean Difference (IV, Random, 95% CI)0.10 [-0.23, 0.42]

    10.1 vs Paroxetine
2138Std. Mean Difference (IV, Random, 95% CI)0.19 [-0.31, 0.68]

    10.2 vs Sertraline
192Std. Mean Difference (IV, Random, 95% CI)-0.06 [-0.47, 0.35]

 11 Depression scale - Change score: decrease=good (acute phase) - missing SDsOther dataNo numeric data

    11.1 vs Paroxetine
Other dataNo numeric data

    11.2 vs Sertraline
Other dataNo numeric data

    11.3 vs Citalopram
Other dataNo numeric data

    11.4 vs Fluoxetine
Other dataNo numeric data

 12 Total Dropout91126Odds Ratio (M-H, Random, 95% CI)1.25 [0.93, 1.69]

    12.1 vs Paroxetine
4334Odds Ratio (M-H, Random, 95% CI)1.03 [0.62, 1.73]

    12.2 vs Sertraline
3238Odds Ratio (M-H, Random, 95% CI)1.13 [0.24, 5.37]

    12.3 vs Fluoxetine
3337Odds Ratio (M-H, Random, 95% CI)1.14 [0.65, 2.00]

    12.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)1.42 [0.75, 2.67]

 13 Dropout due to inefficacy4365Odds Ratio (M-H, Random, 95% CI)1.44 [0.33, 6.33]

    13.1 vs Paroxetine
2180Odds Ratio (M-H, Random, 95% CI)1.00 [0.14, 6.87]

    13.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)5.11 [0.24, 109.17]

 14 Dropout due to side effects8942Odds Ratio (M-H, Random, 95% CI)1.19 [0.62, 2.28]

    14.1 vs Paroxetine
4334Odds Ratio (M-H, Random, 95% CI)0.95 [0.28, 3.26]

    14.2 vs Sertraline
3238Odds Ratio (M-H, Random, 95% CI)1.29 [0.15, 11.33]

    14.3 vs Fluoxetine
2153Odds Ratio (M-H, Random, 95% CI)0.86 [0.19, 3.89]

    14.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)1.80 [0.90, 3.59]

 15 Number of patients experiencing at least one side effect5478Odds Ratio (M-H, Random, 95% CI)0.89 [0.53, 1.51]

    15.1 vs Paroxetine
3281Odds Ratio (M-H, Random, 95% CI)0.95 [0.41, 2.23]

    15.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.70 [0.21, 2.37]

    15.3 vs Fluoxetine
1100Odds Ratio (M-H, Random, 95% CI)0.5 [0.09, 2.86]

 16 Subgroup analysis - Response (acute phase) 1. Fluvoxamine dosing - Standard dosage5542Odds Ratio (M-H, Random, 95% CI)0.92 [0.65, 1.30]

    16.1 vs Paroxetine
2161Odds Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.62]

    16.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.81 [0.36, 1.83]

    16.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)1.00 [0.62, 1.61]

 17 Subgroup analysis - Response (acute phase) 1. Fluvoxamine dosing - High dosage3425Odds Ratio (M-H, Random, 95% CI)1.02 [0.65, 1.60]

    17.1 vs Paroxetine
1120Odds Ratio (M-H, Random, 95% CI)0.8 [0.38, 1.66]

    17.2 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]

    17.3 vs Sertraline
188Odds Ratio (M-H, Random, 95% CI)1.88 [0.77, 4.63]

 18 Subgroup analysis - Response (acute phase) 2. Comparator dosing - Standard dosage2304Odds Ratio (M-H, Random, 95% CI)0.95 [0.60, 1.50]

    18.1 vs Paroxetine
1120Odds Ratio (M-H, Random, 95% CI)0.8 [0.38, 1.66]

    18.2 vs Fluoxetine
1184Odds Ratio (M-H, Random, 95% CI)1.06 [0.59, 1.91]

 19 Subgroup analysis - Response (acute phase) 2. Comparator dosing - High dosage6663Odds Ratio (M-H, Random, 95% CI)0.96 [0.70, 1.33]

    19.1 vs Paroxetine
2161Odds Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.62]

    19.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.21 [0.53, 2.75]

    19.3 vs Fluoxetine
1100Odds Ratio (M-H, Random, 95% CI)0.89 [0.40, 2.03]

    19.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]

 20 Sensitivity analysis - Response (acute phase) 2. Excluding trials dropout rate >20%2188Odds Ratio (M-H, Random, 95% CI)1.27 [0.61, 2.62]

    20.1 vs Sertraline
188Odds Ratio (M-H, Random, 95% CI)1.88 [0.77, 4.63]

    20.2 vs Fluoxetine
1100Odds Ratio (M-H, Random, 95% CI)0.89 [0.40, 2.03]

 21 Sensitivity analysis - Response (acute phase) 3. Worst case scenario ITT8967Odds Ratio (M-H, Random, 95% CI)0.68 [0.43, 1.05]

    21.1 vs Paroxetine
3281Odds Ratio (M-H, Random, 95% CI)0.33 [0.09, 1.15]

    21.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)0.97 [0.47, 1.99]

    21.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)0.84 [0.52, 1.35]

    21.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]

 22 Sensitivity analysis - Response (acute phase) 4. Best case scenario ITT8967Odds Ratio (M-H, Random, 95% CI)1.33 [1.02, 1.74]

    22.1 vs Paroxetine
3281Odds Ratio (M-H, Random, 95% CI)1.77 [1.08, 2.92]

    22.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.44 [0.72, 2.90]

    22.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)1.28 [0.79, 2.07]

    22.4 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]

 23 Sensitivity analysis - Response (acute phase) 5. Excluding trials with imputation methods for calculating response4622Odds Ratio (M-H, Random, 95% CI)0.89 [0.64, 1.24]

    23.1 vs Paroxetine
2221Odds Ratio (M-H, Random, 95% CI)0.75 [0.43, 1.31]

    23.2 vs Fluoxetine
1184Odds Ratio (M-H, Random, 95% CI)1.06 [0.59, 1.91]

