CANADIAN COORDINATING OFFICE FOR HEALTH TECHNOLOGY ASSESSMENT

SELECTIVE SEROTONINREUPTAKE INHIBITORS (SSRIS)

FOR MAJOR DEPRESSION

PART 1

EVALUATION OF THECLINICAL LITERATURE

CCOHTA REPORT 1997: 3E

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Legal Deposit - 1997National Library of CanadaISBN 1-895561-55-8

CANADIAN COORDINATING OFFICE FOR HEALTH TECHNOLOGY ASSESSMENT

SELECTIVE SEROTONINREUPTAKE INHIBITORS (SSRIS)

FOR MAJOR DEPRESSION

PART 1

EVALUATION OF THECLINICAL LITERATURE

DR. EVELINDA TRINDADE

DR. DEVIDAS MENON

AUGUST 1997

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This report was reviewed by externalreviewers and by members of a sub-committee of CCOHTA’s ScientificAdvisory Panel. These individualskindly provided comments on drafts ofthis report. This final document incor-porates most of the Reviewers com-ments, however, CCOHTA takes soleresponsibility for its form and content.

REVIEWERSExternal ReviewersDr. Sten ThelanderPsychiatrist, Swedish Council on TechnologyAssessment in Health CareStockholm, Sweden

Dr. Gilbert PinardDirector, Department of PsychologyMcGill UniversityMontreal, Quebec

Mr. Lawrence AnnableStatistician, AMI Pharmacology Unit,McGill UniversityMontreal, Quebec

SmithKline Beecham Inc.Oakville, Ontario

Eli Lilly Canada Inc.Scarborough, Ontario

Pfizer Canada Inc.Pointe-Claire, Dorval, Quebec

Solvay Pharma Inc.Scarborough, Ontario

Pharmac. New Zealand

Subcommittee MembersDr. Bernie O’BrienAssociate Professor, McMaster UniversityCentre for Evaluation of MedicinesSt. Joseph’s Hospital, Hamilton, Ontario

Dr. Murray KrahnStaff Physician, Division of general Internal Medicine& Clinical EpidemiologyThe Toronto HospitalToronto, Ontario

Dr. Ingrid SketrisCollege of Pharmacy, Dalhousie UniversityHalifax, Nova Scotia

Dr. Andreas LaupacisDirector, Division of Clinical EpidemiologyOttawa Civic HospitalOttawa, Ontario

Table of Contents

1. EXECUTIVE SUMMARY 1

2. INTRODUCTION 2

3. TREATMENTS FOR DEPRESSION 4

4. SOURCES OF CLINICAL EVIDENCE 6

5. METHODS 8Inclusion criteria for trials 8

5.1 Estimation of efficacy 105.2 Estimation of completion and drop-out rates 115.3 Estimation of occurrence of adverse effects 12

6. RESULTS 136.1 Estimation of efficacy 13

6.1.1 SSRIs vs placebo 136.1.2 SSRI vs SSRI 136.1.3 SSRIs vs. classical TCAs 146.1.4 SSRIs vs. other TCAs and other antidepressants 156.1.5 Influence of patient age on effect size differences 186.1.6 Influence of dose on effect size differences 196.1.7 Influence of setting on effect size differences 216.1.8 SSRIs vs. TCAs and other antidepressants: using rate measures 21

6.2 Estimation of completion and of drop-out rates 246.2.1. Estimation of completion rates: SSRI vs. placebo 246.2.2. Estimation of completion rates: SSRI vs. other SSRIs 246.2.3 Estimation of completion rates: SSRIs vs. TCAs and other antidepressants

256.2.4 Drop-outs due to Adverse events 266.2.5 Dropouts due to lack of effect 276.2.6 Combining dropouts due to lack of effect and worsening of symptoms

286.3 Estimation of the occurrence of adverse effects 28

6.3.1 Nausea 286.3.2 Dry mouth 296.3.3. Anorexia 306.3.4. Diarrhea 306.3.5 Constipation 316.3.6. Anxiety 316.3.7. Agitation 31

6.3.8. Insomnia 326.3.9 Palpitations 326.3.10. Urinary disturbances 336.3.11. Fatigue 336.3.12. Tremor 336.3.13. Headache 346.3.14. Nervousness 346.3.15. Blurred vision 356.3.16. Sweating 356.3.17. Dizziness 356.3.18. Hypotension 36

7. CONCLUSIONS 377.1 Efficacy 377.2 Completion rates 377.3 Drop-outs 377.4 Adverse events 37

8. DISCUSSION 38

9. BIBLIOGRAPHY 43

List of Tables

Table 1 Source of Information: number of trials used 7Table 2 RCTs excluded from meta-analyses of efficacy 8

List of Figures

Fig. 1 Unadjusted prevalence estimates associated with a .80 probability of a diagno-sis of depression and of chronically depressed persons by age groupsand sex, Canada 1994-95. 3

Fig. 2 Overview of treatment of depression. 4Fig. 3 Difference in effect size (SSRIs vs. Placebo). 13Fig. 4 Difference in effect size (SSRIs vs. SSRIs). 14Fig. 5 Difference in effect size (SSRIs vs. Tertiary amines) in homogeneous subgroup

of studies. 15Fig. 6 Funnel plot : Effect size difference versus sample size. 15Fig. 7 Differences in effect size (SSRIs vs. other antidepressants). 16Fig. 7 Differences in effect size (SSRIs vs. other antidepressants)-cont’d- 17Fig. 8 Differences in effect size by age categories. 18Fig. 9 Differences in effect size in recurrent and refractory patients. 19Fig. 10 Differences in effect size by dosage (individual SSRIs). 19Fig. 10 Differences in effect size by dosage (individual SSRIs)-cont’d-. 20Fig. 11 Differences in effect size by dosage (SSRIs as a group). 20Fig. 12 Differences in effect size by setting. 21Fig. 13 Differences in rates, 50% or more improvement in HRSD (SSRIs vs. TCAs and

other ADs). 22Fig. 14 Difference in rates, improvement in CGI (SSRIs vs. TCAs and other Ads).

23Fig. 15 Completion rates (SSRIs vs. Placebo). 24Fig. 16 Completion rates (SSRIs vs. SSRIs). 24Fig. 17 Completion rates (SSRIs with TCAs and other antidepressants). 25Fig. 18 Differences in rates of drop-outs due to adverse events (SSRIs vs. TCAs).26Fig. 19 Differences in rates of drop-outs due to lack of efficacy (SSRIs and TCAs).

27Fig. 20 Differences in rates of drop-outs due to lack of efficacy and worsening of

symptoms (SSRIs vs. TCAs). 28Fig. 21 Differences in rates of nausea (SSRIs vs. TCAs). 29Fig. 22 Difference in rates of dry mouth (SSRIs vs. TCAs). 29Fig. 23 Difference in rates of anorexia (SSRIs vs. TCAs). 30Fig. 24 Difference in rates of diarrhea (SSRIs vs. TCAs). 30Fig. 25 Difference in rates of constipation (SSRIs vs. TCAs). 31Fig. 26 Difference in rates of anxiety (SSRIs vs. TCAs). 31

Fig. 32 Difference in rates of tremor (SSRIs vs. TCAs). 34Fig. 33 Difference in rates of headhache (SSRIs vs. TCAs). 34Fig. 34 Difference in rates of nervousness (SSRIs vs. TCAs). 34Fig. 35 Difference in rates of blurred vision (SSRIs vs. TCAs). 35Fig. 36 Difference in rates of sweating (SSRIs vs. TCAs). 35Fig. 37 Difference in rates of dizziness (SSRIs vs. TCAs). 36Fig. 38 Difference in rates of hypotension (SSRIs vs. TCAs). 36

APPENDIXTable of contents

List 1 References of trials included in meta-analyses .. iList 2 References of trials excluded from efficacy meta-analyses but included in completers and / or adverse events meta-anlyses.. xiList 3 References of trials excluded from the meta-analyses .. xiii

Table A1 Dose categories: interval definitions used. xvii

Fig. 1 Differences in effect size (SSRIs vs. Placebo) - individual trials -.. xviiiFig. 2 Differences in effect size (SSRIs vs. SSRIs) - individual trials -.. xxFig. 3 Differences in effect size (Fluoxetine vs. other antidepressants) -

individual trials -.. xxiFig. 4 Differences in effect size (Fluvoxamine vs. other antidepressants) -

individual trials -.. xxiiiFig. 5 Differences in effect size (Paroxetine vs. other antidepressants) -

individual trials -.. xxivFig. 6 Differences in effect size (Sertraline vs. other antidepressants). -

individual trials -.. xxvFig. 7 Differences in rates - 50% or more improvement in HRSD

(Fluoxetine vs. other antidepressants) - individual trials -.. xxviFig. 8 Differences in rates - 50% or more improvement in HRSD

(Fluvoxamine vs. other antidepressants) - individual trials -.. xxviiFig. 9 Differences in rates - 50% or more improvement in HRSD

(Paroxetine vs. other antidepressants) - individual trials -.. xxviiiFig. 10 Differences in rates - 50% or more improvement in HRSD

(Sertraline vs. other antidepressants) - individual trials -.. xxixFig. 11 Differences in rates - improvement in CGI (Fluoxetine vs.

other antidepressants) - individual trials -.. xxxFig. 12 Differences in rates - improvement in CGI (Fluvoxamine

vs. other antidepressants) - individual trials -.. xxxiFig. 13 Differences in rates - improvement in CGI (Paroxetine

vs. other antidepressants) - individual trials -.. xxxiiFig. 14 Differences in rates - improvement in CGI (Sertraline vs.

other antidepressants) - individual trials -.. xxxiiiFig. 15 Differences in rates of completion (SSRIs vs. placebo) - individual trials -.. xxxivFig. 16 Differences in rates of completion (SSRIs vs. other SSRIs) - individual trials -.. xxxviFig. 17 Differences in rates of completion (Fluoxetine vs. other antidepressants)

- individual trials -.. xxxviiFig. 18 Differences in rates of completion (Fluvoxamine vs. other antidepressants)

- individual trials -.. xxxixFig. 19 Differences in rates of completion (Paroxetine vs. other antidepressants)

- individual trials -.. xliFig. 20 Differences in rates of completion (Sertraline vs. other antidepressants)

- individual trials -.. xliiFig. 21 Differences in rates of drop-outs due to adverse events (Fluoxetine vs. TCAs)

- individual trials -.. xliiiFig. 22 Differences in rates of drop-outs due to adverse events (Fluvoxamine vs. TCAs)

- individual trials -.. x1iv

Fig. 23 Differences in rates of drop-outs due to adverse events (Paroxetine vs. TCAs)- individual trials -.. x1v

Fig. 24 Differences in rates of drop-outs due to adverse events (Sertraline vs. TCAs)- individual trials -.. x1vi

Fig. 25 Differences in rates of drop-outs due to lack of effect (Fluoxetine vs. TCAs) - individual trials -.. x1vii

Fig. 26 Differences in rates of drop-outs due to lack of effect (Fluvoxamine vs. TCAs) - individual trials -.. x1viii

Fig. 27 Differences in rates of drop-outs to lack of effect (Paroxetine vs. TCAs) - individual trials -.. x1ix

Fig. 28 Differences in rates of drop-outs to lack of effect (Sertraline vs. TCAs) - individual trials -.. 1

Fig. 29 Differences in rates of nausea (SSRIs vs. TCAs) and method (right symbol)used to elicit AE - individual trials -.. 1i

Fig. 30 Differences in rates of dry mouth (SSRIs vs. TCAs) and method (right symbol)used to elicit AE - individual trials -.. 1iii

Fig. 31 Differences in rates of anorexia (SSRIs vs. TCAs) - individual trials -.. 1vFig. 32 Differences in rates of diarrhea (SSRIs vs. TCAs) - individual trials -.. 1viFig. 33 Differences in rates of constipation (SSRIs vs. TCAs) - individual trials -.. 1viiFig. 34 Differences in rates of anxiety (SSRIs vs. TCAs) - individual trials -.. 1ixFig. 35 Differences in rates of agitation (SSRIs vs. TCAs) - individual trials -... 1xFig. 36 Differences in rates of insomnia (SSRIs vs. TCAs) - individual trials -.. 1xiFig. 37 Differences in rates of palpitations (SSRIs vs. TCAs) - individual trials -.. 1xiiFig. 38 Differences in rates of urinary disturbance (SSRIs vs. TCAs) - individual trials -.. 1xiiiFig. 39 Differences in rates of fatigue (SSRIs vs. TCAs) - individual trials -.. 1xivFig. 40 Differences in rates of tremor (SSRIs vs. TCAs) - individual trials -.. 1xvFig. 41 Differences in rates of headache (SSRIs vs. TCAs) - individual trials -.. 1xviiFig. 42 Differences in rates of nervousness (SSRIs vs. TCAs) - individual trials -.. 1xviiiFig. 43 Differences in rates of blurred vision (SSRIs vs. TCAs) - individual trials -.. 1xixFig. 44 Differences in rates of sweats (SSRIs vs. TCAs) - individual trials -.. 1xxFig. 45 Differences in rates of dizziness (SSRIs vs. TCAs) - individual trials -.. 1xxiFig. 46 Differences in rates of hypotension (SSRIs vs. TCAs) - individual trials -.. 1xxiii

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)FOR MAJOR DEPRESSION

1. EXECUTIVE SUMMARY

162 randomized controlled trials that compare selective serotonin reuptake inhibitors (SSRIs) toplacebo or other antidepressants were reviewed. Meta-analyses were undertaken to compare (i)efficacy, (ii) completion rates, and (iii) adverse effects of individual drugs and drug classes.

Efficacy (as measured by change in the Hamilton Rate Scale for Depression, or by change in theClinical Global Impression scores) was not statistically significantly different among individualSSRIs or between SSRIs as a group and TCAs or other antidepressants. This remained trueregardless of the patient mix, whether they were inpatients or outpatients, age, or drug doses.Although placebo was shown to produce improvement, SSRIs were significantly more effica-cious than placebo.

Completion rates were not statistically significantly different among individual SSRIs or betweenSSRIs as a group and TCAs or other antidepressants (whether patients are elderly or adult, orwhether they are inpatients or outpatients). Completion rates with SSRIs were significantlybetter than with placebo.

Differences in drop-outs (between SSRIs and TCAs) due to lack of effect or worsening of symptomswere not statistically significantly different. Neither were the differences in drop-out rates dueto adverse events, except when adult and outpatient group were combined. In the combinedgroup of adults and outpatients, there were 2% fewer drop-outs due to adverse events, a statisti-cally significant difference.

SSRIs were shown to be associated with statistically significantly more: nausea, anorexia, diarrhea,anxiety, agitation, insomnia and nervousness than TCAs. On the other hand, patients on SSRIshave statistically significantly fewer rates of: dry mouth, constipation, blurred vision anddizziness than with TCAs. The method by which information on adverse events was eliciteddid not significantly alter these findings.

Two previous meta-analyses examining the efficacy of SSRIs reached similar results. However, theanalyses of adverse events reported here have not previously been done.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)FOR MAJOR DEPRESSION

2. INTRODUCTION:

Depression is a common disorder with significant health and cost implications. The Diagnostic andStatistical Manual of Mental Disorders: DSM-IVTM characterizes Major Depressive Disorder(MDD) by the presence of one or more episodes (i.e., at least 2 weeks of depressed mood or lossof interest (or pleasure) in nearly all activities, accompanied by at least four additional symptomsof depression). Its prevalence has been estimated in various populations, particularly throughsurveys. In the United States, for example, it has been estimated that up to one in eight peoplemay need treatment for depression in the course of their lifetime. (Depression Guideline Panel,Agency for Health Care Policy and Research, 1993).

It has also been reported that the 12 month prevalence of a major depressive disorder averages 10.3%(Kessler et al. 1994).

Estimated prevalence figures in Canada are similar. In a 1992 survey commissioned by the CanadianMental Health Association and the Canadian Psychiatric Association one in ten respondents re-ported that they had been diagnosed with depression (Canadian Psychiatric Association and theCanadian Mental Health Association (1992), COMPAS survey of Canadians about mental health,mental illness and depression, Highlights Package. Ottawa: COMPAS Inc.). More recently, ithas been estimated from the 1994/95 National Population Health Survey1 that 6.9% of Canadi-ans aged 12 or over would have reported having suffered depressive symptoms in the previoustwo months; this amounts to approximately 1.7 million individuals. Figure 1 shows prevalenceestimates by sex and age group.

For men and women alike, the prevalence of depressive symptoms is highest among those in the 18 to24 age group, and tends to decrease with age. The difference in prevalence between men andwomen is smallest among those 65 years of age or older. The trend with age is different amongthose considered to be “chronically depressed”, i.e. those who reported suffering symptoms ofdepression for more than 4 weeks in the previous year. Among all of those who reported havingdepressive symptoms, the fraction who were chronically depressed increased with age beyond 24years of age. These fractions may be calculated from Figure 1, and increase from 40% in the 18to 24 age group to about 70% in those over 45 years of age.

1 The National Population Health Survey has been designed to measure the health status of Canadians. 20,000 householdswere surveyed, from across the country. The findings are based on 17,626 respondents, aged 12 and over. Thesurvey design may result in an under representation of elderly individuals. A detailed explanation of the surveymethodology has been published ( Tambay and Gatlin, 1995).

Figure 1.

The use of antidepressants and their costs have been increasing in Canada over recent years. InOntario, for example, the amount of antidepressant medications used increased by 35% from1990/91 to 1994/95. In 1990/91, approximately 100,000 people (8.5% of the elderly popula-tion, 65 years of age or older) were on antidepressants; four years later, this number had in-creased by 30% to 130,000 (by 1994/95; 10% of the elderly population were on antidepressants(ICES 1996)). 15% of the depressed Canadians (>250,000, 70% of whom would be chronicallydepressed) may be using antidepressants, as estimated from the 1994/95 National PopulationHealth Survey (NHS) data, and nearly 3% (>600,000) of whom did not report symptoms ofdepression may be using antidepressants. In a study of the prescription of antidepressants inthe United Kingdom, it has been reported that between 1993 and 1995, the number of prescrip-tions for antidepressants increased by nearly 33% (Donoghue et al 1996).