    23.3 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]

 24 Sensitivity analysis - Mean change from baseline (acute phase) 5. Excluding trials for which the SD had to be borrowed from other trials3230Std. Mean Difference (IV, Random, 95% CI)0.10 [-0.23, 0.42]

    24.1 vs Paroxetine
2138Std. Mean Difference (IV, Random, 95% CI)0.19 [-0.31, 0.68]

    24.2 vs Sertraline
192Std. Mean Difference (IV, Random, 95% CI)-0.06 [-0.47, 0.35]

 25 Sensitivity analysis - Response (acute phase) 6. Wish bias - Fluvoxamine as an investigational drug188Odds Ratio (M-H, Random, 95% CI)1.88 [0.77, 4.63]

    25.1 vs Sertraline
188Odds Ratio (M-H, Random, 95% CI)1.88 [0.77, 4.63]

 26 Sensitivity analysis - Response (acute phase) 7. Funding - Excluding trials funded by the fluvoxamine marketing company3425Odds Ratio (M-H, Random, 95% CI)1.02 [0.65, 1.60]

    26.1 vs Paroxetine
1120Odds Ratio (M-H, Random, 95% CI)0.8 [0.38, 1.66]

    26.2 vs Sertraline
188Odds Ratio (M-H, Random, 95% CI)1.88 [0.77, 4.63]

    26.3 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]

 27 Sensitivity analysis - Response (acute phase) 7. Funding - Trials funded by the fluvoxamine marketing company5542Odds Ratio (M-H, Random, 95% CI)0.92 [0.65, 1.30]

    27.1 vs Paroxetine
2161Odds Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.62]

    27.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.81 [0.36, 1.83]

    27.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)1.00 [0.62, 1.61]

 28 Sensitivity analysis - Response (acute phase) 8. Excluding trials that might include patients with bipolar depression3258Odds Ratio (M-H, Random, 95% CI)0.84 [0.51, 1.39]

    28.1 vs Paroxetine
2161Odds Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.62]

    28.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.81 [0.36, 1.83]

 29 Sensitivity analysis - Response (acute phase) 9. Excluding trials that included patients with psychotic features6630Odds Ratio (M-H, Random, 95% CI)1.01 [0.73, 1.39]

    29.1 vs Paroxetine
2161Odds Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.62]

    29.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.21 [0.53, 2.75]

    29.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)1.00 [0.62, 1.61]

 
Analysis 3.6 Comparison 3 Fluvoxamine versus other SSRIs, Outcome 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Paroxetine

Kato 2006HRSD-2117.2missing4113.9missing39

Kiev 1997HRSD-2117.1missing2917.4missing29

vs Sertraline

Nemeroff 1995HRSD-2116.8missing4615.8missing46

vs Citalopram

Haffmans 1996HRSD-1722.3missing10921.2missing108

vs Fluoxetine

Rapaport 1996HRSD-2115.5missing4714.4missing46

 
Analysis 3.7 Comparison 3 Fluvoxamine versus other SSRIs, Outcome 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Paroxetine

Ansseau 1994HRSD-2113.27.34313.77.938skewed.

Kato 2006HRSD-219.0missing414.6missing39

Kiev 1997HRSD-2110.97.32911.57.429skewed.

vs Sertraline

Nemeroff 1995HRSD-2114.07.64612.26.546skewed.

Rossini 2005HRSD-217.612.33911.311.345skewed.

vs Fluoxetine

Dalery 2003HRSD-1710.0missing8611.3missing91

Rapaport 1996HRSD-219.6missing479.7missing46

vs Citalopram

Haffmans 1996HRSD-1718.0missing10916.6missing108

 
Analysis 3.9 Comparison 3 Fluvoxamine versus other SSRIs, Outcome 9 Depression scale - Change score: decrease=good (early phase) - missing SDs.
Depression scale - Change score: decrease=good (early phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Paroxetine

Ansseau 1994HRSD-21-7.2missing48-6.2missing45

Kiev 1997HRSD-21-7.3missing29-7missing29

vs Sertraline

Nemeroff 1995HRSD-21-7.8missing46-7.4missing46

Rossini 2005HRSD-21-10.1missing39-7.8missing45

vs Citalopram

Haffmans 1996HRSD-17-2.2missing109-3.5missing108

vs Fluoxetine

Rapaport 1996HRSD-21-9.7missing47-11.2missing46

 
Analysis 3.11 Comparison 3 Fluvoxamine versus other SSRIs, Outcome 11 Depression scale - Change score: decrease=good (acute phase) - missing SDs.
Depression scale - Change score: decrease=good (acute phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Paroxetine

Ansseau 1994HRSD-21-13.3missing43-12.3missing38

vs Sertraline

Rossini 2005HRSD-21-23.7missing39-18missing45

vs Citalopram

Haffmans 1996HRSD-17-6.5missing109-8.1missing108

vs Fluoxetine

Dalery 2003HRSD-17-12.3missing86-10.9missing91

Rapaport 1996HRSD-21-15.6missing47-15.9missing46

 
Comparison 4. Fluvoxamine versus SNRIs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response (acute phase): Primary outcome3224Odds Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.85]

    1.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

    1.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)0.40 [0.18, 0.92]

 2 Response (early phase)5351Odds Ratio (M-H, Random, 95% CI)0.73 [0.45, 1.19]

    2.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)0.65 [0.37, 1.15]

    2.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)1.01 [0.39, 2.63]

 3 Remission (early phase)5351Odds Ratio (M-H, Random, 95% CI)0.81 [0.35, 1.86]

    3.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)0.62 [0.22, 1.74]

    3.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)1.54 [0.22, 10.74]

 4 Remission (acute phase)3224Odds Ratio (M-H, Random, 95% CI)0.61 [0.34, 1.08]

    4.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.68 [0.30, 1.51]

    4.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)0.54 [0.23, 1.24]

 5 Depression scale - Endpoint score: low=good (early phase)4274Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.17, 0.32]

    5.1 vs Milnacipran
2172Std. Mean Difference (IV, Random, 95% CI)0.00 [-0.30, 0.31]

    5.2 vs Venlafaxine
2102Std. Mean Difference (IV, Random, 95% CI)0.21 [-0.21, 0.63]

 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed dataOther dataNo numeric data

    6.1 vs Milnacipran
Other dataNo numeric data

 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed dataOther dataNo numeric data

    7.1 vs Venlafaxine
Other dataNo numeric data

 8 Depression scale - Change score: decrease=good (early phase) - missing SDsOther dataNo numeric data

    8.1 vs Milnacipran
Other dataNo numeric data

    8.3 vs Venlafaxine
Other dataNo numeric data

 9 Depression scale - Change score: decrease=good (acute phase) - missing SDsOther dataNo numeric data

    9.1 vs Milnacipran
Other dataNo numeric data

    9.3 vs Venlafaxine
Other dataNo numeric data

 10 Total Dropout5351Odds Ratio (M-H, Random, 95% CI)1.57 [0.93, 2.67]

    10.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.26 [0.65, 2.45]

    10.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)2.29 [0.97, 5.43]

 11 Dropout due to inefficacy3240Odds Ratio (M-H, Random, 95% CI)0.86 [0.34, 2.16]

    11.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)0.86 [0.34, 2.16]

 12 Dropout due to side effects3240Odds Ratio (M-H, Random, 95% CI)2.38 [0.73, 7.78]

    12.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)2.38 [0.73, 7.78]

 13 Sensitivity analysis - Response (acute phase) 3. Worst case scenario ITT3224Odds Ratio (M-H, Random, 95% CI)0.20 [0.05, 0.76]

    13.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

    13.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)0.11 [0.04, 0.29]

 14 Sensitivity analysis - Response (acute phase) 4. Best case scenario ITT3224Odds Ratio (M-H, Random, 95% CI)1.41 [0.43, 4.66]

    14.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

    14.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)2.67 [0.98, 7.26]

 15 Sensitivity analysis - Response (acute phase) 5. Excluding trials with imputation methods for calculating response1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

    15.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

 16 Sensitivity analysis - Response (acute phase) 6. Wish bias - Fluvoxamine as a comparator drug3224Odds Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.85]

    16.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

    16.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)0.40 [0.18, 0.92]

 17 Sensitivity analysis - Response (acute phase) 7. Funding - Excluding trials funded by the fluvoxamine marketing company3224Odds Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.85]

    17.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

    17.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)0.40 [0.18, 0.92]

 18 Sensitivity analysis - Response (acute phase) 8. Excluding trials that might include patients with bipolar depression3224Odds Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.85]

    18.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.23]

    18.2 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)0.40 [0.18, 0.92]

 19 Sensitivity analysis - Response (acute phase) 9. Excluding trials that included patients with psychotic features2111Odds Ratio (M-H, Random, 95% CI)0.40 [0.18, 0.92]

    19.1 vs Venlafaxine
2111Odds Ratio (M-H, Random, 95% CI)0.40 [0.18, 0.92]

 
Analysis 4.6 Comparison 4 Fluvoxamine versus SNRIs, Outcome 6 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Milnacipran

Ansseau 1991bHRSD-2420.88.41920.110.142skewed.

 
Analysis 4.7 Comparison 4 Fluvoxamine versus SNRIs, Outcome 7 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Venlafaxine

Hackett 1998aMADRS10.511.1117.66.831skewed.

Hackett 1998bMADRS10.511.11010.59.328skewed.

 
Analysis 4.8 Comparison 4 Fluvoxamine versus SNRIs, Outcome 8 Depression scale - Change score: decrease=good (early phase) - missing SDs.
Depression scale - Change score: decrease=good (early phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Milnacipran

Ansseau 1991aHRSD-21-11.7missing19-11.6missing42

Ansseau 1991bHRSD-21-11.7missing18-12.4missing41

Clerc 2001HRSD-21-10.9missing56-12.6missing57

vs Venlafaxine

Hackett 1998aMADRS-8.4missing16-11.7missing36

Hackett 1998bMADRS-8.4missing15-10missing35

 
Analysis 4.9 Comparison 4 Fluvoxamine versus SNRIs, Outcome 9 Depression scale - Change score: decrease=good (acute phase) - missing SDs.
Depression scale - Change score: decrease=good (acute phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Milnacipran

Clerc 2001HRSD-21-15.9missing56-20.7missing57

vs Venlafaxine

Hackett 1998aMADRS-21.1missing10-22.2missing28

Hackett 1998bMADRS-21.1missing11-24.1missing31

 
Comparison 5. Fluvoxamine versus newer ADs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response (acute phase): Primary outcome1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.31]

 2 Response (early phase)4Odds Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.72 [0.47, 1.11]

    2.2 vs Moclobemide
3231Odds Ratio (M-H, Random, 95% CI)0.60 [0.26, 1.36]

 3 Remission (early phase)4Odds Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.69 [0.36, 1.30]

    3.2 vs Moclobemide
3231Odds Ratio (M-H, Random, 95% CI)0.47 [0.16, 1.35]

 4 Remission (acute phase)1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)1.19 [0.81, 1.76]

 5 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed dataOther dataNo numeric data

    5.1 vs Mirtazapine
Other dataNo numeric data

    5.2 vs Moclobemide
Other dataNo numeric data

 6 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed dataOther dataNo numeric data

    6.1 vs Mirtazapine
Other dataNo numeric data

    6.2 vs Moclobemide
Other dataNo numeric data

 7 Depression scale - Change score: decrease=good (early phase)1Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    7.1 vs Mirtazapine
1402Std. Mean Difference (IV, Random, 95% CI)0.32 [0.12, 0.51]

 8 Depression scale - Change score: decrease=good (early phase) - missing SDsOther dataNo numeric data

    8.2 vs Moclobemide
Other dataNo numeric data

 9 Depression scale - Change score: decrease=good (acute phase)1Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    9.1 vs Mirtazapine
1402Std. Mean Difference (IV, Random, 95% CI)0.08 [-0.12, 0.28]