The Ontario study reports that expenditures on antidepressants in Ontario for elderly residentsincreased 120% in the same four-year period, from $6.50 per person to $13.25. In recent years,a new class of drugs - selective serotonin reuptake inhibitors (SSRIs) has entered the market. Itis apparent from the National Population Health Survey and other sources that SSRIs are be-coming the drugs of choice for prescribers. In fact the Ontario study cites the shift towardsSSRIs from older drugs as one of two reasons for the observed rapid growth in expenditures onantidepressants in the province. The other cause cited was a greater number of prescriptions forantidepressants generally (ICES 1996). In the UK study of antidepressant prescribing from1993 to 1995, the authors concluded that the prescription rate for SSRIs increased by 133.8%compared to 12.4% for older tricyclic agents (Donoghue et al 1996). Currently, as estimatedfrom the 1994/95 NHS data, about 65% of the chronically depressed would be using SSRIs,and around 35% would be using other antidepressants. Moreover, nearly a third of them wouldbe using more than one drug. Concomitant use of tranquilizers and sleeping pills were reportedby more than 80% of the chronically depressed

14

12

10

8

6

4

2

012 - 17 18 - 24 25 - 44 45 - 64 65 +

9.5

4.65.5

6.1

5.3

2.9

5.3 Q

7.9

3.22.7 2.3

3.1

1.8

4.8 4.6

2.2 Q

12

10

7.7

3.9

Unadjusted prevalence estimates associated with a .80 probability of a diagnosis of depression and chronically depressed persons by age groups and sex, Canada 1994-95

of

FemalesChronically depressed Chronically depressed

MalesSource: National Population Health SurveyNote: Weighted data.

Q - Estimate has high sampling variability

Percent are based on persons who answered questions related to depression and chronicity. Chronic depression isdefined as three or more episodes of at least two weeks or one episodewhich lasted more than four weeks.

%

NHS responders being treated with antidepressants.

It can be estimated that approximately $1 million a day (or $360 million a year) is spent on antide-pressants in Canada. This estimate assumes that one million Canadians are on antidepressanttherapy; and that SSRIs are prescribed two-thirds of the time, and TCAs one-third.

3. TREATMENTS FOR DEPRESSION

The two major forms of treatment for depression are pharmacotherapy and psychotherapy, individu-ally or in combination. In addition, and to a more limited extent, electroconvulsive therapy(ECT) is used, particularly for cases of severe depression or for manic patients. All of thesemodalities have benefits as well as risks. Figure 2 is a decision tree for treatment of depression.Once a diagnosis of depression has been made, patients with “mild”, “moderate” or “severe”depression may be treated using these three modalities in a number of ways.

Condition improvesor stay the same

Condition worsens

Do not seek treatment

DepressiveSymptoms

Seek treatmentDepression diagnosed

"Mild or moderate"depression

"Severe" or "Major"depression

Seek treatment

Suicide

Do not seek treatment

Psychotherapy

Psychotherapy

Pharmacotherapy

Pharmacotherapy

Psychotherapy +Pharmacotherapy

Psychotherapy +Pharmacotherapy

ECT

Fig.2 Overview of treatment of depression

Pharmacotherapy: There are three classes of antidepressants which are most commonly prescribed.Historically, tricyclic antidepressants (TCAs)1 were used as the first line antidepressant. They act

by blocking reuptake of neurotransmitters (serotonin and norepinephrine) presynaptically sothat more of them are available for the transmission of electrical impulses. TCAs now avail-able are amitriptyline, amoxapine, imipramine, clomipramine, desipramine, doxepin,dothiepin2 , maprotiline, nortriptyline, oxaprotiline3, proptriptyline and trimipramine. As is thecase with all antidepressants, TCAs may cause anticholinergic side effects, including drymouth, urinary retention, postural hypotension, blurred vision and constipation. Cardiacarrhythmias may also occur in some cases.

Monoamine oxidase inhibitors (MAOIs), another class of antidepressants, act by inhibitingmonoamine oxidase, an enzyme, from transforming neurotransmitters into metabolites, therebyincreasing the number of these for transmission. The side effects of MAOIs are not unlikethose of TCAs, but patients on MAOIs have to adhere to a diet for tyramine control to preventhypertensive crises. At present, a reversible and selective inhibitor of the MAO-A isoenzyme(RIMA), moclobemide, lacks the side effects of the older MAOIs, tends to cause lessgastrointestinal effects than the SSRIs and has not been reported to interfere with sexual func-tion. However, in Canada, MAOIs or RIMAs are not as widely used as TCAs.

SSRIs are the newest class of drugs for treating depression, and include fluoxetine, fluvoxamine,paroxetine and sertraline, and have been reported to have fewer adverse effects than TCAs orMAOIs; these include nausea, nervousness, diarrhea, agitation, dry mouth, insomnia and anxi-ety. Overall, SSRIs are considerably more expensive than the other drugs, but generic productsof fluoxetine, which have been approved for the Canadian market, have reduced the cost differ-ences with TCAs.

Other new cyclic antidepressants such bupropion3, nefazodone, trazodone and venlafaxine havelittle or no anticholinergic effects but some have also been reported to interfere with sexualfunction. They have been available in Canada but are not yet widely used.

More than half of all outpatients who begin treatment with antidepressants experience markedimprovement or remission of symptoms. In the absence of contraindications, antidepressantsare first-line treatment when there are: moderate to severe symptoms, chronic symptoms,recurrent episodes, hallucinations, melancholic symptoms, family history of depression, orwhen response to psychotherapy alone is incomplete or on the basis of patient preference(Depression Guideline Panel, 1993b).

1In this paper, the terminology TCA is used as synonymous with cyclic amine antidepressants.2 Not available in Canada

Psychotherapy: This treatment is an alternative to drugs. Psychotherapeutic approaches includecognitive therapy, behavioural therapy and inter-personal therapy. Such approaches have beenshown to be effective in a range of cases. Although psychotherapy and drug therapy were tradition-ally thought of as mutually exclusive, combinations of the two have been developed and used.

Several forms of short-term psychotherapy have been shown to be as effective as pharmacotherapyin treating most cases of major depression (Prioleau D. et al., 1983; Schulberg H. C. et al.,1996 and Brown C. et al., 1996) Psychotherapy should be considered particularly when thereare: chronicity or recurrence, no psychotic symptoms, chronic psychosocial problems, or whenthe response to drugs-only treatment has been incomplete, when medication is contraindicated,or because of patient preference (Depression Guideline Panel, 1993b).

Combined treatment: A combination of pharmaco- and psychotherapy should be consideredfor: more severe depression, when there is recurrence with poor recovery between episodes,when single therapy has poor response, when there is significant personality disorder, or again,because of patient preference (Depression Guideline Panel, 1993b).

Electroconvulsive therapy: This treatment is usually reserved for very severe or psychoticdepression or manic states that often do not respond to pharmacotherapy.

The objective of this project was (Part I) to compare SSRIs with each other and withother antidepressants with respect to efficacy, completion rates, adverse events and(Part II) cost-effectiveness in the treatment of major depression.

The therapeutic evaluation consisted of a meta-analysis that compared (i) efficacy, (ii) completionrates, and (iii) adverse effects of individual drugs and drug classes. The individual drugs were(by drug class):

SSRIs - Fluoxetine, Fluvoxamine, Paroxetine, SertralineTCAs -Amitriptyline, Imipramine, Clomipramine, Dothiepin, Doxepin, Maprotiline,

Oxaprotiline, Lofepramine, Desipramine, NortriptylineOther antidepressants1 - Mianserin, Trazodone, Moclobemide, Bupropion, Amineptine,

Nomifensine

4. SOURCES OF CLINICAL EVIDENCE

Extensive literature searches were conducted on the following biomedical bibliographic databases:Medline, EMBASE, PsycINFO, International Pharmaceutical Abstracts, Pascal, Health Plan-ning & Administration (Health), Mental Health Abstracts, PharmacoEconomics & OutcomesNews (ADPR).

1 An insufficient number of randomized trials compared SSRIs to Venlafaxine and Nefazodone.

Initial searches were limited to the period 1990 to 1995 (searches undertaken in August, 1995). Afurther search, covering the literature back to 1980 was also undertaken (in December, 1995).Finally, an update search, for literature published in 1995 and 1996 was run in May, 1996.Keywords used for the primary searches included: serotonin uptake inhibitor(s) or SSRI(s) orantidepressant(s) or monoamine oxidase inhibitor(s) or antidepressive agents, tricyclic. Inmost searches the names of the various drugs were also used. The main searches were thenrestricted to references to randomized controlled trials or clinical trials or reviews.

Throughout the course of the project the recent literature was scanned using Current Contents:Clinical Medicine, and journals received by the CCOHTA library were handsearched. Inaddition, the references from all articles retrieved were scanned. Further references were alsoobtained from bibliographies provided by other researchers. Earlier publications on this sub-ject, in particular the Agency for Health Care Policy and Research clinical practice guidelines,Depression in Primary Care (Depression Guideline Panel, 1993), and the National HealthService Centre for Reviews and Dissemination Treatment of Depression in Primary Care(Effective Health Care Bulletin, 1993), were also checked for additional references.

In all, over 1100 articles were identified. These included two-arm and three-arm trials. All paperswhich reported on a randomized trial of an SSRI against another SSRI, another antidepressant,or placebo were selected for review. Randomized trial characteristics are specified in the meth-ods section below. A total of 162 papers met the criteria for the analysis (see below).

The numbers of individual “trials” of each SSRI against the different comparators are shown in thefollowing table. Since a study reported in a single paper could have multiple comparators, thesum of the numbers of trials in Table 1 below (201) exceeds the total number of individualpapers.

Table 1 - Source of information: number of trials usedSSRI Comparator Fluoxetine Fluvoxamine Paroxetine Sertraline

TCA 43 31 25 5

Other AD* 18 5 2 1

Placebo 21 15 10 5

Other SSRI 8 3 5 4

TOTAL 90 54 42 15

* AD: antidepressant medication.

Table A1 (see Appendix) contains a list of the 162 papers on which this evaluation of SSRIs wasbased.

5. METHODS

Inclusion criteria for trials:

Only double-blind randomized controlled trials (the study design for level I of evidence of efficacy)of antidepressant therapy of 4 to 12 weeks’ duration for major depression (based on DSM-IIVR or DSM-IV criteria) were selected for the meta-analyses. In addition, trials had to providenumerical or graphical data on one or more of the following:

(a) Pre- and post-treatment Hamilton Rate Scale for Depression (HRSD) scores (Hamil-ton, 1960)

(b) Change in HRSD score following treatment(c) Number of patients experiencing 50% or more improvement in HRSD following

treatment(d) Number of patients whose Clinical Global Impression, CGI (Guy, 1976) scores im-

proved very much or markedly following treatment(e) Number of drop-outs(f) Number of adverse events.

The trials meeting these inclusion criteria included single centre and multicentre studies, in hospitaland outpatient settings, with adult and elderly patients. Multicentre trials which were publishedfirst by centre, and then in aggregated fashion, were examined to ensure that the same resultswere not used more than once. Re-analyses of published data and trials that were excludedfrom efficacy meta-analyses are listed in Table 2, along with the reasons for exclusion. Refer-ences of trials included and excluded are listed in Appendix (Lists 1 to 3). Reviews were con-sidered for purposes of discussion only.

Table 2 RCTs excluded from meta-analyses of efficacyYEAR AUTHORS COUNTRY TIME

WKSREASON FOR EXCLUSION FROM META-

ANALYSES OF EFFICACYDRUG

1DRUG

2DRUG

31989 Altamura et al Italy 5 Another publication of Altamura et al., 1989 Fluoxetine Amitryptiline

1994 Arminen et al Denmark 12 Another publication of Arminen etal., 1992 Paroxetine Imipramine

1990 Beasley et al USA 6 Reanalysis of Wernicke 1987, 1988 and 1989 Fluoxetine Placebo

1991b Beasley et al USA 6 Analysis from data of Stark & Hardison 1985 and Cohn& Wilcox 1985

Fluoxetine Imipramine Placebo

1993a Beasley et al USA 5 Analysis from data of Chouinard et al 1985, Feighner et al1985 and Masco & Sheetz 1985

Fluoxetine Amitryptiline

1989 Brasseur et al Belgium 4 Open studyand lack of indication of which tricyclic used Fluoxetine “Tricyclic”

1989 Bressa et al Italy 5 No number of patients in Fluoxetine and Imipramine Fluoxetine Imipramine

1986 Cassano Italy/Nether-land/USA

4 and6

Reanalysis of 8/ 12 RCTs: same as included in Amin etal., 1984

Fluvoxamine Imipramine Placebo

1992 Claghorn et al USA 6 Another publication of Claghorn et al., 1992 Paroxetine Placebo

1992 Claghorn et al USA 6 Reanalysis Rickels 1989, Claghorn 1992, Kiev 1992, andSmith 1992

Paroxetine Placebo

1990 Cohn et al USA 6 Data in Cohn et al 1992 Paroxetine Imipramine Placebo

1982 Coleman &Block

USA 4 Analysis from data of Dick et al 1983, DeWilde et al1982 and Klok et al 1981

Fluvoxamine Clomipramine

1987 Conti et al Italy NA Data bank analysis of RCTs: Amin et al 1984, Cassano etal 1986

Fluvoxamine Imipramine Placebo

1988 Conti Italy 4 Another publication of Conti et al 1985 Fluvoxamine Imipramine Placebo

YR AUTHOR COUNTRY TIMEWK

REASON FOR EXCLUSION FROM META-ANALYSES OF EFFICACY

DRUG 1

DRUG 2

DRUG3

1989 Conti Italy 4 Analysis of 5 RCTs: Amin et al 1984, Cassano et al 1986and others

Fluvoxamine Imipramine Placebo

1992 Dalery et al France 12 Outcome measure with scales other than HRSD:MADRS Amineptine Fluoxetine

1989 Dornseif et al USA 8 Not controlled with placebo, RT contrasting 2 doses, andexcluded early 3 week responders

Fluoxetine 20mg

Fluoxetine 60mg

1991 Dunbar et al UK 6 Analysis of 6 RCTs: Cohn & Wilcox 1992, Feighner &Boyer 1989c, and Shrivastava et al 1992

Paroxetine Imipramine Placebo

1993 Dunbar et al UK 6 Analysis of 6 RCTs: Claghorn et al 1992, Feighner et al1993 and others

Paroxetine Placebo

1990 Dunlop et al USA 6 Included data from Wernicke et al 1987 Fluoxetine Placebo

1987 Emrich et al Germany Cross-over design, 3 weeks of randomized active drug. Fluvoxamine Oxaprotiline

1992 Feighner USA 6 Same data as Dunbar 1991 Paroxetine Imipramine Placebo1993 Feighner USA 6 Reanalysis of 6 RCTs, same data as Dunbar 1991 Paroxetine Imipramine Placebo1986 Fieve et al USA 6 Another publication of Fieve et al.,1986 Fluoxetine Placebo

1992 Gasperini et al Italy 6 Outcome measure with scales other than HRSD:MADRS Fluvoxamine Amitryptiline

1987 Goodnick et al USA 6 Reanalysis of Stark et al 1985 Fluoxetine Placebo

1992 Gray et al USA 24 Outcome measure with scales other than HRSD:MADRS Fluoxetine Placebo

1989 Guillibert et al France 6 Data included in Link and Dunbar 1992 Paroxetine Clomipramine

1991 Hendrickx et al Belgium 4 Outcome measure with scales other than HRSD:MADRS Fluvoxamine Placebo

1995 Heiligenstein et al USA 6 Analysis of the same data as Tollefson 1995 Fluoxetine Placebo

1991 Judd Australia 6 Preliminary report of publication of Judd et al.,1993 Fluoxetine Amitryptiline

1995 Kasper et al Austria 4 Analysis of 5 RCTs: Amin et al 1984, Cassano et al 1986and others

Fluvoxamine Imipramine

1995 Koran et al USA 6 Analysis of the same data as Tollefson 1995 Fluoxetine Placebo

1996 Lauritsen et al Denmark 6 -24

2 concurrent interventions: antidepressant drugs andElectroconvulsive Therapy

Paroxetine Imipramine Placebo

1989 Levine et al UK 6 Another publication of Levine et al.,1987 Fluoxetine Imipramine

1994 Lonnqvist et al Finland 6 Analysis of sub-group of Lonnqvist et al 1994 Moclobemide Fluoxetine

1995 Lonnqvist et al Finland 12 Analysis of continuation of Lonnqvist et al 1994 Moclobemide Fluoxetine

1990 Moller et al Denmark 4 Reanalysis of 8 RCTs: Danish University AntidepressantGroup 1989

Paroxetine Clomipramine

1993 Moon & Lane UK 4 Same data as Moon et al., 1990 Sertraline Clomipramine

1993b Montgomery &Dunbar

UK 6 Same data as published by Dunbar et al 1993: Claghorn etal 1992, Feighner et al 1993 and others

Paroxetine Placebo

1991 Ottevanger Netherland 4 Analysis of 5 RCTs: Amin 1984 and others Fluvoxamine Clomipramine

1993 Pelicier &Schaeffer

France 5 Outcome measure with scales other than HRSD:MADRS Paroxetine Clomipramine

1990 Perez & Ashford UK 6 Outcome measure with scales other than HRSD:MADRS Fluvoxamine Mianserin

1991 Rahman et al UK 6 Outcome measure with scales other than HRSD:MADRS Fluvoxamine Dothiepin

1984 Reimherr et al USA 6 Pooled data RCT and Open studies Fluoxetine

1988 Reimherr et al USA 8 Preliminary report of Reimherr et al., 1990a Sertraline Amitrityline Placebo1985 Rickels et al USA 6 RT without placebo control, 2 schedules: q.d. & b.i.d. Fluoxetine q.d. Fluoxetine 2 x

1992 Rickels et al USA 6 Another publication of Rickels et al 1989 Paroxetine Placebo

1992 Skausig Denmark 12 Sub-group analysis of Danish University AntidepressantGroup 1989

Paroxetine Imipramine

1995 Small et al USA 6 Analysis of the same data as Tollefson 1995 Fluoxetine Placebo

1996 Small et al USA 6 Re-analysis of the Tollefson 1995 Fluoxetine Placebo

1991 Thompson UK 6 Outcome measure with scales other than HRSD:MADRS.RCT and open study

Sertraline Placebo

1991 Usher et al USA 6 Data included in Wernicke et al 1988 Fluoxetine

1993 Wade et al UK 6 RT without placebo control, compare 2 schedules Paroxetine

1986 Wagner et al Germany 6 Re-analysis of 8 RCTs: Amin 1984 and Others Fluvoxamine Placebo

1986 Wakelin Nether-lands

4 Re-analysis of 4 RCTs: Amin et al 1984, Wagner et al1985, Itil et al 1983 and Block & Coleman 1983

Fluvoxamine Imipramine

1989 Wernicke et al USA 6 Re-analysis of 3 RCTs: Wernicke et al 1987, Wernicke etal., n/d, and N/A reference

Fluoxetine Placebo

1987 Young et al USA 6 Outcome measure with scales other than HRSD:MADRS Fluoxetine Amitryptiline

Quantitative data from the included individual randomized trials were tabulated. Where appropriate(and possible) meta-analyses using the random-effects model and hierarchical Bayesian meta-analyses were conducted using the Hedges and Olkin method to obtain estimates of effect sizes(Hedges and Olkin, 1985). The Confidence Method Profile (Fast Pro software)

was used for rate differences. Q statistics and respective p-values were calculated to assesshomogenity across studies.