 10 Total Dropout4Odds Ratio (M-H, Random, 95% CI)Subtotals only

    10.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.83 [0.52, 1.33]

    10.2 vs Moclobemide
3231Odds Ratio (M-H, Random, 95% CI)1.41 [0.73, 2.71]

 11 Dropout due to inefficacy4Odds Ratio (M-H, Random, 95% CI)Subtotals only

    11.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)2.02 [0.60, 6.82]

    11.2 vs Moclobemide
3231Odds Ratio (M-H, Random, 95% CI)0.62 [0.14, 2.71]

 12 Dropout due to side effects4Odds Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.60 [0.31, 1.17]

    12.2 vs Moclobemide
3231Odds Ratio (M-H, Random, 95% CI)1.51 [0.64, 3.53]

 13 Number of patients experiencing at least one side effect3Odds Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 vs Moclobemide
3231Odds Ratio (M-H, Random, 95% CI)2.29 [1.35, 3.88]

 14 Sensitivity analysis - Response (acute phase) 3. Worst case scenario ITT1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    14.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.77 [0.51, 1.15]

 15 Sensitivity analysis - Response (acute phase) 4. Best case scenario ITT1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    15.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.95 [0.64, 1.42]

 16 Sensitivity analysis - Response (acute phase) 5. Excluding trials with imputation methods for calculating response1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    16.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.31]

 17 Sensitivity analysis - Mean change from baseline (acute phase) 5. Excluding trials for which the SD had to be borrowed from other trials1Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    17.1 vs Mirtazapine
1402Std. Mean Difference (IV, Random, 95% CI)0.08 [-0.12, 0.28]

 18 Sensitivity analysis - Response (acute phase) 6. Wish bias - Fluvoxamine as a comparator drug1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    18.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.31]

 19 Sensitivity analysis - Response (acute phase) 8. Excluding trials that might include patients with bipolar depression1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    19.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.31]

 20 Sensitivity analysis - Response (acute phase) 7. Funding - Excluding trials funded by the fluvoxamine marketing company1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    20.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.31]

 21 Sensitivity analysis - Response (acute phase) 9. Excluding trials that included patients with psychotic features1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    21.1 vs Mirtazapine
1412Odds Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.31]

 
Analysis 5.5 Comparison 5 Fluvoxamine versus newer ADs, Outcome 5 Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (early phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Mirtazapine

Schoemaker 2002HRSD-1716.5missing20314.8missing199

vs Moclobemide

Bocksberger 1993MADRS31.59.81920.010.819skewed.

 
Analysis 5.6 Comparison 5 Fluvoxamine versus newer ADs, Outcome 6 Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data.
Depression scale - Endpoint score: low=good (acute phase) - missing SDs or skewed data

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Mirtazapine

Schoemaker 2002HRSD-1716.5missing20314.8missing199

vs Moclobemide

Bocksberger 1993MADRS31.59.81920.010.819skewed.

 
Analysis 5.8 Comparison 5 Fluvoxamine versus newer ADs, Outcome 8 Depression scale - Change score: decrease=good (early phase) - missing SDs.
Depression scale - Change score: decrease=good (early phase) - missing SDs

StudyDepression scaleFluvoxamine; meanSDncomparator; meanSDnNote

vs Moclobemide

Barrelet 1991HRSD-17-10.3missing25-10.1missing26

Bocksberger 1993NADRS-11.8missing19-21.9missing19

Bougerol 1992HRSD-17-8.4missing61-9.0missing65

 
Comparison 6. Fluvoxamine versus other conventional psychotropic drugs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response (early phase)140Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.1 vs Sulpiride
140Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 2 Remission (early phase)140Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]

    2.1 vs Sulpiride
140Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]

 3 Depression scale - Endpoint score: low=good (early phase)140Std. Mean Difference (IV, Random, 95% CI)0.47 [-0.16, 1.10]

    3.1 vs Sulpiride
140Std. Mean Difference (IV, Random, 95% CI)0.47 [-0.16, 1.10]

 4 Depression scale - Change score: decrease=good (early phase)140Std. Mean Difference (IV, Random, 95% CI)0.52 [-0.11, 1.15]

    4.1 vs Sulpiride
140Std. Mean Difference (IV, Random, 95% CI)0.52 [-0.11, 1.15]

 5 Total Dropout140Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.1 vs Sulpiride
140Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 7. Side effect profile: Fluvoxamine vs TCAs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Cardiovascular - Hypertension / tachycardia4363Odds Ratio (M-H, Random, 95% CI)1.56 [0.51, 4.78]

    1.1 vs Imipramine
136Odds Ratio (M-H, Random, 95% CI)1.64 [0.31, 8.68]

    1.2 vs Clomipramine
132Odds Ratio (M-H, Random, 95% CI)5.0 [0.22, 112.88]

    1.3 vs Amitriptyline
2295Odds Ratio (M-H, Random, 95% CI)1.04 [0.19, 5.81]

 2 Cardiovascular - Hypotension / bradycardia8930Odds Ratio (M-H, Random, 95% CI)0.40 [0.21, 0.79]

    2.1 vs Imipramine
4560Odds Ratio (M-H, Random, 95% CI)0.24 [0.10, 0.62]

    2.2 vs Clomipramine
275Odds Ratio (M-H, Random, 95% CI)1.23 [0.38, 4.02]

    2.3 vs Amitriptyline
2295Odds Ratio (M-H, Random, 95% CI)0.20 [0.03, 1.18]

 3 Dermatological - Dermatitis / rash3348Odds Ratio (M-H, Random, 95% CI)0.89 [0.17, 4.61]

    3.1 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)0.54 [0.05, 5.99]

    3.2 vs Desipramine
140Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]

    3.3 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)5.14 [0.24, 110.89]

 4 Dermatological - Sweating111248Odds Ratio (M-H, Random, 95% CI)0.49 [0.28, 0.88]

    4.1 vs Imipramine
7972Odds Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.66]

    4.2 vs Clomipramine
3216Odds Ratio (M-H, Random, 95% CI)0.88 [0.45, 1.73]

    4.3 vs Amitriptyline
160Odds Ratio (M-H, Random, 95% CI)2.07 [0.18, 24.15]

 5 Gastrointestinal - Increased salivation130Odds Ratio (M-H, Random, 95% CI)9.33 [0.96, 90.94]

    5.1 vs Imipramine
130Odds Ratio (M-H, Random, 95% CI)9.33 [0.96, 90.94]

 6 Gastrointestinal - Dry mouth171736Odds Ratio (M-H, Random, 95% CI)0.27 [0.19, 0.38]

    6.1 vs Imipramine
91055Odds Ratio (M-H, Random, 95% CI)0.24 [0.16, 0.34]

    6.2 vs Clomipramine
3216Odds Ratio (M-H, Random, 95% CI)0.43 [0.22, 0.81]

    6.3 vs Amitriptyline
3318Odds Ratio (M-H, Random, 95% CI)0.11 [0.01, 1.06]

    6.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.42 [0.16, 1.06]

    6.5 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.08 [0.01, 0.70]

 7 Gastrointestinal - Oral discomfort / taste disturbance2308Odds Ratio (M-H, Random, 95% CI)0.43 [0.06, 2.98]

    7.1 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)0.36 [0.01, 8.85]

    7.2 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.47 [0.04, 5.45]

 8 Gastrointestinal - Vomiting / nausea181805Odds Ratio (M-H, Random, 95% CI)2.35 [1.80, 3.07]

    8.1 vs Imipramine
91055Odds Ratio (M-H, Random, 95% CI)2.23 [1.59, 3.14]

    8.2 vs Clomipramine
3216Odds Ratio (M-H, Random, 95% CI)2.13 [1.06, 4.27]

    8.3 vs Amitriptyline
4387Odds Ratio (M-H, Random, 95% CI)2.86 [1.31, 6.23]

    8.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)3.01 [1.00, 9.11]

    8.5 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)2.71 [0.90, 8.19]

 9 Gastrointestinal - Constipation151666Odds Ratio (M-H, Random, 95% CI)0.53 [0.35, 0.80]

    9.1 vs Imipramine
81008Odds Ratio (M-H, Random, 95% CI)0.50 [0.27, 0.93]

    9.2 vs Clomipramine
3216Odds Ratio (M-H, Random, 95% CI)0.55 [0.27, 1.09]

    9.3 vs Amitriptyline
2295Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.25]

    9.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.64 [0.25, 1.60]

    9.5 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.31 [0.03, 3.08]

 10 Gastrointestinal - Diarrhoea5518Odds Ratio (M-H, Random, 95% CI)2.98 [1.08, 8.20]

    10.1 vs Imipramine
2136Odds Ratio (M-H, Random, 95% CI)6.38 [1.27, 32.04]

    10.2 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)0.36 [0.01, 8.85]

    10.3 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)1.82 [0.66, 5.00]

    10.4 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)9.81 [0.51, 189.07]

 11 Gastrointestinal - Weight gain4425Odds Ratio (M-H, Random, 95% CI)0.53 [0.25, 1.09]

    11.1 vs Imipramine
130Odds Ratio (M-H, Random, 95% CI)1.0 [0.23, 4.31]

    11.2 vs Clomipramine
186Odds Ratio (M-H, Random, 95% CI)0.24 [0.05, 1.22]

    11.3 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)3.27 [0.13, 81.01]

    11.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.44 [0.16, 1.21]

 12 Gastrointestinal - Weight loss4226Odds Ratio (M-H, Random, 95% CI)2.76 [1.20, 6.34]

    12.1 vs Imipramine
266Odds Ratio (M-H, Random, 95% CI)1.88 [0.53, 6.67]

    12.2 vs Clomipramine
186Odds Ratio (M-H, Random, 95% CI)7.76 [0.91, 66.05]

    12.3 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)2.83 [0.79, 10.21]

 13 Gastrointestinal - Increased appetite2335Odds Ratio (M-H, Random, 95% CI)0.77 [0.08, 7.04]

    13.1 vs Imipramine
1100Odds Ratio (M-H, Random, 95% CI)0.32 [0.03, 3.18]

    13.2 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)3.27 [0.13, 81.01]

 14 Gastrointestinal - Anorexia61104Odds Ratio (M-H, Random, 95% CI)1.17 [0.54, 2.53]

    14.1 vs Imipramine
5869Odds Ratio (M-H, Random, 95% CI)1.12 [0.47, 2.68]

    14.2 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)2.18 [0.19, 24.38]

 15 Neuropsychiatric - Blurred vision5500Odds Ratio (M-H, Random, 95% CI)0.47 [0.23, 0.97]

    15.1 vs Clomipramine
2118Odds Ratio (M-H, Random, 95% CI)0.38 [0.06, 2.30]

    15.2 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.39]

    15.3 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.57 [0.21, 1.56]

    15.4 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.47 [0.04, 5.45]

 16 Neuropsychiatric - Dizziness / vertigo / faintness141592Odds Ratio (M-H, Random, 95% CI)0.27 [0.19, 0.38]

    16.1 vs Imipramine
91055Odds Ratio (M-H, Random, 95% CI)0.24 [0.15, 0.38]

    16.2 vs Clomipramine
186Odds Ratio (M-H, Random, 95% CI)0.21 [0.05, 0.80]

    16.3 vs Amitriptyline
2304Odds Ratio (M-H, Random, 95% CI)0.31 [0.11, 0.83]

    16.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.22 [0.07, 0.70]

    16.5 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.75 [0.18, 3.06]

 17 Neuropsychiatric - Fatigue / tiredness / asthenia5565Odds Ratio (M-H, Random, 95% CI)0.95 [0.52, 1.73]

    17.1 vs Imipramine
2200Odds Ratio (M-H, Random, 95% CI)1.06 [0.25, 4.56]

    17.2 vs Clomipramine
2130Odds Ratio (M-H, Random, 95% CI)0.86 [0.40, 1.85]

    17.3 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)1.64 [0.27, 9.98]

 18 Neuropsychiatric - Headache161621Odds Ratio (M-H, Random, 95% CI)1.09 [0.73, 1.62]

    18.1 vs Imipramine
81008Odds Ratio (M-H, Random, 95% CI)1.20 [0.71, 2.01]