Additional data which were presented in the selected trials were also tabulated and used as feasible.These include: country of study, mean patient age, setting, clinical classification, previous history ofrecurrent episodes, intensity of current symptoms, fixed or variable drug dose regimens and level ofdose, period of antidepressant treatment, concomitant drugs used, and statistical tests employed.

5.1 Estimation of efficacy

The clinical effect of antidepressants is measured using two possible scoring systems: the HamiltonRate Scale for Depression (HRSD) or the Clinical Global Impression (CGI). In this review, efficacyof treatment was assessed in three ways:

(a) Change in HRSD score following treatment - this is an “effect size” measure(b) Number of patients whose HRSD score improved by 50% or more following treatment -

a “rate” measure(c) Number of patients who had a response of 1 or 2 in the CGI score, ie. those who had

improved very much or markedly - also a “rate” measure

(a) The effect size ES in the difference between the means in the two groups (in this case, the meansare the changes in HRSD in the SSRI group and the Comparator group respectively), weighted bythe inverse of the standard deviation (SD) (Hunter and Schmidt, 1990, p. 271).

ES = ª HRSD SSRI - ª HRSD COMPSD

The standard deviation SD is the pooled within-group standard deviation, as described by Hunterand Schmidt (1990). Because of the dispersion in results of studies with a total of fewer then 50patients, the method of Hedges and Olkin was used to adjust the effect size (Hedges and Olkin,1981, Table 2). The pooled effect size for each group of trials was then calculated as the weightedsum of individual effect sizes ESi. The weight of each trial wi is the inverse of the variance of thattrial divided by the sum of the inverses of variances of all trials.

µ = ëwiESiEffect size is a guide in assessing the clinical importance of an intervention, and as a general con-vention, the interpretation of effect-size follows a simple rule: mean estimates of effect size from0.2 to 0.49 are considered small; 0.5 to 0.79 moderate, and 0.8 or above robust (McDowell I. andNewell C., 1996). Reliability was tested by plotting effect size against sample size - a funnel plot,which is shown in Figure 6.

Individual RCT results were quantitatively synthesized, and the efficacy was compared as follows(drug(s) versus comparator(s)):

1. SSRIs vs. placebo2. SSRI vs. SSRI3. SSRIs vs. TCAs and other antidepressants

In the SSRI vs. TCA trials, subgroup analyses were performed.

(i) Effect of heterogeneity of patient population: Only those trials were included which explic-itly excluded patients with major systematic diseases (serious renal, hepatic, hematologicalor cardiovascular problems; unstable systemic medical condition or clinically significantabnormal laboratory values at the initial evaluation; on reserpine or methyldopa, alcohol orsubstance abuse or dependence, chronic or organic brain disease, mental deficiency orepilepsy, and patients with schizophrenia or other psychotic disorders, or serious history ofmany episodes.)

(ii) Effect of patient age: Trials were subgrouped according to whether the patients were “adults”(greater than 18 yrs. of age, mean less than 60) or “elderly” (60 yrs. or older) and meta-analyses were performed on both groups.

(iii) Effect of “patient setting”: Trials were subgrouped according to whether the study had inpa-tients or outpatients. The two groups were meta-analysed separately.

(iv) Effect of dosage: Four dose categories - low, standard, medium and high - were defined (SeeTable 4 in Appendix). Pooled effect size differences between SSRIs and the comparatorswere calculated in each dose category.

(b) A second efficacy measure was the proportion of patients in each arm whose HRSD score im-proved by at least 50% after treatment. The rate difference and 95% confidence interval werecalculated for each trial. The mean weighted rate difference was calculated using the Bayesianhierarchical meta-analyses. FastPro software was used for these calculations.

(c) The third measure of efficacy was the proportion of patients who had very much or markedimprovement in the CGI score (categories 1 or 2). Pooled rate differences were calculated as in (b)above.

5.2 Estimation of completion and drop-out rates

Patient “compliance” to drug treatment is an important issue when its effect on a population isconsidered. However, it is often difficult to estimate compliance based on patients stopping medi-cation themselves, as there may be many reasons for this. In this study, “completion rate” reportedin the published literature was used as a proxy of “acceptability”, and in an indirect way, an esti-mate of compliance.

All studies that met the inclusion criteria were reviewed to identify those in which numbers ofpatients who stopped taking the medication (“drop outs”) were reported. Numbers of

patients dropping out for one of four documented reasons : adverse effects, a perceived lack ofeffect, worsening of symptoms, and “other reasons” (which were not described in further detail inthe papers) were extracted. For each study, the completion rate (CSSRI - Ccomp)for each arm wascalculated either directly (number of patients on the drug at the end of the study ÷ number thatstarted treatment) or as the complement of the total drop-out rate ((number that started - number thatdropped out during the course of the study) ÷ number that started treatment), depending on whatwas reported in the study. The completion rate differences were then calculated for each study.Weighted mean rate differences and the overall mean and 95% confidence intervals were calculatedusing FastPro (Eddy and Hasselblad, 1992) using hierarchical Bayesian meta-analyses.

5.3 Estimation of occurrence of adverse effects

Adverse events were reported in 82 out of the 104 trials comparing SSRIs with TCAs. Three addi-tional trials were excluded due to the use of non-comparable scale. These 82 trials were scanned toidentify (a) the type of adverse event and (b) the number of patients who reported each adverseevent. The methods by which information on each adverse event was elicited from patients werealso recorded.

In the 82 trials, more than 50 different adverse events were reported. Two exclusion criteria werethen used: (1) fewer than 20 patients in the trial, (2) information on occurrence not available forboth drugs, and (3) fewer than 6 trials reporting occurrence of a particular adverse event. This left18 of the most prevalent adverse events (reported for both drugs) for subsequent analysis: nausea,dry mouth, anorexia, diarrhea, constipation, anxiety, agitation, insomnia, palpitations, urinarydisturbances, fatigue, tremor, headache, nervousness, blurred vision, sweating, dizziness and hypo-tension.

Rare adverse events have not been included in this analysis. In the case of suicide, for example, allof the RCTs excluded potentially suicidal patients. But in 6 out of all studies reviewed here, 5patients on SSRIs and 1 on a TCA were reported as having committed suicide.

Reporting of adverse effects may depend on how information is obtained from patients. In these 82trials, the following methods of eliciting adverse effect information were used: a checklist, asking adirect generic or an indirect question, spontaneous reporting by a patient or the Dosage Record andTreatment Emergent Symptom Scale (DOTES) with or without dosage record (Guy, NIMH 1976).In some trials, the method of eliciting this information was not explicitly specified.

Some methods are likely to overestimate adverse event occurrence, e.g. by suggesting to patientsthat such symptoms are acceptable (e.g. with checklists). Other methods, e.g. asking indirect ques-tions, may be less suggestive. In the literature reviewed, 22 trials used checklists, 19 used indirectquestioning, 21 trials used only spontaneous reporting, 10 used DOTES (“write-in” scale or appliedby the interviewer); 11 did not report the specific method used. In 3 trials, more than one methodwas used.

For 2 of the 18 adverse effects analysed - nausea and dry mouth - meta-analyses were done to verifywhether the method of elicitation would influence calculated adverse event rate differences betweendrugs.

6. RESULTS

6.1 Estimation of efficacy :

6.1.1 SSRIs vs placebo

Forty-eight studies compared SSRIs to a placebo. See Figure 3 below. (Figure 1 in the Appendixpresents individual trial results). Results of homogeneity tests (Q, p-values) are also shown.

The estimated pooled effect differences for each one of the four SSRIs considered were similar, withsimilar 95% confidence intervals. The mean difference in effect size was 0.55 in favour of the drug;this was a statistically significant result (95% confidence interval: 0.40 to 0.70), indicating a moder-ate mean antidepressant effect.

6.1.2 SSRI vs SSRI

Ten studies compared one SSRI with another. See Figure 4 below (Figure 2 in the Appendixpresents individual trial results). Results of homogeneity tests (Q, p-values) are also shown.

Fluoxetine was used in 8 of these 10 studies, but as the comparator drug in each case (i.e. fluoxetinewas not the first drug, it was the comparator against which the effectiveness of another SSRI wasmeasured). In order to obtain estimates of differences in effect-size between fluoxetine and the otherSSRIs, the data of these 8 trials were analyzed as though fluoxetine was the first drug in the trial(Inversed Series).

In 8 of the 10 trials, the first drug appears to have a slightly (but non-significantly) better efficacy(as measured by the effect-size) than the comparator.

Fig.3 Differences in effect size (SSRIs vs. placebo)

Standardised Effect Size differencewith 95% Confidence Interval

48 2787 2016

20 1461 937 0.048

0.624

0.587

0.684

0.682

13 513 471

10 363 360

5 450 248

Fig.4 Differences in effect size (SSRIs vs. SSRIs)

49

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There were no significant differences in effect size between SSRIs. The same conclusion wasreached when the efficacy was determined using the number of patients whose HRSD score im-proved by 50% or more, or the number of patients who had a response of 1 or 2 on the CGI score.

6.1.3 SSRIs vs. classical TCAs

46 trials compared SSRIs with imipramine, amitriptyline or clomipramine in the more homogene-ous group of patients described in Section 4.1. See Figure 5 below (the individual results of thesetrials are in Figure 3 of the Appendix and marked with an i ). Results of homogeneity tests (Q, p-values) are also shown.

The mean difference in effect size between SSRIs and amitriptyline / imipramine (39 trials) was-0.06, with a 95% confidence interval of -0.20 to 0.09. This was a not statistically significant result.

Fig.5 Differences in effect size (SSRIs vs. tertiary amines) in homogeneous subgroup of studies

Standardised Effect Size differencewith 95% Confidence Interval

12 315 325 0.098

0.001

0.335

0.109

0.089

0.062

13 344 351

11 484 484

3

39

46

336

1479

1781

336

1396

1693

An extended meta-analysis with all 46 trials with nearly 1700 patients in each arm, showed similarresults (pooled ES difference: -0.05, 95% confidence interval: -0.18 to 0.09).

6.1.4 SSRIs vs. other TCAs and other antidepressants

Effect size difference between SSRIs and TCAs and other antidepressants calculated for each of the118 trials found to meet the inclusion criteria, was plotted against the sample size of the respectivestudy (See Figure 6 below) .

The funnel plot (Wilson, A., and Henry, D. A., 1992) was symmetrical suggesting that there waslittle publication bias.

Fig 6. Funnel plot: Effect size difference versus sample size

118 study sample sizes

Eff

ect s

ize

diff

eren

ce

(SS

RIs

vs.

oth

er a

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ssan

nts)

-1.2

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0 50 100 150 200 250 300 350 400 450 500

117 trials were then meta-analysed to verify the influence of the inclusion of antidepressants otherthan imipramine, amitryptiline or clomipramine. See Figure 7 below (Figure 3 in the Appendixpresents individual trial results). Results of homogeneity tests (Q, p-values) are also shown. Onestudy comparing fluoxetine with milnacipran was excluded from the analysis because of the similarmode of action of the two drugs.

Meta-analysis of the 96 RCTs of SSRI vs. TCAs yielded a pooled effect size difference of -0.013).The 95% confidence interval was from -0.10 to 0.07. Again, this was not statistically significant.

The pooled difference between SSRI and other antidepressants (21 trials) was calculated to be 0.008in favour of the SSRI drugs. This difference, too, was not statistically significant (95% confidenceinterval: -0.06 to 0.07).

When all 117 trials of SSRIs vs. non-SSRI antidepressants were pooled, once again there was nostatistically significant difference between the two groups (mean difference in effect size, -0.01;95% confidence interval: -0.08 to 0.06).

Fig.7 Differences in effect size (SSRIs vs. other antidepressants)

Standardised Effect Size differencewith 95% Confidence Interval

Cont.

3

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2 54 50 0.372

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//

Fig.7 Differences in effect size (SSRIs vs. other antidepressants) -cont'd-

Standardised Effect Size differencewith 95% Confidence Interval

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Fig.8 Differences in effect size by age categories

1404

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In elderly patients, overall effect size difference was -0.007 (95% confidence range: -0.25 to 0.25)for SSRIs compared with TCAs and 0.19 (95% confidence interval: -0.29 to 0.68) compared withother antidepressants. These effect differences are similar to those found in the adult trials (ES:-0.013, 95% confidence interval: -0.09 to 0.06) although for fluoxetine and sertraline there is a trendof slightly smaller effect estimates amid elderly patients compared with adults (the individual resultsof these trials in elderly patients are marked with one “e” in the Figure 3 of the Appendix)

These two sets of trials were also subgrouped according to whether the study contained informationon patients treated for recurrent or refractory depression. The results are shown in Figure 9 on thenext page. There are no significant differences between any of the four groups.

6.1.5 Influence of patient age on effect size differences

There were 104 trials in which “adult” patients (age 19 or over) were enrolled, and 11 in which“elderly” patients (age 80 or over) were enrolled [4 additional trials with elderly patients wereexcluded because only measures other than HRSD and CGI scales were used] (See Figure 8).

Fig.9 Differences in effect size in recurrent and refractory patients

Standardised Effect Size differencewith 95% Confidence Interval

89 3427 3442 0.024

0.075

0.050

0.013

15 677 695

9 431 410

2 297 215

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Fig.10 Differences in effect size by dosage (individual SSRIs)

//

Cont.

6.1.6 Influence of dose on effect size differences

20 trials used fixed doses of the SSRI, and in 95 trials the dose was variable. In 2 other trials,levels of doses of the drugs were not specified. Also, one study comparing fluoxetine withminalcipram was excluded as described in Section 5.1.4 (See Figure 10). Results of homogeneitytests (Q, p-values) are also included. Standard doses of SSRIs were used in 72 trials, medium dosesin 16 and high doses in the remaining 17. Specific groups of studies including the same SSRIcategories of doses vs. TCAs at low (100 mg or less) or standard doses (above 100 mg) are shown inFigure 10. Smaller groups of studies in most of the dose categories made the estimates more dis-perse. The lines with the sub-totals for increasing standard doses of each of the 4 SSRIs are in“bold-italic” characters. These estimates and the 2 sub-sets of it: low and standard doses of TCAs,show the effect of the pooling of these 2 types of trials. Figure 11 shows a summary of the pooledresults comparing SSRIs vs. TCAs.

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Fig.10 Differences in effect size by dosage (individual SSRIs) -cont'd-

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Fig.11 Differences in effect size by dosage (SSRIs as a group)

Mean baseline HRSD score was slightly higher in the medium-dose trials (26.4) compared to stand-ard doses (25.2) and high doses (25.6) when compared to tertiary amines. Medium doses of SSRIshad a slightly higher effect than standard doses. But this was not statistically significant. Paradoxi-cally, higher doses yielded slightly lower effects, but again this was not statistically significant. Theeffect size difference between standard-dose SSRIs and low-dose (under 100mg) TCAs was slightlyin favour of SSRIs (0.05), based on 21 studies, but again this was not statistically significant.

6.1.7 Influence of setting on effect size differences

There were 24 trials of SSRIs vs. TCAs on inpatients. There was no significant difference in effectsize between the SSRI and its comparator in any of the 24 trials. Results of homogeneity tests (Q, p-values) are also included (the individual results of these trials in hospitalized patients are markedwith one “h”, or “o” for outpatients, in the Figure 3 of the Appendix).

When 30 trials (24 with only hospitalized patients and 6 with less than a outpatients) were pooled,the effect size difference was -0.08 (95% confidence range: -0.21 to 0.05). (See Figure 12 below.)

320

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Fig.12 Differences in effect size by setting

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6.1.8 SSRIs vs. TCAs and other antidepressants: using rate measures

Rates of response, i.e. numbers of patients who had at least 50% reduction in HRSD scores, showedsimilar results as the efficacy measured by the effect size differences.

The SSRIs, as a group had a weighted mean difference of -4% (fewer responders with SSRIs thanTCAs), but a 4% better response than other antidepressants. These differences were not statisticallysignificant. Overall, the pooled mean rate difference was a statistically non-significant -1% (95%confidence interval: -8% to 6%). (See Figure 13 below) Figures 7 - 10 in the Appendix containresults of individual studies.

Fig. 13 Differences in rates, 50% or more improvement in HRSD (SSRIs vs. TCAs and other ADs)

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One-arm meta-analysis yielded a probability of response, in terms of having at least 50% reductionin HRSD scores, of 0.58 for the SSRIs (95% confidence interval: 0.54 to 0.63) vs. 0.61 for the TCAs(95% confidence interval: 0.52 to 0.72) and 0.26 (95% confidence interval: 0.21 to 0.31) for theplacebo control.

The weighted mean rate difference (of patients reaching CGI category 1 or 2) in the 25 trials ofSSRIs against TCAs was 0.4% more response with the SSRIs (95% confidence interval: -7% to7%). It was 1% in 10 trials of SSRIs against other antidepressant trials (95% confidence interval: -16% to 18%). Overall, the mean rate difference was -0.2% (95% confidence interval: -6% to 6%).However, none of these three rate differences was statistically significant. (See Figure 14 on nextpage). Figures 11 - 14 in the Appendix contain the results of individual studies.