    18.2 vs Clomipramine
132Odds Ratio (M-H, Random, 95% CI)1.5 [0.33, 6.83]

    18.3 vs Amitriptyline
4387Odds Ratio (M-H, Random, 95% CI)0.27 [0.07, 1.11]

    18.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)1.82 [0.66, 5.00]

    18.5 vs Desipramine
147Odds Ratio (M-H, Random, 95% CI)0.86 [0.26, 2.79]

    18.6 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)1.5 [0.24, 9.55]

 19 Neuropsychiatric - Tremor121247Odds Ratio (M-H, Random, 95% CI)0.50 [0.33, 0.75]

    19.1 vs Imipramine
6663Odds Ratio (M-H, Random, 95% CI)0.60 [0.32, 1.13]

    19.2 vs Clomipramine
3216Odds Ratio (M-H, Random, 95% CI)0.45 [0.15, 1.37]

    19.3 vs Amitriptyline
2295Odds Ratio (M-H, Random, 95% CI)0.40 [0.08, 1.88]

    19.4 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.31 [0.03, 3.08]

 20 Neuropsychiatric - Involuntary movement other than tremor3499Odds Ratio (M-H, Random, 95% CI)1.06 [0.32, 3.47]

    20.1 vs Imipramine
2430Odds Ratio (M-H, Random, 95% CI)1.28 [0.36, 4.58]

    20.2 vs Amitriptyline
169Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.99]

 21 Neuropsychiatric - Insomnia91039Odds Ratio (M-H, Random, 95% CI)1.26 [0.82, 1.92]

    21.1 vs Imipramine
6674Odds Ratio (M-H, Random, 95% CI)1.44 [0.87, 2.39]

    21.2 vs Clomipramine
2130Odds Ratio (M-H, Random, 95% CI)0.82 [0.37, 1.81]

    21.3 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)5.49 [0.26, 115.67]

 22 Neuropsychiatric - Sleepiness / drowsiness151585Odds Ratio (M-H, Random, 95% CI)0.94 [0.66, 1.33]

    22.1 vs Imipramine
81019Odds Ratio (M-H, Random, 95% CI)1.08 [0.80, 1.46]

    22.2 vs Clomipramine
132Odds Ratio (M-H, Random, 95% CI)1.09 [0.25, 4.71]

    22.3 vs Amitriptyline
4387Odds Ratio (M-H, Random, 95% CI)0.24 [0.05, 1.21]

    22.4 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.56 [0.22, 1.42]

    22.5 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.02]

 23 Neuropsychiatric - Agitation / anxiety8984Odds Ratio (M-H, Random, 95% CI)1.64 [0.94, 2.84]

    23.1 vs Imipramine
5644Odds Ratio (M-H, Random, 95% CI)2.24 [1.01, 4.97]

    23.2 vs Clomipramine
132Odds Ratio (M-H, Random, 95% CI)1.87 [0.15, 22.94]

    23.3 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)0.71 [0.19, 2.58]

    23.4 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)1.25 [0.31, 5.08]

 24 Neuropsychiatric - Manic symptom2565Odds Ratio (M-H, Random, 95% CI)0.86 [0.06, 11.58]

    24.1 vs Imipramine
1330Odds Ratio (M-H, Random, 95% CI)0.23 [0.03, 2.11]

    24.2 vs Amitriptyline
1235Odds Ratio (M-H, Random, 95% CI)3.3 [0.34, 32.19]

 25 Neuropsychiatric - Completed suicide2118Odds Ratio (M-H, Random, 95% CI)2.87 [0.29, 28.65]

    25.1 vs Clomipramine
2118Odds Ratio (M-H, Random, 95% CI)2.87 [0.29, 28.65]

 26 Neuropsychiatric - Suicide wishes / gestures / attempts3489Odds Ratio (M-H, Random, 95% CI)0.65 [0.17, 2.48]

    26.1 vs Imipramine
1330Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.80]

    26.2 vs Clomipramine
186Odds Ratio (M-H, Random, 95% CI)0.95 [0.18, 5.00]

    26.3 vs Dothiepin
173Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.00]

 27 Genitourinary - Problems urinating6818Odds Ratio (M-H, Random, 95% CI)0.44 [0.23, 0.83]

    27.1 vs Imipramine
2409Odds Ratio (M-H, Random, 95% CI)0.18 [0.04, 0.71]

    27.2 vs Amitriptyline
2295Odds Ratio (M-H, Random, 95% CI)0.55 [0.10, 2.94]

    27.3 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.51 [0.19, 1.38]

    27.4 vs Desipramine
140Odds Ratio (M-H, Random, 95% CI)0.32 [0.01, 8.26]

 28 Genitourinary - Sexual dysfunction174Odds Ratio (M-H, Random, 95% CI)0.75 [0.29, 1.99]

    28.1 vs Nortriptyline
174Odds Ratio (M-H, Random, 95% CI)0.75 [0.29, 1.99]

 
Comparison 8. Side effect profile: Fluvoxamine vs Heterocyclics

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Gastrointestinal - Dry mouth282Odds Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.20]

    1.1 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.20]

 2 Gastrointestinal - Vomiting / nausea4207Odds Ratio (M-H, Random, 95% CI)4.80 [1.47, 15.67]

    2.1 vs Maprotiline
282Odds Ratio (M-H, Random, 95% CI)2.26 [0.71, 7.17]

    2.2 vs Mianserin
2125Odds Ratio (M-H, Random, 95% CI)9.62 [1.96, 47.30]

 3 Neuropsychiatric - Dizziness / vertigo / faintness2104Odds Ratio (M-H, Random, 95% CI)0.14 [0.04, 0.48]

    3.1 vs Maprotiline
142Odds Ratio (M-H, Random, 95% CI)0.13 [0.03, 0.56]

    3.2 vs Mianserin
162Odds Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.58]

 
Comparison 9. Side effect profile: Fluvoxamine vs other SSRIs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Cardiovascular - Hypertension / tachycardia1120Odds Ratio (M-H, Random, 95% CI)2.67 [0.11, 66.85]