Fig. 14 Difference in rates, improvement in CGI (SSRIs vs. TCAs and other ADS)

15 631 639

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One-arm meta-analysis of these trials yielded a probability of response (of patients reaching CGI category 1 or 2) of 0.57 for the SSRIs (95% confidence interval: 0.51 to 0.63) vs. 0.68 for the TCAs(95% confidence interval: 0.60 to 0.78) and 0.25 (95% confidence interval: 0.13 to 0.37) for theplacebo control.

These results (using rate differences) are similar to the results based on effect sizes differences, i.e.there is a slight trend of superior results with TCAs but overlapping of confidence limits and non-significant differences, indicative of the robustness of the analyses.

Eighteen other studies of SSRIs vs. all other antidepressants reported more detailed CGI data. Ameta-analysis of the data on patients who improved markedly (i.e. reached category 1) showedsimilar results for the three SSRIs studied: 6% for fluoxetine, -9% for fluvoxamine and 1.5% forparoxetine. (Overall difference: -0.1%). None of these was statistically significant. Interestingly,from the four trials that reported CGI measures by both patient and physician, it is concluded thatregardless of the antidepressant, patients perceived a lower CGI than physicians did.

6.2 Estimation of completion and of drop-out rates

6.2.1. Estimation of completion rates: SSRI vs. placebo

The number of patients accepting medication until the end of the trial, or not discontinuing thetreatment, out of the total starting therapy or placebo was reported in 43 studies, that are summarizedbelow. (See Figure 15 below and Figure 15 in the Appendix for individual trials results.)

Fig.15 Completion rates (SSRIs vs. placebo)

43

20

12

8

3 302 306211

280 275178 147

1697

366

1426

334

1028

216

768

210

197

2645 23411635 1322

Overall, pooling these 43 trials, using SSRIs accomplished an 8% better completion mean rate thanplacebo (95%CI: 4 to 13%). This was statistically significant.

6.2.2. Estimation of completion rates: SSRI vs. other SSRIs

Completion rates were estimated in 11 RCTs of one SSRI against another SSRI. (See Figure 16below and Figure 16 in the Appendix for individual trials results.)

6.2 Estimation of completion and of drop-out rates

6.2.1. Estimation of completion rates: SSRI vs. placebo

The number of patients accepting medication until the end of the trial, or not discontinuing the treatment, outof the total starting therapy or placebo was reported in 43 studies, that are summarized below. (See Figure15 below and Figure 15 in the Appendix for individual trials results.)

Fig.15 Completion rates (SSRIs vs. placebo)

43

20

12

8

3 302 306211

280 275178 147

1697

366

1426

334

1028

216

768

210

197

2645 23411635 1322

Overall, pooling these 43 trials, using SSRIs accomplished an 8% better completion mean rate than pla-cebo (95%CI: 4 to 13%). This was statistically significant.

6.2.2. Estimation of completion rates: SSRI vs. other SSRIs

Completion rates were estimated in 11 RCTs of one SSRI against another SSRI. (See Figure 16 belowand Figure 16 in the Appendix for individual trials results.)

Regardless of which or how many SSRIs were pooled, all of the estimates cited above lacked statisticalsignificance indicating similar completion rates among these 4 SSRIs.

6.2.3 Estimation of completion rates: SSRIs vs. TCAs and other antidepressants

SSRI completion rate differences with the comparators were obtained pooling the 116 trials vs. TCAs andother antidepressants. (See Figure 17 below and Figures 17 - 20 in the Appendix for individual trialsresults.)

The overall estimate indicated similar completion as with the TCAs (mean rate difference of 1%, with aconfidence interval from -6% to 7%, which is not statistically significant.

Fig.17 Completion rates (SSRIs with TCAs and other antidepressants)

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Total SSRI completion rate estimated by one arm hierarchical Bayesian meta-analysis was 67% vs. 62%with TCAs, with similar 95% confidence limits, reinforcing that SSRI completion rate is not statisticallysignificantly different from the completion rate obtained with TCAs.

Pooling of the 25 trials using one of the 4 SSRIs vs. other antidepressants resulted in a mean rate differ-ence of 0.4%, i.e. slightly more patients would complete their trials than those using other antidepressants.95% confidence limits of -5% to 6%, a trend which also is not statistically significant.

Additional meta-analyses were conducted to compare completion rates between hospitalized patients andoutpatients, and between adult and elderly patients. Nearly 3% more hospitalized patients vs. 0.01%outpatients completed the trials with fluoxetine or paroxetine as compared to TCAs, but completion rates inthe two groups were essentially the same with fluvoxamine or TCAs. 1.7% more elderly patients vs. -0.4%of adult patients on fluoxetine or paroxetine completed the trials than those on TCAs. None of these werestatistically significant results.

6.2.4 Drop-outs due to Adverse events

70 RCTs provided detailed data for the analysis of rates of drop-outs due to adverse events. In individualtrials, there were no statistically significant differences in the rates between any of the 4 SSRIs and thecomparators (whether it was another SSRI or TCAs). A summary of the meta-analytic results are in Figure18 below.

Fig.18 Differences in rates of drop-outs due to adverse events (SSRIs vs. TCAs)

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Meta-analyses of various sets of trials were conducted. The pooled rate differences in drop-out ratesbetween individual SSRIs and tertiary, secondary or quaternary amines, or versus TCAs a group wereestimated. These differences were consistently similar among the 4 SSRIs, -2% and -3%; none werestatistically significant. Multi-centre trials were pooled and the meta-analytical mean rate difference, be-tween the 4 SSRIs and all TCAs, of -3% fewer drops due to adverse events with SSRIs (95%CI: -7 to0.4%), was also not statistically significant.

Additional meta-analyses were done to compare all SSRIs with all TCAs in the groups - inpatients /outpa-tients and elderly /adult patients. The differences in the first two groups between SSRIs and TCAs were-2.3% vs. -3% and -1.7% vs. -2.9%, respectively, but were not statistically significant. There were signifi-cantly fewer drop-outs with SSRIs than TCAs in trials with adults and outpatients; this difference was -2%. Overall weighted mean difference between SSRIs and TCAs was -2.2% (95% confidence interval:-4.5 to 0.9%). Although most of these estimates were not statistically significant the magnitude of differ-ences are similar but in the opposite direction of the estimates of dropouts due to lack of effect described inthe next session (For detailed study estimates see Figures 21-24 in the Appendix).

6.2.5 Dropouts due to lack of effect

51 SSRI vs. TCA trials reported details on drop-outs and had comparative information on the lack effi-cacy.

957

402

1167

328

2854

1011

405

1073

254

2743

Fig.19 Differences in rates of drop-outs due to lack of efficacy (SSRIs and TCAs)

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The pooled rate differences in drop-out rates between individual SSRIs and TCAs were not statisticallysignificant (See Figure 19 below). These differences ranged from -1.6%, more drop-outs with the use ofTCA comparators than sertraline to 1.9% more drop-outs with the other SSRIs. Meta-analysis of themulti-centre trials produced a mean rate difference of 0.5% fewer drop-outs due to lack of effect whenTCA was used (95%CI: -1.5 to 2.5%). Mean rate difference between SSRIs and TCAs, in inpatients /outpatients, elderly and adult groups, all showed no statistically significant difference between SSRIs andTCAs (all 2% or less). Also, an overall meta-analysis showed a mean rate difference of 0.4%, fewer drop-outs with TCAs (95%CI: -1.3 to2%) (See Figures 25 - 28 in the Appendix for details of each study).

6.2.6 Combining dropouts due to lack of effect and worsening of symptoms

There were 57 trials in which the numbers of patients who stopped taking the medication either because ofa lack of effect or because there was a worsening of symptoms were reported. (See Figure 20 below)

1274

440

1244

362

3320

1277

426

1100

284

3087

Fig.20 Differences in rates of drop-outs due to lack of efficacy and worsening of symptoms (SSRIs vs. TCAs)

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27

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22

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215

30

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21

340

In 56 of these, the differences in rates of drop-out between the two drugs were not statistically significant.Pooling of the data resulted in rate differences, (1.8% more drop-outs with fluoxetine vs. TCAs, 0.5%more with fluvoxamine vs. TCAs, 0.6% more with paroxetine vs. TCAs and 1.6% fewer drop-outs withsertraline) which in all cases, were not statistically significant.

Mean rate differences among inpatients showed 3% more dropouts with SSRIs (1%: outpatients) and1.7% more drop-outs with elderly patients using SSRIs, slightly more than with adults (0.8%). The overallmean rate difference, 0.8% more drop-outs either because of a lack of effect or because there was aworsening of symptoms, with the use of SSRIs (95%CI: -0.9 to 2.6%) was also non significant.

6.3 Estimation of the occurrence of adverse effects

In 8 of these 18 meta-analytical studies, no statistically significant differences existed between the two typesof drugs when the results were pooled. Analyses of these 18 adverse events are described below.

6.3.1 Nausea (See Figure 21 below and Figure 29 in the Appendix for details on each study)Nausea rates were reported in 48 trials (22 with fluoxetine, 14 with fluvoxamine, 8 with paroxetine and 4with sertraline).The pooled nausea rate difference was 10.3%, i.e. there were 10.3% more patients that reported nauseawith the use of the SSRI. This difference was statistically significant (95% confidence interval: 7.3% to13.3%).

Fig.21 Differences in rates of nausea (SSRIs vs. TCAs)

22

14

8

4

48

125 1093 1096246

136 78 442 460

56 39 501 471

113 30 387 309

551 272 2423 2336

Further analyses were done to look at the method of elicitation of information on nausea from patients.

Method No. of trials Pooled result 95% CI Statistically Significant

ChecklistSpontaneous reportIndirect questionsTES/DOTESUnspecified

1119895

9.5% more with SSRI 6.5% more with SSRI12% more with SSRI 9% more with SSRI15% more with SSRI

4% to 15%4% to 9%5% to 20%-1% to 19%5% to 25%

YesYesYesNoYes

Fig.22 Difference in rates of dry mouth (SSRIs vs. TCAs)

28

13

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5

56

171 1288 1299269

194 207 460 479

93 221 782 762

104 211 478 414

660 810 3008 2954

Three other meta-analyses were done: SSRIs vs.amitriptyline/imipramine (using the homogeneous subgroupof trials defined in Section 5.1.4); SSRIs vs. all amitriptyline/imipramine studies; SSRIs vs. all TCAs. In allcases, there was statistically significantly more nausea with SSRIs (11%, 9.5% and 10% respectively).

6.3.2 Dry mouth (See Figure 22 and Figure 30 in the Appendix for details on each study)When all trials of SSRIs vs. TCAs were combined, a pooled estimate of the difference in dry mouth ratesbetween the two classes of drugs was found to be -28.1%. This was statistically significant (95% confi-dence interval: -34.9% to -24.8%). (See Figure 22 below.)

Method No. of trials Pooled result 95% CI Statistically Significant

ChecklistSpontaneousreportIndirect questionsTES/DOTESUnspecified

1214884

-22% more with TCAs-30.6% more with TCAs-25% more with TCAs-32% more with TCAs-42.4% more with TCAs

-34% to -11.5%-39.6% to -21.6%

-38% to -12%-45% to -18%

-54.9% to -29.9%

YesYesYesYesYes

Additional meta-analyses were done as described in Section 5.3.1. In all cases, there was statisticallysignificantly more dry mouth with TCAs (30%, 29.5%, 28% in the three meta-analyses).

6.3.3. Anorexia (See Figure 23 below and Figure 31 in the Appendix for details on each study)

Fig.23 Difference in rates of anorexia (SSRIs vs. TCAs)

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When the 11 SSRI vs. TCA trials were pooled, there was a statistically significant difference: 5% moreanorexia occurred with SSRIs (95% confidence interval: 0.6% to 9%).

6.3.4. Diarrhea (See Figure 24 below and Figure 32 in the Appendix for details on each study.)

Fig.24 Difference in rates of diarrhea (SSRIs vs. TCAs)

15

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7 143 14614

5 149 14727

21 236 14114

10 361 28480

135 43 889 718

A meta-analysis of all 15 trials produced a pooled diarrhea rate difference of 9% more diarrhea withSSRIs. This difference was statistically significant (95% confidence interval: 4% to 14%).

6.3.5 Constipation (See Figure 25 below and Figure 33 in the Appendix for details on each study.)

Fig.25 Difference in rates of constipation (SSRIs vs. TCAs)

23

12

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5

49

112 258 1117 1159

87 150 434 453

40 69 478 414

76 137 760 764

315 614 2789 2790

When all 49 trials were combined by meta-analysis, the pooled rate difference was -11%, more constipa-tion with the use of the TCAs. The 95% confidence interval was -14% to -8%. This was statisticallysignificant.

6.3.6. Anxiety (See Figure 26 below and Figure 34 in the Appendix for details on each study.)

Fig.26 Difference in rates of anxiety (SSRIs vs. TCAs)

11

3

3

17

51 500 51784

20 3 104 102

9 8 221 222

113 62 825 841

When the 17 trials were pooled, an estimate of 3% was obtained for the mean rate difference of anxiety.This was statistically significant (95% confidence interval: 0.8% to 5.5%, more anxiety with the SSRIs).

6.3.7. Agitation (See Figure 27 below and Figure 35 in the Appendix for details on each study.)Eleven studies comparing SSRIs and TCAs reported agitation rates for both drugs.The meta-analytic pooled estimate of the difference in rates of agitation was 6% more when using SSRIs.This was statistically significant (95% confidence interval: 1% to 10%).

Fig.27 Difference in rates of agitation (SSRIs vs. TCAs)

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0 110 11213

19 10 114 119

6 3 79 78

38 31 310 229

76 44 613 543

6.3.8. Insomnia (See Figure 28 below and Figure 36 in the Appendix for details on each study.)

Fig.28 Difference in rates of insomnia (SSRIs vs. TCAs)

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55 842 847113

36 32 219 226

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232 129 1903 1829

A meta-analysis of all comparative trials reporting rates of insomnia produced a pooled estimate of the ratedifference of 4% more insomnia with SSRIs, which was statistically significant at the 95% level (confidenceinterval: 1% to 6%).

6.3.9 Palpitations (See Figure 29 below and Figure 37 in the Appendix for details on each study.)

Fig.29 Difference in rates of palpitations (SSRIs vs. TCAs)

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9 150 1498

26 242 1

460 57010 30

393 32518 14

38 54 1029 1068

The pooled estimate of difference between SSRIs and TCAs in rates of palpitations was -2.4%, more withthe TCAs, but this was not statistically significant (95% confidence interval: -5% to 0.2%).

6.3.10. Urinary disturbances (See Figure 30 below and Figure 38 in the Appendix for details on eachstudy.)

Fig.30 Difference in rates of urinary disturbance (SSRIs vs. TCAs)

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30 35 176 187

314 31418 21

0 14 310 229

30 35 176 187

67 98 1165 1133

When the 14 trials were meta-analysed, no significant difference in rates of urinary disturbance was found.This difference was -2.6%, more urinary disturbance with the TCAs (95% confidence interval: -6.5% to1.3%, not statistically significant).

6.3.11. Fatigue (See Figure 31 below and Figure 39 in the Appendix for details on each study.)

Fig.31 Difference in rates of fatigue (SSRIs vs. TCAs)

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128 147 1318 1296

395 31848 56

38 21 441 432

18 23 153 155

43 329 39124

A meta-analysis was performed on the set of 23 trials. There was a mean -2.4% difference in rates offatigue (fewer with the SSRI group), but this was not statistically significant (95% confidence interval:-5.7% to 0.9%).

6.3.12. Tremor (See Figure 32 below and Figure 40 in the Appendix for details on each study.)

When all 34 trials were pooled, the difference in tremor rates was small (-1.4%) and not statistically signifi-cant (95% confidence interval: -3.7% to 0.9%).

Fig.32 Difference in rates of tremor (SSRIs vs. TCAs)

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4

158 953 971142

94 78 458 411

145 14213 13

47 36 444 380

296 285 2000 1904

6.3.13. Headache (See Figure 33 below and Figure 41 in the Appendix for details on each study.)

Fig.33 Difference in rates of headache (SSRIs vs. TCAs)

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4

100 581 593120

63 51 265 278

58 38 355 351

56 30 448 376

297 219 1649 1598

A meta-analysis of all trials was done. The pooled estimate of the rate difference of 2.5% more headachewith the SSRIs was obtained, but this was not statistically significant (95% confidence interval: -0.01% to5%).

6.3.14. Nervousness (See Figure 34 below and Figure 42 in the Appendix for details on each study.)

Fig.34 Difference in rates of nervousness (SSRIs vs. TCAs)

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10 67 469 48486

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1 161 806 1

104 72 755 687

The pooled difference in rate of cases of nervousness was 4% more with the SSRI treated group. This wasstatistically significant (95% confidence interval: 0.6% to 7.4%).

6.3.15. Blurred vision (See Figure 35 below and Figure 43 in the Appendix for details on each study.)

Fig.35 Difference in rates of blurred vision (SSRIs vs. TCAs)

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106 527 53663

14 84 9016

300 29913 21

161 8010 0

102 141 1072 1005

A meta-analysis of all these 19 trials yielded a mean rate difference estimate of -2.8% more blurred visionwith the TCAs. This was statistically significant (95% confidence interval: -5.4% to -0.02%).

6.3.16. Sweating (See Figure 36 below and Figure 44 in the Appendix for details on each study.)

Fig.36 Difference in rates of sweats (SSRIs vs. TCAs)

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90 616 65375

40 63 313 321

35 59 359 351

23 13 365 280

173 225 1653 1605

When all trials were pooled, the resulting rate difference was -3.6% more sweating with the TCAs, whichwas a statistically significant difference (95% confidence interval: -6.7% to -0.4%).

6.3.17. Dizziness (See Figure 37 below and Figure 45 in the Appendix for details on each study.)

Thirty-seven trials reported rates of dizziness for both drugs.

A meta-analysis of all trials yielded a pooled rate difference of -9%. This was statistically significant (95%confidence limits: -12% to -6%) more dizziness with TCAs.

Fig.37 Difference in rates of dizziness (SSRIs vs. TCAs)

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212 945 95978

79 115 372 383

73 100 491 458

81 87 421 414

311 514 2229 2214

6.3.18. Hypotension (See Figure 38 below and Figure 46 in the Appendix for details on each study.)

55

Fig.38 Differences in rates of hypotension (SSRIs vs TCAs)

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There were 8 studies reporting rates of hypotension for both drugs. A meta-analysis of these 8 trials yieldeda pooled rate difference of -4.7%, more hypotension with TCAs but without statistical significance: 95%confidence interval from -13% to 3.5%. In order to increase precision of estimates, the trials excluded apriori (having less than 20 patients treated with each drug) were included a posteriori (additional informationwas available in 1 study with fluoxetine and 3 trials with fluvoxamine). A pooled estimate for these 12 trialsbecome -6%, still without statistical significance: 95% confidence interval of -14% to 2%.

Occurrence of symptoms like hypotension that are not frequently reported in randomized trials, are esti-mated to need a pool of more than 500 patients treated with each drug in order to establish whether adifference exists with more precision.

7. CONCLUSIONS

7.1 Efficacy

There are no statistically significant differences in efficacy between:

(i) individual SSRIs (see Figures 3 and 4 in the text; 1 and 2 in Appendix)(ii) SSRIs as a group and TCAs or other antidepressants (see Figures 5, 6, 7,13,14)(iii) SSRIs as a group and TCAs regardless of the patient mix, whether patients are treated in hospital or

as outpatients, whether they are adult or elderly patients, and regardless of drug doses (see Figures8-12).

SSRIs are significantly more efficacious than placebo, although placebo does produce improvement (seeFigure 3 in the text and Figure 1 in Appendix).

7.2 Completion rates

There are no statistically significant differences in completion rates between:

(i) individual SSRIs (see Figure 16)(ii) SSRIs and TCAs and other antidepressants, regardless of whether patients are adult or elderly and

whether they are hospitalized or outpatients (see Figure 17)

SSRIs have significantly better completion rates than placebo (see Figure 15).

7.3 Drop-outs

There are no statistically significant differences in dropout rates between:

(i) SSRIs and TCAs, due to adverse effects, except when adult and outpatient groups are combined (seeFigure 18)

(ii) SSRIs and TCAs, due to a lack of effect or worsening of symptoms (see Figure 19)

SSRIs are associated with 2% significantly fewer dropouts due to adverse effects in the adult/outpatientgroups.

7.4 Adverse events

SSRIs are associated with statistically significantly more nausea, anorexia, diarrhea, anxiety, agitation,insomnia and nervousness than TCAs (see Figures 21, 23, 24, 25, 27, 28, 34).

SSRIs are associated with statistically significantly less dry mouth, constipation, blurred vision, sweats anddizziness then TCAs. (See Figures 22, 25, 26, 35, 36, 37).

The method of elicitation of information on adverse events does not significantly alter these conclusions.

8. DISCUSSION

Meta-analysis of the clinical evidence on SSRIs confirms that these four SSRIs exert a moderate antide-pressant effect (ES difference between 0.4 to 0.7 over placebo). Comparative studies have demonstratedthat the probability that SSRIs induce response is somewhat inferior to TCAs. Thus, a mean of 57% ofpatients treated with SSRIs reached categories 1 and 2 of the CGI and 58 % had a 50% reduction in theirHRSD scores, compared to 61% and 68% respectively when TCAs were used. The two-arm meta-analysis translates such response into a 0.4% and -4% difference with TCAs and 1% and -5% differencewith other antidepressants. A baseline comparison resulting from the one-arm meta-analysis of these studiesalso indicates that a response can also be obtained with placebo (p = 0.25, 95% confidence limits of 0.13to 0.40). Indeed, placebo studies produce a pooled mean reduction of 6.6 points in HRSD scores com-pared to a pooled mean reduction of 12 points for SSRIs.

The effect size of these four SSRIs, in the 46 trials with homogeneous patient inclusion criteria (vs.amitriptyline, imipramine or clomipramine) which were analysed, is not statistically significantly different fromclassical TCAs in alleviating symptoms in episodes of major depression. This result is also true in the ex-tended meta-analyses of 117 studies vs. all TCAs or other antidepressants, -0.01 and 0.008 respectively,whether with outpatients or hospitalized patients, or with elderly or adult patients (see Figures 7 - 9 in thistext). SSRIs used at higher doses appear to induce less of an effect than standard or medium doses (seeTable 1 in the Appendix for definitions, and Figures 10 and 11 of this text) even with the same baselineHRSD scores as those used at the other dosage levels.

The level of effect or probability of response remains similar using any of these four SSRIs when theseries in the studies were inverted, i.e. from the 8 series comparing fluoxetine to fluvoxamine, paroxetine orsertraline. There was no extra benefit in using one or another SSRI. However, a mean additional effect of0.04 could be obtained with the pool including only the original trials. Identical results could be reproducedwith fluvoxamine, paroxetine and sertraline. Each one of these estimates has a wide and non-significantconfidence interval (mainly due to the scarcity of the data); only 11 randomized trials compared one SSRIwith another.

Two previous meta-analyses (Song et al., 1993, 49 studies, Möller et al.,1994, 25 studies vs. imipramineand Anderson et al., 1994, 55 where 5 studies used citalopram) also found similar results. Only studiesusing placebo, or small groups, in the latter meta-analysis, were analysed under the random effects model.Mean estimate of SSRI effect size over placebo, was inferior (ES = 0.41, which is a small effect) to ourfindings (ES = 0.55, a rather moderate effect). Paucity of data (11 trials) may explain these differences.Controversy was raised (Anderson et al., 1994) from the first meta-analytical study (Song et al., 1993)due to the inclusion of comparators others than TCAs. For discussion, we analysed separately effect sizedifferences of the TCAs and other antidepressants -TCAs remain the gold standard - and no statisticallysignificant differences could be found either with TCAs or any other class of antidepressant products (seeFigures 5 and 7, at pages 13 to 16 of this text, and Figures 3 - 6 in the Appendix for individual trials re-sults).

Adherence to the treatment involves multi-factorial determinants of compliance and these publishedstudies report only an approximation to compliance which is the rate of completion. In theory, it is reason-able to believe that patients remaining in the trials until their completion accept the treatment. SSRIs did notincrease the rate of completion significantly in these 117 trials analysed (1%, more completion with SSRIs),not significantly different regardless of which dose of SSRI or comparator. SSRIs improved completionrates from 4% to 13% as compared with placebo. Similar results have been published in previous meta-analyses by Song et al.,1993, Anderson and Tomenson, 1995, and Hotopf et al., 1996. Although thesemeta-analyses presented increasing number of trials, with increased precision in estimates, 2 of them choseto use cross-product calculations better suited to evaluate case-control studies. Although the distortion ofrisk, produced by interpreting odds ratios (ORs) as if they were relative risk (RRs), may be negligible in theassessment of less rare events, it presents clinical disadvantages. ORs may overestimate both benefits andharms of a treatment and the distortion becomes greater when occurrence of a more severe event becomesmore prevalent in the control group. The major drawback, however, is conceptual, in that it requiresrandomized trials to be assumed as having fixed effects and only binary outcomes. Relative or absolute riskdifferences are less friendly, harder to calculate and validate but are more adequate tools to assess benefitof an intervention over a gold standard (Capelleri et al., 1996 and Sackett et al., 1996).

Discontinuations due to lack of effect ranged from -1.3% more with TCAs to 2% more with SSRIs. Asimilar result was obtained when adding to these the patients who dropped out due to the worsening ofsymptoms. Discontinuations due to adverse events, mean -2%, from -0.3% to -4% more with TCAs, werestatistically significant only when the trials of adults and outpatients were considered together. Results fromthe analysis of the studies with inpatients, -3%, and elderly patients, -2%, were not statistically significantlydifferent. Again, the use of the SSRI produced a very modest benefit.

Another meta-analysis using ORs has reported contradictory results; this is possibly due to the method-ology used (Montgomery et al., 1994). The authors assumed that when drop-outs were not explicitlyspecified for one of the drugs in the trial, the number of drop-outs was zero. Using this methodology,Montgomery et al. found 27% fewer discontinuations due to side effects from SSRIs than TCAs, and 19%fewer than other antidepressants. In contrast, our analysis yields ranges from -0.4% to -4% fewerdiscontinuations due to side effects in the adult/outpatient groups (the single estimate that reached statisticalsignificance). Clinically, it means that a physician needs to treat 50 adult outpatients with SSRIs in order toprevent 1 drop-out due to adverse events. If a patient discontinues a TCA treatment, the physician will stillhave the option of changing to an alternative drug. For drop-outs due to a lack of effect, our analysis founda range from 1.3% fewer to 2% more drop-outs with SSRIs. This was similar to Montgomery et al., 1994(See Figures 18 and 19 in this text and Figures 21 - 28 in the Appendix). Bayesian meta-analysis of onearm to estimate the maximum likelihood (MLE) of rates of discontinuations due to side effects, resulted inan interval from 11 to 14% discontinuations due to side effects with SSRIs vs. 17 to 23% with TCAs. Withthis method, discontinuations due to the lack of effect ranged from 8% to 10% with SSRIs vs. 6% to 9%

with TCAs. Other reasons reported discontinuation of SSRI treatment ranging from 10 to 13% vs. 8 to12% with TCAs. The sum of these lower and upper 95% confidence limits demonstrates the overlap ofthese estimates, reinforcing the evidence provided by the estimates of all comparative analyses which havedemonstrated no statistically significant difference between SSRIs and TCAs. In short-term trials, one thirdof the treated patients will discontinue pharmacotherapy regardless of the drug used.

During these 4 to 12 week trials, 2 out of each 3 patients would complete pharmacotherapy but only onewould remit (would have reduced at least 50% of HRSD scores or succeed to have very much or markedimprovement in CGI).

Caution is still needed, however, in the interpretation of these results due to the relative merit of usingrates of stopping a treatment as a proxy for tolerance of a treatment. Bayesian methods may be moreadequate to evaluate the studies but may not overcome conceptual flaws.

Concerning the treatment emergent events, SSRIs induced significantly more nausea in 7% to 13% of thepatients treated, from 4% to 14% more diarrhea, 1% to 9% more anorexia, 1% to 6% more anxiety, 1%to 10% more agitation, from 2% to 6% more insomnia and 1% to 7% more nervousness. Paroxetine mayinduce less nausea than the other SSRIs but this evidence is weak. The use of SSRIs would prevent 25%to 35% dry mouth induced by the use of an TCA, from 8% to 14% constipation, from 0.02% to 5%blurred vision, from 0.4% to 7% sweating and from 6% to 12% dizziness occurring in patients treated withTCAs.

Anxiety and agitation are part of the clinical debate since the introduction of the SSRIs into the market.Since SSRI associated nervousness, insomnia, nausea and vomiting seemed to be related to dose, thepresence of these adverse events may reflect a functional increase in central serotonin activity, or serotoninsensitivity, which clearly has an excitatory role in pituitary-adrenal regulation. It is thus physiologicallyplausible that the worsening of hyper arousal symptoms may be associated with an increased capacity tocommit suicide (Teicher, M. H. et al., 1993). The interval shown in meta-analysis for agitation ranged from1% to 10% more with the use of an SSRI than with TCA. It may mean that 1 out of each 10 or 100 pa-tients may be exposed to a higher risk of a worse outcome when treated with an SSRI. Although anassociation of SSRIs with nervousness and anxiety were announced in some reviews 1 decade ago (Lader,M., 1988) a number of publications had recommended the use of SSRIs as anxiolytic. Moreover, measur-ing anxiety may be confounded by the use of concomitant benzodiazepines (which are effective antianxietyagents) by nearly half of these patients (Uhlenhuth E.H. et al., 1982).

The statistical significance of certain adverse events did not change with the method which was used toelicit its occurrence from patients.

Some of the SSRI or TCA treatment emergent symptoms that did not achieve statistical significance haveclinical significance and have been debated over the past decade. The trends made explicit in the meta-analysis are summarized in Figures 21 to 38 in this text, but the estimated rate difference in each study isdetailed in Figures 29 to 46 in Appendix. Postural hypotension, particularly among elderly patients, may be

of clinical significance. Only 8 trials with more than 20 patients reported information; 4 additional trials withless than 20 treated patients with each drug were sequentially excluded and included in the hypotensionmeta-analysis. The estimate showed a trend toward 5% and 6% more hypotension with TCAs than withSSRIs; none of these estimates reached statistical significance. For this level of occurrence of a symptommore than 500 patients require to be treated in each arm to detect a significant difference. More systematicreports of these adverse occurrences are also required to increase precision of these estimates. Overall,haematological and biochemical parameters did not reveal any clinically important values or trends in eitherdrug class.

With the exception of chloral hydrate or short-acting benzodiazepines (reported in 58% of the RCTs) forinsomnia and sleep disturbances, none of the adverse symptoms were reported to require additionalpharmacotherapy. Other management strategies included eventual dose reductions, discontinuations andchange of drugs. The third of patients discontinuing SSRI therapy due to adverse events are associated withnausea and gastrointestinal discomfort, and one fifth because of anxiety, agitation or nervousness. Where asthe third of TCAs treated patients discontinuations due to adverse events are associated to dry mouth,constipation or dizziness. Reported information for both arms of the antidepressant treatments, evidencedthat adverse events burden is similar with the drug classes, with the same symptoms occurring but atvariable intensities. Predominance of nausea with SSRIs and dry mouth with TCAs may, however, unblindthe health care provider or an informed patient.

Rare adverse events were not analysed in this paper due to lack of information on the event for bothdrugs in the same publication. Suicide and suicide attempts are among the rare events that we could notanalyse and may require other management strategies, e.g. hospitalisation. In a review, Freemantle N et al.,1994, assumed that SSRIs have nil toxicity and that severely depressed patients would not find other meansof committing suicide. Under these assumptions, in average, one suicide due to fatal poisoning with TCAalone out of 2,000 person years at risk, could be avoided by treating severe depressed patients withSSRIs. Instead, a switch to the newer tricyclic and related antidepressants was concluded to be more cost-effective.

Meta-analyses are limited to published literature (the Figure 6 in this text indicates little publication bias).Only published double-blind randomized trials were included in order to increase quality and accuracy ofestimates. Although only randomized double-blind trials were pooled, some reported more complete datathan others. Only 40% of the RCTs reported standard deviations for the means; we therefore assumed themissing standard deviations to be similar to the average of the ones published with the same pair of drugs.Thus, studies comparing paroxetine with placebo may appear less favourably due to the scarcity of data inthe publications. Also, authors conclusions were contradictory with results in efficacy estimated directlyfrom the data in 17% of the trials. Multiple publications and reanalyses excluded handled efficacy, with-drawals and missing data differently when compared with original papers, and also increased the requiredtime and effort to screen for original data. Conflicts of interest could not be evaluated.

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Feighner, J. P., Boyer, W. F., Meredith, C. H., Hendrickson, G. G. (1989b). A placebo-controlled inpatient comparison offluvoxamine maleate and imipramine in major depression. International Clinical Psychopharmacology, 4 : 239-244.

Feighner, J. P., Boyer, W. F. (1989c). Paroxetine in the treatment of depression: A comparison with imipramine andplacebo. Acta Psychiatrica Scandinavica, 80 (Suppl 350) : 125-129.

Feighner, J. P., Gardner, E. A., Johnston, J. A., Batey, S. R., Khayrallah, M. A., Ascher, J. A., et al. (1991). Double-blindcomparison of bupropion and fluoxetine in depressed outpatients. Journal of Clinical Psychiatry, 52 (8) : 329-335.

Ferreri, M. (1989). Fluoxetine versus amineptine in the treatment of outpatients with major depressive disorders. Interna-tional Clinical Psychopharmacology, 4 (Suppl 1) : 97-101.

Fieve, R. R., Goodnick, P. J., Peselow, E., Schlegel, A. (1986). Fluoxetine response: Endpoint vs pattern analysis. Interna-tional Clinical Psychopharmacology, 1 (4) : 320-323.

Fudge, J. L., Perry, P. J., Garvey, M. J., Kelly, M. W. (1990). A comparison of the effect of fluoxetine and trazodone on thecognitive functioning of depressed outpatients. Journal of Affective Disorders, 18 (4) : 275-280.

Gagiano, C. A., Müller, P. G., Fourie, J., Le Roux, J. F. (1989). The therapeutic efficacy of paroxetine: (a) An open study inpatients with major depression not responding to antidepressants; b) A double-blind comparison with amitriptyline indepressed outpatients. Acta Psychiatrica Scandinavica, 80 (Suppl 350) : 130-131.

Gattaz, W. F., Vogel, P., Kick, H.,Kohnen, R. (1995). Moclobemide versus fluoxetine in the treatment of inpatients withmajor depression. Journal of Clinical Psychopharmacology, 15 (4 Suppl 2) : 35S-40S.

Geerts, S., Bruynooghe, F., De Cuyper, H., Demeulemeester, F., Haazen, L. (1994). Moclobemide versus fluoxetine formajor depressive episodes. Clinical Neuropharmacology, 17 (Suppl 1) : S50-S57.

Geretsegger, C., Böhmer, F., Ludwig, M. (1994). Paroxetine in the elderly depressed patient: Randomized comparison withfluoxetine of efficacy, cognitive and behavioural effects. International Clinical Psychopharmacology, 9 (1) : 25-29.

Geretsegger, C., Stuppaeck, C. H., Mair, M., Platz, T., Fartacek, R., Heim, M. (1995). Multicenter double blind study ofparoxetine and amitryptyline in elderly depressed inpatients. Psychopharmacology, 119 (3) : 277-281.

Ginestet, D. (1989). Fluoxetine in endogenous depression and melancholia versus clomipramine. International ClinicalPsychopharmacology, 4 (Suppl 1) : 37-40.

Gonella, G., Baignoli, G., Ecari, U. (1990). Fluvoxamine and imipramine in the treatment of depressive patients: Adouble-blind controlled study. Current Medical Research and Opinion, 12 (3) : 177-184.

Guelfi, J. D., Dreyfus, J. F., Pichot, P. (1983). A double-blind controlled clinical trial comparing fluvoxamine withimipramine. British Journal of Clinical Pharmacology, 15 (Suppl 3) : 411S-417S.

Guy, W., Wilson, W. H., Ban, T. A., King, D. L., Manov, G., Fjetland, O. K. (1984). A double-blind clinical trial offluvoxamine and imipramine in patients with primary depression. Psychopharmacology Bulletin, 20 (1) : 73-78.