    1.1 vs Paroxetine
1120Odds Ratio (M-H, Random, 95% CI)2.67 [0.11, 66.85]

 2 Cardiovascular - Hypotension / bradycardia1120Odds Ratio (M-H, Random, 95% CI)4.66 [0.53, 41.16]

    2.1 vs Paroxetine
1120Odds Ratio (M-H, Random, 95% CI)4.66 [0.53, 41.16]

 3 Dermatological - Dermatitis / rash188Odds Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.92]

    3.1 vs Sertraline
188Odds Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.92]

 4 Dermatological - Sweating2157Odds Ratio (M-H, Random, 95% CI)0.34 [0.12, 0.96]

    4.1 vs Paroxetine
160Odds Ratio (M-H, Random, 95% CI)0.22 [0.05, 0.91]

    4.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.56 [0.13, 2.49]

 5 Gastrointestinal - Dry mouth2157Odds Ratio (M-H, Random, 95% CI)1.13 [0.54, 2.38]

    5.1 vs Paroxetine
160Odds Ratio (M-H, Random, 95% CI)1.59 [0.53, 4.77]

    5.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.86 [0.31, 2.33]

 6 Gastrointestinal - Vomiting / nausea6649Odds Ratio (M-H, Random, 95% CI)0.79 [0.46, 1.36]

    6.1 vs Paroxetine
2180Odds Ratio (M-H, Random, 95% CI)0.91 [0.46, 1.78]

    6.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.78 [0.73, 4.33]

    6.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)0.49 [0.21, 1.13]

 7 Gastrointestinal - Constipation160Odds Ratio (M-H, Random, 95% CI)0.46 [0.08, 2.75]

    7.1 vs Paroxetine
160Odds Ratio (M-H, Random, 95% CI)0.46 [0.08, 2.75]

 8 Gastrointestinal - Diarrhoea3257Odds Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.82]

    8.1 vs Paroxetine
160Odds Ratio (M-H, Random, 95% CI)0.36 [0.10, 1.33]

    8.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.56 [0.20, 1.59]

    8.3 vs Fluoxetine
1100Odds Ratio (M-H, Random, 95% CI)0.37 [0.13, 1.07]

 9 Gastrointestinal - Anorexia2281Odds Ratio (M-H, Random, 95% CI)0.57 [0.17, 1.95]

    9.1 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.62 [0.16, 2.36]

    9.2 vs Fluoxetine
1184Odds Ratio (M-H, Random, 95% CI)0.34 [0.01, 8.56]

 10 Neuropsychiatric - Dizziness / vertigo / faintness3238Odds Ratio (M-H, Random, 95% CI)0.72 [0.33, 1.60]

    10.1 vs Paroxetine
2141Odds Ratio (M-H, Random, 95% CI)0.65 [0.22, 1.92]

    10.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.82 [0.25, 2.64]

 11 Neuropsychiatric - Fatigue / tiredness / asthenia2157Odds Ratio (M-H, Random, 95% CI)0.56 [0.19, 1.64]

    11.1 vs Paroxetine
160Odds Ratio (M-H, Random, 95% CI)0.72 [0.15, 3.54]

    11.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.46 [0.11, 1.94]

 12 Neuropsychiatric - Headache6642Odds Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.31]

    12.1 vs Paroxetine
3261Odds Ratio (M-H, Random, 95% CI)0.96 [0.37, 2.52]

    12.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.79 [0.33, 1.92]

    12.3 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.60]

 13 Neuropsychiatric - Tremor3277Odds Ratio (M-H, Random, 95% CI)0.58 [0.21, 1.63]

    13.1 vs Paroxetine
2180Odds Ratio (M-H, Random, 95% CI)0.60 [0.14, 2.51]

    13.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.56 [0.13, 2.49]

 14 Neuropsychiatric - Insomnia3257Odds Ratio (M-H, Random, 95% CI)1.17 [0.68, 2.01]

    14.1 vs Paroxetine
160Odds Ratio (M-H, Random, 95% CI)1.71 [0.52, 5.62]

    14.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.72 [0.30, 1.73]

    14.3 vs Fluoxetine
1100Odds Ratio (M-H, Random, 95% CI)1.51 [0.64, 3.55]

 15 Neuropsychiatric - Sleepiness / drowsiness3277Odds Ratio (M-H, Random, 95% CI)1.06 [0.32, 3.46]

    15.1 vs Paroxetine
2180Odds Ratio (M-H, Random, 95% CI)0.45 [0.02, 9.92]

    15.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)1.62 [0.60, 4.41]

 16 Neuropsychiatric - Agitation / anxiety5465Odds Ratio (M-H, Random, 95% CI)0.73 [0.40, 1.35]

    16.1 vs Paroxetine
2180Odds Ratio (M-H, Random, 95% CI)1.31 [0.13, 12.78]

    16.2 vs Sertraline
2185Odds Ratio (M-H, Random, 95% CI)1.12 [0.45, 2.80]

    16.3 vs Fluoxetine
1100Odds Ratio (M-H, Random, 95% CI)0.47 [0.21, 1.05]

 17 Neuropsychiatric - Manic symptom1120Odds Ratio (M-H, Random, 95% CI)2.67 [0.11, 66.85]

    17.1 vs Paroxetine
1120Odds Ratio (M-H, Random, 95% CI)2.67 [0.11, 66.85]

 18 Neuropsychiatric - Completed suicide1217Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.12]

    18.1 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.12]

 19 Neuropsychiatric - Suicide wishes / gestures / attempts4621Odds Ratio (M-H, Random, 95% CI)1.99 [0.39, 10.05]

    19.1 vs Paroxetine
1120Odds Ratio (M-H, Random, 95% CI)2.67 [0.11, 66.85]

    19.2 vs Fluoxetine
2284Odds Ratio (M-H, Random, 95% CI)0.74 [0.05, 10.05]

    19.3 vs Citalopram
1217Odds Ratio (M-H, Random, 95% CI)9.26 [0.49, 174.04]