Harris, B., Szulecka, T. K., Anstee, J. A. (1991). Fluvoxamine versus amitriptyline in depressed hospitalout-patients: Amulticentre, double-blind, comparative trial. British Journal of Clinical Research, 2 : 89-99.

Hutchinson, D. R., Tong, S., Moon, C. A., Vince, M., Clarke, A. (1992). Paroxetine in the treatment of elderly depressedpatients in general practice: A double-blind comparison with amitriptyline. International Clinical Psychopharmacology, 6(Suppl. 4) : 43-51.

Itil, T. M., Shrivastava, R. K., Mukherjee, S., Coleman, B. S., Michael, S. T. (1983). A double-blind placebo-controlledstudy of fluvoxamine and imipramine in out-patients with primary depression. British Journal of Clinical Pharmacology,15 (Suppl 3) : 433S-438S.

Judd, F. K., Moore, K., Norman, T. R., Burrows, G. D., Gupta, R. K., Parker, G. (1993). A multicentre double blind trial offluoxetine versus amitriptyline in the treatment of depressive illness. Australian and New Zealand Journal of Psychiatry,27 (1) : 49-55.

Keegan, D., Bowen, R. C., Blackshaw, S., Saleh, S., Dayal, N., Remillard, F., et al. (1991). A comparison of fluoxetine andamitriptyline in the treatment of major depression. International Clinical Psychopharmacology, 6 : 117-124.

Kerkhofs, M., Rielaert, C., de Maertelaer, V., Linkowski, P., Czarka, M., Mendlewicz, J. (1990). Fluoxetine in major depres-sion : Efficacy, safety and effects on sleep polygraphic variables. International Clinical Psychopharmacology, 5 : 253-260.

Kiev, A. (1992). A double-blind, placebo-controlled study of paroxetine in depressed outpatients. Journal of ClinicalPsychiatry, 53 (2) : 27-29.

Klok, C. J., Brouwer, G. J., van Praag, H. M., Doogan, D. (1981). Fluvoxamine and clomipramine in depressed patients: Adouble-blind clinical study. Acta Psychiatrica Scandinavica, 64 (1) : 1-11.

Kuha, S., Mehtonen, O. P., Henttonen, A., Naarala, M. (1991). The efficacy of fluoxetine versus maprotiline in depressedpatients and by dose. Nordisk Psykiatrisk Tidsskrift, 45 : 109-117.

Kuhs, H., Rudolf, G. A. (1989). A double-blind study of the comparative antidepressant effect of paroxetine andamitriptyline. Acta Psychiatrica Scandinavica, 80 (Suppl 350) : 145-146.

La Pia, S., Giorgio, D., Ciriello, R., Sannino, A., De Simone, L., Paoletti, C., et al. (1992). Evaluation of the efficacy, tolerabil-ity and therapeutic profile of fluoxetine versus mianserin in the treatment of depressive disorders in the elderly. CurrentTherapeutic Research, 52 (6) : 847-858.

Laakmann, G., Blaschke, D., Engel, R., Schwarz, A. (1988). Fluoxetine vs amitriptyline in the treatment of depressedout-patients. British Journal of Psychiatry, 153 (Suppl 3) : 64-68.

Lam, R. W., Gorman, C. P., Michalon, M., Steiner, M., Levitt, A. J., Corral, M. R., et al. (1995). Multicenter,placebo-controlled study of fluoxetine in seasonal affective disorder. American Journal of Psychiatry, 152 (12) :1765-1770.

Lapierre, Y. D., Browne, M., Horn, E., Oyewumi, L. K., Sarantidis, D., Roberts, N., et al. (1987). Treatment of major affectivedisorder with fluvoxamine. Journal of Clinical Psychiatry, 48 (2) : 65-68.

Laursen, A. L., Mikkelsen, P. L., Rasmussen, S., Le Fèvre Honoré, P. (1985). Paroxetine in the treatment of depression: Arandomized comparison with amitriptyline. Acta Psychiatrica Scandinavica, 71 : 249-255.

Levine, S., Deo, R., Mahadevan, K. (1989). A comparative trial of a new antidepressant, fluoxetine. International ClinicalPsychopharmacology, 4 (Suppl 1) : 41-45.

Link, C., Dunbar, G. (1992). An overview of studies comparing the efficacy, safety, and tolerability of paroxetine andclomipramine. Nordic Journal of Psychiatry, 46 (Suppl 27) : 17-22.

Loeb, C., Albano, C., Gandolfo, C. (1989). Fluoxetine versus imipramine. International Clinical Psychopharmacology, 4(Suppl 1) : 75-79.

Lonnqvist, J., Sintonen, H., Syvalahti, E., Appelberg, B., Koskinen, T., Mannikko, T., et al. (1994). Antidepressant efficacyand quality of life in depression: A double-blind study with moclobemide and fluoxetine. Acta PsychiatricaScandinavica, 89 : 363-369.

Lydiard, R. B., Laird, L. K., Morton Jr., W. A., Steele, T. E., Kellner, C., Laraia, M. T., et al. (1989). Fluvoxamine, imipramine,and placebo in the treatment of depressed outpatients: Effects on depression. Psychopharmacology Bulletin, 25 (1) :68-70.

Manna, V., Martucci, N., Agnoli, A. (1989). Double-blind controlled study on the clinical efficacy and safety of fluoxetine

vs clomipramine in the treatment of major depressive disorders. International Clinical Psychopharmacology, 4 (Suppl 1) :81-88.

March, J. S., Kobak, K. A., Jefferson, J. W., Mazza, J., Greist, J. H. (1990). A double-blind, placebo-controlled trial offluvoxamine versus imipramine in outpatients with major depression. Journal of Clinical Psychiatry, 51 (5) : 200-202.

Masco, H. L., Sheetz, M. S. (1985). Double-blind comparison of fluoxetine and amitriptyline in the treatment of majordepressive illness. Advances in Therapy, 2 (6) : 275-284.

Mertens, C., Pintens, H. (1988). Paroxetine in the treatment of depression. A double blind multicentre study versusmianserin. Acta Psychiatrica Scandinavica, 77 : 683-688.

Miller, S. M., Naylor, G. J., Murtagh, M., Winslow, G. (1989). A double-blind comparison of paroxetine and placebo in thetreatment of depressed patients in a psychiatric outpatient clinic. Acta Psychiatrica Scandinavica, 80 (Suppl 350) :143-144.Möller, H.-J., Berzewski, H., Eckmann, F., Gonzalves, N., Kissling, W., Knorr, W., et al. (1993). Double-blind multicenterstudy of paroxetine and amitriptyline in depressed inpatients. Pharmacopsychiatry, 26 : 75-78.

Moon, C. A., Jago, W., Wood, K., Doogan, D. P. (1994). A double-blind comparison of sertraline and clomipramine in thetreatment of major depressive disorder and associated anxiety in general practice. Journal of Psychopharmacology, 8 (3) :171-176.

Muijen, M., Roy, D., Silverstone, T., Mehmet, A., Christie, M. (1988). A comparative clinical trial of fluoxetine, mianserinand placebo in depressed outpatients. Acta Psychiatrica Scandinavica, 78 : 384-390.

Mullin, J. M., Pandita-Gunawardena, V. R., Whitehead, A. M. (1988). A double-blind comparison of fluvoxamine anddothiepin in the treatment of major affective disorder. British Journal of Clinical Practice, 42 (2) : 51-55.

Nathan, R. S., Perel, J. M., Pollock, B. G., Kupfer, D. J. (1990). The role of neuropharmacologic selectivity in antidepressantaction: Fluvoxamine versus desipramine. Journal of Clinical Psychiatry, 51 (9) : 367-372.

Nemeroff, C. B., Ninan P. T., Ballenger J., Lydiard R. B., Feighner J., Patterson W. M., Greist J. H. 1995. Double-blindmulticenter comparison of fluvoxamine versus sertraline in the treatment of depressed outpatients. Depression 3 : 163-169.

Nielsen, O. A., Morsing, I., Petersen, J. S., Larsen, T., Moller, S. E., Manniche, P. M., (1991). Paroxetine and imipraminetreatment of depressive patients in a controlled multicentre study with plasma amino acid measurements. ActaPsychiatrica Scandinavica, 84 : 233-241.

Nielsen, B. M., Behnke, K., Arup, P., Christiansen, P. E., Geisler, A., Ipsen, E., et al. (1993). A comparison of fluoxetine andimipramine in the treatment of outpatients with major depressive disorder. Acta Psychiatrica Scandinavica, 87 : 269-272.

Noguera, R., Altuna, R., Alvarez, E., Ayuso, J. L., Casais, L., Udina, C. (1991). Fluoxetine vs. clomipramine in depressedpatients: A controlled multicentre trial. Journal of Affective Disorders, 22 (3) : 119-124.

Nolen, W. A., van de Putte, J. J., Dijken, W. A., Kamp, J. S., Blansjaar, B. A., Kramer, H. J., et al. (1988). Treatment strat-egy in depression: 1. Non-tricyclic and selective reuptake inhibitors in resistant depression: A double-blind partialcrossover study on the effects of oxaprotiline and fluvoxamine. Acta Psychiatrica Scandinavica, 78 : 668-675.

Norton, K. R., Sireling, L. I., Bhat, A. V., Rao, B., Paykel, E. S. (1984). A double-blind comparison of fluvoxamine,imipramine and placebo in depressed patients. Journal of Affective Disorders, 7 (3-4) : 297-308.

Øhrberg, S., Christiansen, P. E., Severin, B., Calberg, H., Nilakantan, B., Borup, A., et al. (1992). Paroxetine and imipraminein the treatment of depressive patients in psychiatric practice. Acta Psychiatrica Scandinavica, 86 : 437-444.

Ottevanger, E. A. (1995). Fluvoxamine and clomipramine in depressed hospitalised patients: Results from a randomised,double-blind study. Encéphale, 21 (4) : 317-321.

Pakesch, G., Dossenbach, M. (1991). Wirkung und sicherheit von fluoxetin versus clomipramin bei ambulanten patientenmit einem depressiven syndrom in einer klinischen prüfung bei niedergelassenen Ärtzen. Wiener KlinischeWochenschrift, 103 (6) : 176-182.

Perry, P. J., Garvey, M. J., Kelly, M. W., Cook, B. L., Dunner, F. J., Winokur, G. (1989). A comparative trial of fluoxetineversus trazodone in outpatients with major depression. Journal of Clinical Psychiatry, 50 (8) : 290-294.

Peselow, E. D., Filippi, A-M., Goodnick, P., Barouche, F., Fieve, R. R. (1989). The short- and long-term efficacy ofparoxetine HCI: A. Data from a 6-week double-blind parallel design trial vs. imipramine and placebo. PsychopharmacologyBulletin, 25 (2) : 267-271.Peters, U. H., Lenhard, P., Metz, M. (1990). Ambulante therapie der depression mit fluoxetin - eine multizentrischedoppelblindstudie. Nervenheilkunde, 9 : 28-31.

Poelinger, W., Haber, H. (1989). Fluoxetine 40mg vs maprotiline 75mg in the treatment of out-patients with depressivedisorders. International Clinical Psychopharmacology, 4 (Suppl 1) : 47-50.

Porro, V., Fiorenzoni, S., Menga, C., de Cristofaro, A., Bertolino, A. (1988). Single-blind comparison of the efficacy offluvoxamine versus placebo in patients with depressive syndrome. Current Therapeutic Research, 43 (4) : 621-629.

Preskorn, S. H., Silkey, B., Beber, J., Dorey, (1991). Antidepressant response and plasma concentrations of fluoxetine.Annals of Clinical Psychiatry, 3 (2) : 147-151.

Rahman, M. K., Akhtar, M. J., Savla, N. C., Sharma, R. R., Kellett, J. M., Ashford, J. J. (1991). A double-blind randomisedcomparison of fluvoxamine with dothiepin in the treatment of depression in elderly patients. British Journal of ClinicalPractice, 45 (4) : 255-258.

Rapaport, M., Coccaro, E., Sheline, Y., Perse, T., Holland, P., Fabre, L., et al. (1996). A comparison of fluvoxamine andfluoxetine in the treatment of major depression. Journal of Clinical Psychopharmacology, 16 (5) : 373-378.

Reimherr, F. W., Chouinard, G., Cohn, C. K., Cole, J. O., Itil, T. M., LaPierre, Y. D., et al. (1990). Antidepressant efficacy ofsertraline: A double-blind, placebo- and amitriptyline-controlled, multi-center comparison study in outpatients with majordepression. Journal of Clinical Psychiatry,. 51 (12 Suppl B) : 18-27.

Remick, R. A., Keller, F. D., Gibson, R. E., Carter, D. (1989). A comparison between fluoxetine and doxepin in depressedpatients. Current Therapeutic Research, 46 (5) : 842-848.

Remick, R. A., Claman, J., Reesal, R., Gibson, R. E., Agbayewa, M. O., Lam, R. W., et al. (1993). Comparison of fluoxetineand desipramine in depressed outpatients. Current Therapeutic Research, 53 (5) : 457-465.

Remick, R. A., Reesal, R., Oakander, M., Allen, J., Claman, J., Ramirez, C. E., et al. (1994). Comparison of fluvoxamine and

amitriptyline in depressed outpatients. Current Therapeutic Research, 55 (3) : 243-250.

Reynaert, C., Parent, M., Mirel, J., Janne, P., Haazen, L. (1995). Moclobemide versus fluoxetine for a major depressiveepisode. Psychopharmacology, 118 (2) : 183-187.

Rickels, . K., Amsterdam, J.D., Avallone, M. F. (1986). Fluoxetine in major depression: A controlled study. CurrentTherapeutic Research, 39 (4) : 559-563.

Rickels, K., Amsterdam, J., Clary, C., Fox, I., Schweizer, E., Weise, C. (1989). A placebo-controlled, double-blind, clinicaltrial of paroxetine in depressed outpatients. Acta Psychiatrica Scandinavica, 80 (Suppl 350) : 117-123.

Robertson, M. M., Abou-Saleh, M. T., Harrison, D. A., Nairac, B. L., Edwards, D. R., Lock, T., et al. (1994). A double-blindcontrolled comparison of fluoxetine and lofepramine in major depressive illness. Journal of Psychopharmacology, 8 (2) :98-103.

Ropert, R. (1989). Fluoxetine versus clomipramine in major depressive disorders. International ClinicalPsychopharmacology, 4 (Suppl 1) : 89-95.

Roth, D., Mattes, J., Sheehan, K. H., Sheenan, D. V. (1990). A double-blind comparison of fluvoxamine, desipramine andplacebo in outpatients with depression. Progress in Neuropsychopharmacology and Biological Psychiatry, 14 : 929-939.

Shrivastava, R. K., Shrivastava, S. H., Overweg, N., Blumhardt, C. L. (1992). A double-blind comparison of paroxetine,imipramine, and placebo in major depression. Journal of Clinical Psychiatry, 53 (2 Suppl) : 48-51.Orsel Donbak, S., Turkçapar, M. H., Ozturk Kiliç, E. Z., Demirergi, N., Akdemir, A., et al. (1995). Moclobemide andsertraline in the treatment of depressive disorders: A comparative study. Acta Psychiatrica Belgica, 95 (3) : 139-151.

South Wales Antidepressant Drug Trial Group. (1988). A double-blind multi-centre trial of fluoxetine and dothiepin inmajor depressive illness. International Clinical Psychopharmacology, 3 : 75-81.

Staner, L., Kerkhofs, M., Detroux, D., Leyman, S., Linkowski, P., Mendlewicz, J. (1995). Acute, subchronic and withdrawalsleep EEG changes during treatment with paroxetine and amitriptyline: A double-blind randomized trial in major depres-sion. Sleep, 18 (6) : 470-477.

Stark, P., Hardison, C. D. (1985). A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo inoutpatients with major depressive disorder. Journal of Clinical Psychiatry, 46 (3 Sec. 2) : 53-58.

Tamminen, T. T., Lehtinen, V. V. (1989). A double-blind parallel study to compare fluoxetine with doxepin in the treatmentof major depressive disorders. International Clinical Psychopharmacology, 4 (Suppl 1) : 52-56.

Taneri, Z., Köhler, R. (1989). Fluoxetine versus nomifensine in outpatients with neurotic or reactive depressive disorder.International Clinical Psychopharmacology, 4 (Suppl 1) : 57-61.

Tollefson, G. D., Bosomworth, J. C., Heiligenstein, J. H., Potvin, J. H., Holman, S., Fluoxetine Collaborative Study Group(1995). A double-blind, placebo-controlled clinical trial of fluoxetine in geriatric patients with major depression. Interna-tional Psychogeriatrics, 7 (1) : 89-104.

van Moffaert, M., Bartholomé, F., Cosyns, P., De Nayer, A.R., Mertens, C. (1995). A controlled comparison of sertralineand fluoxetine in acute and continuation treatment of major depression. Human Psychopharmacology, 10 (5) : 393-405.

Wernicke, J. F., Dunlop, S. R., Dornseif, B. E., Zerbe, R. L. (1987). Fixed-dose fluoxetine therapy for depression.Psychopharmacology Bulletin, 23 (1) : 164-168.

Wernicke, J. F., Dunlop, S. R., Dornseif, B. E., Bosomworth, J. C., Humbert, M. (1988). Low-dose fluoxetine therapy fordepression. Psychopharmacology Bulletin, 24 (1) : 183-188.

Williams, R., Edwards, R. A., Newburn, G. M., Mullen, R., Menkes, D. B., Segkar, C. (1993). A double-blind comparison ofmoclobemide and fluoxetine in the treatment of depressive disorders. International Clinical Psychopharmacology, 7 (3-4): 155-158.

List 2. References excluded from efficacy analyses but included in completers or/and adverse events meta-analyses.

Bocksberger, J. P., Gachoud, J. P., Richard, J., Dick, P. (1993). Comparison of the efficacy of moclobemide andfluvoxamine in elderly patients with a severe depressive episode. European Psychiatry, 8 (6) : 319-324.

Coleman, B. S., Block, B. A. (1982). Fluvoxamine maleate, a serotonergic antidepressant; a comparison withchlorimipramine. Progress in Neuro-psychopharmacology and Biological Psychiatry, 6 (4-6) : 475-478.

Dalery, J., Rochat, C., Peyron, E., Bernard, G. (1992). Etude comparative de l’efficacité et de l’acceptabilité de l’amineptineet de la fluoxétine chez des patients dépressifs majeurs. Encephale, 18 : 257-262.

Dunbar, G. C., Cohn, J. B., Fabre, L. F., Feighner, J. P., Fieve, R. R., Mendels, J., et al. (1991). A comparison of paroxetine,imipramine and placebo in depressed-outpatients. British Journal of Psychiatry, 159 : 394-398.

Dunlop, S. R., Dornseif, B. E., Wernicke, J. F., Potvin, J. H. (1990). Pattern analysis shows beneficial effect of fluoxetinetreatment in mild depression. Psychopharmacology Bulletin, 26 (2) : 173-180.

Gasperini, M., Gatti, F., Bellini, L., Anniverno, R.,Smeraldi, R. (1992). Perspectives in clinical psychopharmacology ofamitriptyline and fluvoxamine: A double-blind study in depressed inpatients. Neuropsychobiology, 26 : 186-192.

Hendrickx, B., van Moffaert, M., Spiers, R., von Frenckell, R. (1991). The treatment of psychocutaneous disorders: A newapproach. Current Therapeutic Research, 49 (1) : 111-119.

Moon, C., Vince, M. (1996). Treatment of major depression in general practice: A double-blind comparison of paroxetineand lofepramine. British Journal of Clinical Practice, 50 (5) : 240-244.

Moon, C. A., Jesinger, D. K. (1991). The effects of psychomotor performance of fluvoxamine versus mianserin in de-pressed patients in general practice. British Journal of Clinical Practice, 45 (4) : 259-262.

Pélicier, Y., Schaeffer, P. (1993). Etude multicentrique en double aveugle comparant l’efficacité, et la tolérance de laparoxétine et de la clomipramine dans la dépression réactionnelle du sujet âgé. L’Encephale, 19 (3) : 257-261.

Perez, A., Ashford, J. J. (1990). A double-blind, randomized comparison of fluvoxamine with mianserin in depressiveillness. Current Medical Research and Opinion, 12 (4) : 234-241.

Phanjoo, A., Wonnacott, S., Hodgson, A. (1991). Double-blind comparative multi-centre study of fluvoxamine andmianserin in the treatment of major depressive episode in elderly people. Acta Psychiatrica Scandinavica, 83 : 476-479.

Tignol, J. (1993). A double-blind, randomized, fluoxetine-controlled multicenter study of paroxetine in the treatment ofdepression. The use of paroxetine, a serotonin reuptake inhibitor, in the treatment of depression. Journal of ClinicalPsychopharmacology, 13 (6 Suppl 2) : S18-S22.

Wagner, W., Cimander, K., Schnitker, J., Koch, H. F. (1986). Influence of concomitant psychotropic medication on theefficacy and tolerance of fluvoxamine. Advances in Pharmacotherapy, 2 : 34-56.

Wakelin, J. S. (1986). Fluvoxamine in the treatment of the older depressed patient: Double-blind, placebo-controlled data.

International Clinical Psychopharmacology, 1 (3) : 221-230.

Young, J. P., Coleman, A., Lader, M. H. (1987). A controlled comparison of fluoxetine and amitriptyline in depressedout-patients. British Journal of Psychiatry, 151 : 337-340.

List 3. References of trials excluded:

Altamura, A. C., Percudani, M., Guercetti, G., Invernizzi, G. (1989). Efficacy and tolerability of fluoxetine in the elderly: Adouble-blind study versus amitriptiline. International Clinical Psychopharmacology, 4 (Suppl 1) : 103-106.

Arminen, S. L., Ikonen, U., Pulkkinen, P., Leinonen, E., Mahlanen, A., Koponen, H., et al. (1994). A 12-week double-blindmulti-centre study of paroxetine and imipramine in hospitalized depressed patients. Acta Psychiatrica Scandinavica, 89(6) : 382-389.

Beasley, C. M., Bosomworth, J. C., Wernicke, J. F. (1990). Fluoxetine: Relationships among dose, response, adverseevents, and plasma concentrations in the treatment of depression. Psychopharmacology Bulletin, 26 (1) : 18-24.

Beasley, C. M., Dornseif, B. E., Bosomworth, J. C., Sayler, M. E., Rampey, A. H., Heiligenstein, J. H., et al. (1991b).Fluoxetine and suicide: A meta-analysis of controlled trials of treatment for depression. BMJ, 303 (6804) : 685-692.

Beasley, C. M., Sayler, M. E., Potvin, J. H. (1993). Fluoxetine versus amitriptyline in the treatment of major depression: Amulticenter trial. International Clinical Psychopharmacology, 8 : 143-149.

Brasseur, R. (1989). A multicentre open trial of fluoxetine in depressed out-patients in Belgium. International ClinicalPsychopharmacology, 4 (Suppl 1) : 107-111.

Bressa, G. M., Brugnoli, R., Pancheri, P. (1989). A double-blind study of fluoxetine and imipramine in major depression.International Clinical Psychopharmacology, 4 (Suppl 1) : 69-73.

Cassano, G. B., Conti, L., Massimetti, G., Mengali, F., Waekelin, J. S., Levine, J. (1986). Use of a standardized documenta-tion system (BLIPS/BDP) in the conduct of a multicenter international trial comparing fluvoxamine, imipramine, andplacebo. Psychopharmacology Bulletin, 22 (1) : 52-58.

Claghorn, J. L., Kiev, A., Rickels, K., Smith, T., Dunbar, G. C. (1992). Paroxetine versus placebo: A double-blind compari-son in depressed patients. Journal of Clinical Psychiatry, 53 (12) : 434-438.

Claghorn, J. L. (1992). The safety and efficacy of paroxetine compared with placebo in a double-blind trial of depressedoutpatients. Journal of Clinical Psychiatry, 53 (Suppl 2) : 33-35.

Conti, L., Placidi, G. F., Dell’Osso, L., Lenzi, A., Cassano, G. B. (1987). Therapeutic response in subtypes of major depres-sion. New Trends in Experimental and Clinical Psychiatry, 3 (2) : 101-107.

Conti, L., Dell’Osso, L., Re, F., Musetti, L., Cassano, G.B. (1988). Fluvoxamine maleate: Double-blind clinical trial vsplacebo in hospitalized depressed patients. CurrentTherapeutic Research, 43 (3) : 468-480.

Conti, L., Dell’Osso, L. (1989). Clinical predictors of response to fluvoxamine, imipramine, and placebo. New Trends inExperimental and Clinical Psychiatry, 5 (4) : 221-229.

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Goodnick, P. J., Fieve, R. R., Peselow, E. D., Barouche, F., Schlegel, A. (1987). Double-blind treatment of major depressionwith fluoxetine: Use of pattern analysis and relation of HAM-D score to CGI change. Psychopharmacology Bulletin, 23(1) : 162-163.

Gray, D. S., Fujioka, K., Devine, W., Bray, G. A. (1992). A randomized double-blind clinical trial of fluoxetine in obesediabetics. International Journal of Obesity, 16 (Suppl 4) : S67-S72.

Guillibert, E., Pelicier, Y., Archambault, J. C., Chabannes, J. P., Clerc, G., Desvilles, M., et al. (1989). A double-blind,multicentre study of paroxetine versus clomipramine in depressed elderly patients. Acta Psychiatrica Scandinavica, 80(Suppl 350) : 132-134.

Heiligenstein, J. H., Ware, J. E., Beusterien, K. M., Roback, P. J., Andrejasich, C., Tollefson, G. D. (1995). Acute effects offluoxetine versus placebo on functional health and well-being in late-life depression. International Psychogeriatrics, 7(Suppl) : 125-137.

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The studies reporting only the usual range of doses (e.g. fluvoxamine 100-300 mg, paroxetine 10-50 mg orsertraline 50-200 mg) were assumed to use standard dose.

Table A1. Dose categories : interval definitions used

Drug doses reported use in the studies were either fixed or variable, its means or at least 3 consecutiveweeks of use allowed categorization of dosage as low, standard , medium and high as follows:

Drug Category Minimum Maximum

Fluoxetine Low 5 mg 5 mg

Standard 20 mg 29 mg

Medium 30 mg 39 mg

High 40 mg 80 mg

Fluvoxamine Low 50 mg 150 mg

Standard 151 mg 199 mg

Medium 200 mg 249 mg

High 250 mg 300 mg

Paroxetine Low 10 mg 19 mg

Standard 20 mg 29 mg

Medium 30 mg 34 mg

High 35 mg 50 mg

Sertraline Low 50 mg 99 mg

Standard 100 mg 150 mg

Medium 151 mg 199 mg

High 200 mg 300 mgThe studies reporting only the usual range of doses (e.g. fluvoxamine 100-300 mg, paroxetine 10-50

mg or sertraline 50-200 mg) were assumed to use standard dose.

Cohn & Wilcox 1985

Fabre & Crismon 1985

Cohn et al 1989

Fabre & Putman 1987 (Fluox.20mg)

Fabre & Putman 1987 (Fluox.40mg)

Fabre & Putman 1987 (Fluox.60mg)

Feighner et al 1989a

Fieve et al 1986

Lam et al 1995

Muijen et al 1988

Rickels et al 1986

Stark & Hardison 1985

Tollefson et al 1995

Wernicke et al 1987 (Fluox. 20mg)

Wernicke et al 1987 (Fluox. 40mg)

Wernicke et al 1987 (Fluox. 60mg)

Wernicke et al 1988 (Fluox. 5mg)

Wernicke et al 1988 (Fluox. 20mg)

Wernicke et al 1988 (Fluox. 40mg)

Byerley et al 1988 (Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

- 1 0- 2 21Standardised Effect Size with 95% Confidence Interval

FluoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

32

54

30

22

22

25

25

61

40

36

26

18

142

335

100

103

105

96

96

93

29

58

29

26

12

59

9

32

28

24

169

336

48

78

20 1461 937Mean effect difference Fluoxetine vs. Placebo

Fig.1 Differences in effect size ( SSRIs vs. Placebo)

FluvoxamineComparator

Amin et al 1984

Claghorn et al 1996

Claghorn et al 1996

Dominguez et al 1985

Fabre 1996

Feighner et al 1989b

Itil et al 1983

Lapierre 1987

Lydiard et al 1989

March et al 1990

Norton et al 1984

Porro et al 1988

Roth et al 1990

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

13 513 471Mean effect difference Fluvoxam. vs. Placebo

161

50

23

35

50

31

22

22

18

17

33

21

30

150

50

22

31

50

19

22

20

18

14

25

20

30

//

//

//

//ME=2.70

Cont.

Claghorn et al 1992a

Cohn et al 1992

(Placebo)

(Placebo)

32

35

26

36

Amin et al1989 (50mg.)

Amin et al1989 (100mg.)

Amin et al1989 (200mg.)

Fabre et al 1995

Reimherr et al 1990a

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

7

8

8

278

149

7

91

150

5 450 248Mean effect difference Sertraline vs. Placebo

SSRIs Placebo

Mean effect difference SSRIs vs. Placebo 48 2787 2016

Sertraline

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

Fig.1 Differences in effect size (SSRIs vs. Placebo)

10 363 360Mean effect difference Paroxetine vs. Placebo

Kiev 1992

Miller et al 1989

Feighner & Boyer 1989c

Peselow et al 1989a

Rickels et al 1989

Smith & Glaudin 1992

Shrivastava 1992

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

ParoxetineComparator

Comparator

39

34

22

40

49

33

40

37

32

25

42

53

33

40

Fabre 1992 (Placebo) 39 37

- 1 0- 2 21Standardised Effect Size with 95% Confidence Interval

Bennie 1995

Aguglia et al 1993

Van Moffaert et al 1995

(Sertraline)

(Sertraline)

(Sertraline)

- 1 0- 2 21Standardised Effect Size with 95% Confidence Interval

FluoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

40

144

82

48

142

83

Geretsegger 1994

Chouinard et al 1994

De Wilde et al 1993

Gagiano 1993

(Paroxetine)

(Paroxetine)

(Paroxetine)

(Paroxetine)

101

41

102

37

45

52

45

54

Rapaport 1996 (Fluvoxamine) 49 51

4

1

239 238Fluoxetine vs. Paroxetine

3 266 273Fluoxetine vs. Sertraline

3 273 266Sertraline vs. Fluoxetine

1

1

4 238 239Paroxetine vs. Fluoxetine

Chouinard et al 1994

De Wilde et al 1993

Gagiano 1993

Geretsegger 1994

(Fluoxetine)

(Fluoxetine)

(Fluoxetine)

(Fluoxetine)

ParoxetineComparator

102

37

45

54

101

41

45

52

5 294 303Mean effect difference Parox. vs. others SSRIs

Ansseau et al 1994 (Fluvoxamine) 56 64

Aguglia et al 1993

Bennie 1995

Van Moffaert et al 1995

Nemeroff et al 1995

(Fluoxetine)

(Fluoxetine)

(Fluoxetine)

(Fluvoxamine)

SertralineComparator

48

142

83

46

40

144

82

49

Fig.2 Differences in effect size (SSRI vs. SSRIs)

FluvoxamineComparator

Rapaport et al 1996

Ansseau et al 1994b

Nemeroff et al 1995

Mean effect difference Fluvo. vs. others SSRIs

(Fluoxetine)

(Paroxetine)

(Sertraline)

3

51

64

49

164

49

56

46

151

4 319 315Mean effect difference Sertr. vs. others SSRIs

8 554 562Mean effect difference Fluox. vs. others SSRIs

Chouinard 1985

Feighner 1985a

Fawcett et al 1989

Judd et al 1993

Keegan et al 1991

Kerkhofs et al 1990

Laakmann et al 1988

Masco et al 1985

Peters et al 1990

Preskorn 1991

Beasley et al 1993b

Bremner 1984

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Feighner et al 1989a

Levine et al 1989

Loeb et al 1989

Manna et al 1989

Noguera et al 1991

Pakesch & Dosenbach 1991(20mg)

Pakesch & Dosenbach 1991(20mg)

Pakesch & Dosenbach 1991(40mg)

Pakesch & Dosenbach 1991(40mg)

Ropert 1989

Mean Difference with ClomipramineEffect

Nielsen et al 1993

Stark & Hardison 1985

Mean Difference with ImipramineEffect

Ginestet 1989

Altamura et al 1991 (Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

FluoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

14 14

23

20

22

30

20

9

63

20

40

29

28

20

22

28

22

10

65

21

41

31

11 290 302Mean Effect Difference with Amitryptiline

56

20

62

20

32 34

54 54

30 30

61 59

30 30

15 15

29

185

30

186

10 512 520

28 26

15 15

60

38

7

38

8

60

39

9

39

9

71 72

265 2698

Fig.3 Differences in effect size (Fluoxetine vs. other antidepressants)

- 1 0- 2 21Standardised Effect Size with 95%

Confidence Interval Cont.

Corne & Halll 1989

Dowling et al 1990

South Wales ADTG 1988

Mean Difference with DothiepinEffect

()Dothiepin

()Dothiepin

()Dothiepin

49

30

51

30

31 28

1091103

e h

o

o

o

o

o

o

o

o

o

o

ho

o

o

o

o

o

o

o

h

h

o

o

o

o

o

o

o

o

o

h/o

eho

: without systemic deseases, substance abuse or dependence and other psychiatric disorder: Elderly

: Hospitalized patients

: Outpatients

- 1 0- 2 21Standardised Effect Size with 95%

Confidence Interval

De Jonghe et al 1991a

Kuha et al 1991

Ferreri 1989

Mean Difference with Quaternary AminesEffect

Poelinger & Haber 1989

Feighner et al 1991a

Ansseau et al 1994

Bensacon et al 1993

La Pia et al 1992

Muijen et al 1988

Gattaz et al 1995

Geerts 1994

Lonnqvist 1994

Reynaert et al 1985

Williams et al 1993

Taneri & Kohler 1989

Beasley et al 1991a

Debus et al 1988

Falk et al 1989

Fudge et al 1990

Perry et al 1989

(Maprotiline)

(Maprotiline)

(Amineptine)

(Maprotiline)

(Bupropion)

(Milnacipran)

(Mianserine)

(Mianserine)

(Mianserine)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Nomifensine)

(Trazodone)

(Trazodone)

(Trazodone)

(Trazodone)

(Trazodone)

73

24

31

30

62

93

33

20

26

34

25

107

50

60

20

65

22

14

21

21

69

22

32

35

60

97

32

20

27

36

24

102

51

62

20

61

21

13

17

19

126127

Bowden et al 1993

Remick et al 1993

Fabre et al 1991

(Desipramine)

(Desipramine)

(Nortriptyline)

FluoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

28 30

26

102

20

102

3 156 152Mean Effect Difference with Secondary Amines

3

1

Mean Difference with Others ADEffect 59761116

Fig.3 Differences in effect size (Fluoxetine vs. other antidepressants)

& Cohn 1985Feighner

Remick et al 1989

Tamminen & Lehtinen 1989

Mean Difference with DoxepinEffect

Robertson 1994

Mean Difference with Tertiary AminesEffect

()Doxepin

()Doxepin

()Doxepin

(Lofepramine)

78 79

38 37

26 25

3 142 141

93

1434

90

1429

1

36

e oh/o

h/o

h/o

h

h

h/o

o

o

o

o

o

e o

o

o

h/o

h/o

h/o

o

o

o

o

e o

o

o

o

o

: without systemic deseases, substance abuse or dependence and other psychiatric disorder: Elderly

: Hospitalized patients

: Outpatients

12Fluoxetine vs. Amitriptyline and Imipramine 315 325

eho

Mean Effect Difference with Amitryptiline

Amin et al 1984

Amore et al 1989

Bramanti et al 1988

Claghorn et al 1996

Dominguez et al 1985

Fabre1996

Feighner et al 1989b

Gonella et al 1990

Guelfi et al 1983

Guy et al 1984

Itil et al 1983

Nathan et al 1990

Roth et al 1990

Mean Difference with Secondary AminesEffect

Mean Difference with Tertiary AminesEffect

Lapierre 1987

Lydiard et al 1989

March et al 1990

Norton et al 1984

Mean Effect Difference with Imipramine

Harris et al 1991

Remick et al 1994

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Desipramine)

(Desipramine)