 20 Genitourinary - Sexual dysfunction4422Odds Ratio (M-H, Random, 95% CI)0.55 [0.26, 1.14]

    20.1 vs Paroxetine
2141Odds Ratio (M-H, Random, 95% CI)0.75 [0.29, 1.91]

    20.2 vs Sertraline
197Odds Ratio (M-H, Random, 95% CI)0.28 [0.07, 1.12]

    20.3 vs Fluoxetine
1184Odds Ratio (M-H, Random, 95% CI)0.52 [0.05, 5.80]

 
Comparison 10. Side effect profile: Fluvoxamine vs SNRIs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Cardiovascular - Hypertension / tachycardia3240Odds Ratio (M-H, Random, 95% CI)0.54 [0.21, 1.42]

    1.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)0.54 [0.21, 1.42]

 2 Cardiovascular - Hypotension / bradycardia2127Odds Ratio (M-H, Random, 95% CI)0.71 [0.28, 1.77]

    2.1 vs Milnacipran
2127Odds Ratio (M-H, Random, 95% CI)0.71 [0.28, 1.77]

 3 Dermatological - Dermatitis / rash2127Odds Ratio (M-H, Random, 95% CI)1.43 [0.22, 9.16]

    3.1 vs Milnacipran
2127Odds Ratio (M-H, Random, 95% CI)1.43 [0.22, 9.16]

 4 Dermatological - Sweating1113Odds Ratio (M-H, Random, 95% CI)3.17 [0.32, 31.43]

    4.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)3.17 [0.32, 31.43]

 5 Gastrointestinal - Increased salivation3240Odds Ratio (M-H, Random, 95% CI)0.36 [0.04, 3.38]

    5.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)0.36 [0.04, 3.38]

 6 Gastrointestinal - Dry mouth3240Odds Ratio (M-H, Random, 95% CI)1.15 [0.56, 2.36]

    6.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.15 [0.56, 2.36]

 7 Gastrointestinal - Oral discomfort / taste disturbance1113Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.36]

    7.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.36]

 8 Gastrointestinal - Vomiting / nausea3240Odds Ratio (M-H, Random, 95% CI)1.95 [1.09, 3.50]

    8.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.95 [1.09, 3.50]

 9 Gastrointestinal - Constipation3240Odds Ratio (M-H, Random, 95% CI)1.12 [0.45, 2.76]

    9.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.12 [0.45, 2.76]

 10 Gastrointestinal - Diarrhoea3240Odds Ratio (M-H, Random, 95% CI)1.52 [0.59, 3.89]

    10.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.52 [0.59, 3.89]

 11 Gastrointestinal - Weight gain2127Odds Ratio (M-H, Random, 95% CI)0.51 [0.05, 4.76]

    11.1 vs Milnacipran
2127Odds Ratio (M-H, Random, 95% CI)0.51 [0.05, 4.76]

 12 Gastrointestinal - Weight loss2127Odds Ratio (M-H, Random, 95% CI)0.86 [0.34, 2.16]

    12.1 vs Milnacipran
2127Odds Ratio (M-H, Random, 95% CI)0.86 [0.34, 2.16]

 13 Gastrointestinal - Anorexia1113Odds Ratio (M-H, Random, 95% CI)1.02 [0.06, 16.69]

    13.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)1.02 [0.06, 16.69]

 14 Neuropsychiatric - Blurred vision2127Odds Ratio (M-H, Random, 95% CI)1.66 [0.66, 4.14]

    14.1 vs Milnacipran
2127Odds Ratio (M-H, Random, 95% CI)1.66 [0.66, 4.14]

 15 Neuropsychiatric - Dizziness / vertigo / faintness3240Odds Ratio (M-H, Random, 95% CI)1.13 [0.50, 2.52]

    15.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.13 [0.50, 2.52]

 16 Neuropsychiatric - Fatigue / tiredness / asthenia1113Odds Ratio (M-H, Random, 95% CI)0.5 [0.04, 5.68]

    16.1 vs Milnacipran
1113Odds Ratio (M-H, Random, 95% CI)0.5 [0.04, 5.68]

 17 Neuropsychiatric - Headache3240Odds Ratio (M-H, Random, 95% CI)1.33 [0.59, 3.01]

    17.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.33 [0.59, 3.01]

 18 Neuropsychiatric - Tremor3240Odds Ratio (M-H, Random, 95% CI)1.49 [0.56, 3.93]

    18.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.49 [0.56, 3.93]

 19 Neuropsychiatric - Involuntary movement other than tremor3240Odds Ratio (M-H, Random, 95% CI)2.82 [0.87, 9.10]

    19.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)2.82 [0.87, 9.10]

 20 Neuropsychiatric - Insomnia3240Odds Ratio (M-H, Random, 95% CI)1.60 [0.62, 4.10]

    20.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.60 [0.62, 4.10]

 21 Neuropsychiatric - Sleepiness / drowsiness3240Odds Ratio (M-H, Random, 95% CI)1.68 [0.62, 4.54]

    21.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.68 [0.62, 4.54]

 22 Neuropsychiatric - Agitation / anxiety3240Odds Ratio (M-H, Random, 95% CI)1.95 [0.72, 5.30]

    22.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)1.95 [0.72, 5.30]

 23 Genitourinary - Problems urinating3240Odds Ratio (M-H, Random, 95% CI)0.59 [0.14, 2.55]

    23.1 vs Milnacipran
3240Odds Ratio (M-H, Random, 95% CI)0.59 [0.14, 2.55]

 
Comparison 11. Side effect profile: Fluvoxamine vs newer ADs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Cardiovascular - Hypotension / bradycardia1Odds Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 vs Moclobemide
140Odds Ratio (M-H, Random, 95% CI)3.15 [0.12, 82.16]

 2 Dermatological - Sweating2Odds Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 vs Moclobemide
2170Odds Ratio (M-H, Random, 95% CI)1.67 [0.41, 6.70]

 3 Gastrointestinal - Dry mouth3Odds Ratio (M-H, Random, 95% CI)Subtotals only