- 1 0- 2 21Standardised Effect Size with 95% Confidence Interval

FluvoxamineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

35 34

16

51

17

51

161

15

30

50

153

15

30

50

35

50

35

50

31 35

10 10

74 77

17 19

22 25

22

18

17

33

585

21

20

18

30

588

20 20

30 30

2 50 50

81681225

Dick & Ferrero 1983

Klok et al 1981

Ottevanger 1995

Mean Difference with ClomipramineEffect

De Wilde et al 1983a2

De Wilde et al 1983a1

De Wilde & Doogan 1982

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

()Clomipramine

15

21

15

23

15

15

17 15

16 18

20 20

104 1066

Mullin et al 1988 ()Dothiepin 36371

Nolen et al 1988

Fluvoxamine vs. Amitriptyline and Imipramine

(Oxaproptyline) 35

351

35

344

1

13

De Jonghe et al 1991a (Maproptiline) 24241

2

15

Mean Difference with Quaternary AminesEffect 24241

Brunner 1994

Bougerol 1992

(Amineptine)

(Moclobemide)

20

61

20

62

Mean Difference with Others ADEffect 2 81 82

Fig.4 Differences in effect size (Fluvoxamine vs. other antidepressants)

e o

o

o

o

o

o

o

o

o

o

o

o

o

o

o

o

o

o

o

o

h

h

h

h

h

h

h

h

h

h/o

: without systemic deseases, substance abuse or dependence and other psychiatric disorder: Elderly

: Hospitalized patients

: Outpatients

eho

Arminen et al 1994

Cohn et al 1992

Fabre 1992

Faighner & Boyer 1989c

Nielsen et al 1991

Dorman 1992

Mertens 1988

Mean Difference with Tertiary AminesEffect

Øhrberg 1992

Peselow et al 1989a

Shrivastava 1992

Mean Effect Difference with Imipramine

Bascara 1989

Battegay et al 1985

Byrne 1989

Bignamini & Rapisarda 1992

Geretsegger 1995

Hutchinson et al 1992

Kukhs & Rudolph 1989

Laursen et al 1985

Möller et al 1993

Staner et al 1995

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Mianserin)

(Mianserin)

Mean Difference with Others ADEffect

- 1 0- 2 21Standardised Effect Size with 95% Confidence Interval

ParoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

27

11

35

156

23

10

35

153

44

56

20

21

112

21

47

32

20

23

110

19

25 32

35 31

39

39

37

40

16 15

74

40

40

308

77

40

40

312

29 28

36 31

2 65 59

1162120022

Bourin 1990

Link and Dunbar1992

Danish University ADG 1990

()Clomipramine

()Clomipramine

()Clomipramine

42

155

56

43

154

46

Dunner et al 1992

Paroxetine vs. Amitriptyline and Imipramine

(Doxepin) 135

484

136

484

1

13

Mean Rate Difference with Clomipramine 253 2434

Mean Effect Difference with Amitryptiline 503 47210

8

Fig.5 Differences in effect size (Paroxetine vs. other antidepressants)

e o

e o

e o

e

e o

e o

o

o

o

o

o

o

o

o

o

o

o

h

h

h

h

h

h

h/o

h/o

: without systemic deseases, substance abuse or dependence and other psychiatric disorder: Elderly

: Hospitalized patients

: Outpatients

eho

Moon et al 1994

Sertraline vs. Amitriptyline and Imipramine

(Clomipramine) 51

336

55

336

1

3

Mean Difference with Tertiary AminesEffect

Bersani 1994

Cohn et al 1990

Reimherr et al 1990a

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

- 1 0- 2 21Standardised Effect Size with 95% Confidence Interval

SertralineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

34 34

161

149

80

149

3183954

Sibel et al 1995 (Moclobemide) 27 28

Mean Effect Difference with Amitryptiline 344 2633

1

Fig.6 Differences in effect size (Sertraline vs. other antidepressants)

e o

o

o

o

o

: without systemic deseases, substance abuse or dependence and other psychiatric disorder: Elderly

: Hospitalized patients

: Outpatients

eho

Feighner 1985a

Keegan et al 1991

Bremner 1984

Cohn et al 1989

Levine et al 1989

Mean rateifference Fluoxetine vs. d Imipramine

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

FluoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

22

20

22

22

2 42 44Mean rateifference Fluoxetine vs. dAmitryptiline

20 20

30 30

30 30

3 80 80

Fig.7 Differences in rates - 50% or more improvement in HRSD (Fluoxetine vs. other antidepressants)

De Jonghe et al 1991a

Ferreri 1989

Mean ifference vs. Quaternary AminesrateFluox. d

Feighner et al 1991a

Muijen et al 1988

Gattaz et al 1995

Lonnqvist 1994

Williams et al 1993

Debus et al 1988

Perry et al 1989

(Maprotiline)

(Amineptine)

(Bupropion)

(Mianserine)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Trazodone)

(Trazodone)

73

73

31

62

26

34

107

60

22

21

69

69

32

60

27

36

102

62

21

19

Bowden et al 1993 (Desipramine) 28

28

30

301Mean rateifference Fluox. vs. d Secondary Amines

5 122 124Mean rateifference Fluoxetine vs. d Tertiary Amines

15

7

586

223

582

223

Mean rateifference Fluoxetine vs. all comparators d

Mean rateifference Fluoxetine vs. TCAs d

1

Mean rateifference Fluoxetine vs. o d thers AD 3593638

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

FluvoxamineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

Fig.8 Differences in rates - 50% or more improvement in HRSD (Fluvoxamine vs. other antidepressants)

Lydiard et al 1989

De Wilde et al 1982

Nolen et al 1988

Mean rateifference Fluvoxamine vs. d all comparators

(Imipramine)

(Clomipramine)

(Oxaproptiline)

18 20

15 15

35 35

3 68 70

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

ParoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

Fig.9 Differences in rates - 50% or more improvement in HRSD (Paroxetine vs. other antidepressants)

Battegay et al 1985

Geretsegger 1995

Möller et al 1993

Mean ifference Paroxetine vs.rate d Amitryptiline

(Amitryptiline)

(Amitryptiline)

(Amitryptiline)

11

44

10

47

112 110

3 167 167

Feighner & Boyer 1989c

Øhrberg 1992

Peselow et al 1989a

Mean ifference Paroxetine vs.rate d Imipramine

Mean ifference Paroxetine vs.rate d TCAs

Dorman 1992

Mean ifference Paroxetine vs.rate d all comparators

(Imipramine)

(Imipramine)

(Imipramine)

(Mianserin)

39 40

74

40

77

40

3

6

1

7

153

320

29

349

158

325

28

353

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

(Moclobemide)

SertralineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

28 27

4

3

1

389 311Mean rateifference Sertraline vs. all comparators d

Fig.10 Differences in rates - 50% or more improvement in HRSD (Sertraline vs. other antidepressants)

Sibel et al 1995

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

161

149

51

361

80

149

55

284

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1994

Mean rate difference Sertraline vs. TCAs

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Laakmann et al 1988

Masco et al 1986

Peters 1990

Bremner 1984

Byerley et al 1988

Nielsen et al 1993

Mean rateifference Fluoxetine vs. d Imipramine

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

FluoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

63

20

40

65

21

41

3 123 127Mean rateifference Fluoxetine vs. dAmitryptiline

16 19

32

18

34

18

3

2

66 71

Corne & Hall 1989 (Dothiepin) 49 51

Remick et al 1989

Mean rateiff. Fluoxetine vs. d Others Tertiary Amines

(Doxepin) 38

87

36

87

Fig.11 Differences in rates - improvement in CGI (Fluoxetine vs. other antidepressants)

Feighner et al 1991a

Geerts 1994

Lonnqvist 1994

Reynaert et al 1995

Williams 1993

Taneri & Köhler

(Bupropion)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Nomifensine)

60

13

107

42

60

15

60

15

102

38

62

13

Fabre et al 1991 (Nortriptiline) 58

58

64

641Mean rateifference Fluox. vs. d Secondary Amines

8 276 285Mean rateifference Fluoxetine vs. d Tertiary Amines

15 630 639Mean rateifference Fluoxetine vs. all comparators d

Mean rateifference Fluoxetine vs. o d thers AD 2902976

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

FluvoxamineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

Fig.12 Differences in rates - improvement in CGI (Fluvoxamine vs. other antidepressants)

Harris 1991

Bramanti et al 1988

Claghorn et al 1996

Guy et al 1984

Itil et al 1983

Mean rateifference Fluvoxamine vs. d Imipramine

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

24 26

28 29

20

17

22

21

19

25

4 87 94

(Dothiepin)

Brunner 1994

Bocksberger et al 1993

Bougerol et al 1992

(Amineptine)

(Moclobemide)

(Moclobemide)

20

20

37

20

19

37

Roth et al 1990 (Desipramine) 27

27

24

241Mean rateifference Fluvox. vs. d Secondary Amines

1

1

26 24Mullin et al 1988

6 137 144Mean rateifference Fluvoxamine vs. d Tertiary Amines

10 241 244Mean rateifference Fluvoxamine vs. all comparators d

Mean rateifference Fluvoamine vs. o d thers AD 76773

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Mean rateifference Paroxetine vs. Amitriptyline d

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

ParoxetineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

28

58

25

94

31

32

32

79

2

2

1

1

119 111Mean rateifference Paroxetine vs. Imipramine d

Mean rateifference Paroxetine vs. others AD d

Fig.13 Differences in rates - improvement in CGI (Paroxetine vs. other antidepressants)

Geretsegger et al 1995

Hutchinson et al 1992

Arminen et al 1994

Claghorn & Feighner 1993

6Mean rateifference Paroxetine vs. all comparators d 301 267

5Mean rateifference Paroxetine vs. dTertiary Amines 265 236

(Mianserin) 36

36

31

31

(Lofepramine) 60 62Moon & Vince 1996

Mertens 1988

86 63

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

(Amitriptyline)

(Amitriptyline)

(Dothiepin)

SertralineComparator

Numberof

treated patients

N ofstudies

Comparatorsdrugs

Author/s and yearof study publication

Number of

controlpatients

30

161

83

26

110

96

4 325 264Mean rateifference Sertraline vs. dTertiary Amines

Fig.14 Differences in rates - improvement in CGI (Sertraline vs. other antidepressants)

Bersani 1994

Cohn et al 1990

Doogan & Langdon 1994

(Clomipramine) 51 32Moon et al 1994

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Mean rate difference Fluoxetine vs. Placebo

Beasley et al 1991b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Fabre & Crismon 1985

Fabre & Putman 1987 (Fluox. 20)

Fabre & Putman 1987 (Fluox. 40)

Fabre & Putman 1987 (Fluox. 60)

Feighner et al 1989a

Lam et al 1995

Muijen et al 1988

Rickels et al 1986

Stark & Hardison 1985

Tollefson et al 1995

Wernicke et al 1987 (Fluox. 20)

Wernicke et al 1987 (Fluox. 40)

Wernicke et al 1987 (Fluox. 60)

Wernicke et al 1988 (Fluox. 5)

Wernicke et al 1988 (Fluox. 20)

Wernicke et al 1988 (Fluox. 40)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

233

32

54

30

22

25

22

25

61

36

26

18

185

335

100

103

105

93

96

96

1697

222

29

58

29

26

12

12

12

59

32

28

24

169

336

48

48

48

78

78

78

1426

16

16

10

30

34

14

10

98

263

60

62

47

55

61

64

1028

11 14

105

20

35

17

61

16

16

10

5

5

19

31

16

18

74

271

27

27

27

42

42

42

768

5

Fig.15 Differences in rates of completion (SSRIs vs. placebo)

Fluoxetine

Fluvoxamine

Comparator

Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

31

37

22

22

18

17

19

33

22

20

18

14

12

22

10

7

17

13

21

20

11

15

17

12

Feighner et al 1989b

Hendrickx et al 1991

Itil et al 1983

Lapierre 1987

Lydiard et al 1989

March et al 1990

Norton et al 1984

Roth 1990

33

30

25

30

29

24

22

26

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

50

23

33

50

50

22

31

50

20

9

21

31

20

9

16

22

Claghorn et al et al 1996

Conti et al 1985

Dominguez et al 1985

Fabre 1996

216 210 366 334Mean rate difference Fluvoxamine vs. Placebo

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Cont.

Sertraline Comparator

35 361219Reimherr et al 90a

(Placebo)

(Placebo)

(Placebo)

99

168

101

169

90

95

83

109

Doogan & Langdon 1994

Fabre et al 1995

211

1635

197

1322

302

2645

306

2341

Mean rate difference Sertraline vs. Placebo

Mean rate difference SSRIs vs. Placebo

Fig.15 Differences in rates of completion (SSRIs vs.placebo )

35

39

39

22

40

40

33

36

36

37

25

42

40

33

12

17

20

20

31

18

11

19

31

23

12

29

26

17

Cohn et al 1992

Fabre 1992

Feigher & Boyer 1989

Miller et al 1989

Peselow et al 1989a

Shrivastava 1992

Smith & Glaudin 1992

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

(Placebo)

32 261821Claghorn et al 1992

178 147 280 275Mean rate difference with Placebo

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Par oxetine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Fig.16 Differences in rates of completion (SSRI vs. other SSRIs)

Fluoxetine Comparator

Fluvoxamine Comparator

Paroxetine Comparator

Sertraline Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

47

40

31

41

118

46

41

41

31

128

51

54

49

154

49

52

48

49

149

Rapaport et al 1996

Ansseau et al 1994b

Nemeroff et al 1995

Nemeroff et al 1995

Mean effect diff. Fluvoxamine vs others SSRIs

46

71

32

35

43

87

25

127

66

532

47

68

71

31

37

45

89

35

106

69

527

49

101

102

41

45

52

88

40

144

82

642

51

102

101

37

45

54

90

48

142

83

652

37

48

45

142

54

90

83

48

56

384

321

41

40

45

144

52

88

82

64

391

315

310

251

309

249

68

31

35

37

106

45

89

69

40

32

25

35

127

43

87

66

41

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Rapapport et al 1996

Chouinard et al 1994

Chouinard et al 1994

De Wilde et al 1993

Geretsegger 1994

Tignol 1993

Bennie 1995

Aguglia et al 1993

Van Moffaert et al 1995

Gagiano 1993

(Fluvoxamine)

(Paroxetine)

(Paroxetine)

(Paroxetine)

(Paroxetine)

(Paroxetine)

(Sertraline)

(Sertraline)

(Sertraline)

Mean effect diff. Fluoxetine vs. others SSRIs

De Wilde et al 1993

Gagiano 1993

Geretsegger 1994

Tignol 1993

Ansseau et al 1994

(Fluoxetine)

(Fluoxetine)

(Fluoxetine)

(Fluoxetine)

(Fluvoxamine)

(Fluvoxamine)

Mean effect diff. Paroxetine vs. others SSRIs

Aguglia et al 1993

Bennie 1995

Van Moffaert et al 1995

(Fluoxetine)

(Fluoxetine)

(Fluoxetine)

Mean effect diff. Sertraline vs. others SSRIs

(Fluoxetine)

(Fluoxetine)

(Paroxetine)

(Sertraline)

: Original values from studies publishing as first drug

: inversed series, i.e. original control is placed as treatment at study

o

o

o

o

o

o

o

o

o

o

o

o

Fawcett 1989

Feighner 1985

Judd et al 1993

Keegan et al 1991

Kerkhofs et al 1990

Masco et al 1985

Preskorn 1991

Bremner 1984

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Ropert 1989

1985bFeighner

Remick et al 1989

Tamminen & Lehtinen 1989

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

()Doxepin

()Doxepin

()Doxepin

23 28

20

22

30

20

16

20

30

260

20

32

54

30

61

30

29

185

497

28

60

71

49

30

31

78

20

22

28

22

18

21

31

275

20

34

54

30

59

30

30

186

505

26

60

72

51

30

28

79

38

26

37

25

21

12

19

23

18

9

19

20

210

17

20

35

17

30

22

21

55

34

15

16

41

25

21

18

47

Beasley et al 1993a (Amitriptyline) 65 7157 47

Altamura et al 1989 (Amitriptyline) 14 1412 10

9

13

23

Beasley et al 1993b (Imipramine) 56 6223 24

19

10

18

14

185

20

14

30

28

22

106

285

15

44

48

44

22

21

31

27

21

90

275

22

17

24

272 273 411 408Mean rate Difference with Others Tert. Amines

757 743 1168 1188Mean rate Difference with Tertiary Amines

Mean rate Difference with Secondary Amines

Mean rate Difference with Amitriptyline

Mean rate Difference with Imipramine

Stark & Hardison 1985

Feighner et al 1989a

Levine et al 1989

Nielsen et al 1993

Corne & Hall1988

Dowling et al 1990

South Wales ADTG 1988

Ginestet 1989

Noguera et al 1991

Chouinard 1985 (Amitriptyline)

()Clomipramine

()Clomipramine

()Dothiepin

()Dothiepin

()Dothiepin

28

26

30

20

Bowden et al 1993

Remick et al 1993

(Desipramine)

(Desipramine)

23

24

22

15

102

156

102

152

(Nortriptyline) 63

110

Fabre et al 1991 57

94

Fig.17 Differences in rates of completion (Fluoxetine vs. other antidepressants)

Fluoxetine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Cont.

Fig.17 Differences in rates of completion (Fluoxetine vs. other antidepressants)

Fluoxetine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Ansseau et al 1994 (Milnacipran)

1628 1595 2307 2320Mean rate Difference with all comparators

75 74 93 97

Mean rate Difference with Others AD

Dalery et al 1992

Ferreri1989

Feighner et al 1991a

Robertson 1994

Bensacon et al 1993

Muijen et al 1988

Gattaz et al 1995

Geerts 1994

Lonnqvist 1994

Reynaert et al 1985

Williams et al 1993

Taneri & Kohler 1989

Beasley et al 1991a

Debus et al 1988

Falk et al 1989

Fudge et al 1990

Perry et al 1989

(Amineptine)

(Amineptine)

(Bupropion)

(Lofepramine)

(Mianserine)

(Mianserine)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Moclobemide)

(Nomifensine)

(Trazodone)

(Trazodone)

(Trazodone)

(Trazodone)

(Trazodone)

82

31

62

90

33

26

34

25

107

50

60

20

65

22

14

21

21

763

87

32

60

93

32

27

36

24

102

51

62

20

61

21

13

17

19

757

14

27

13

85

43

43

15

43

14

10

16

17

577

29 30

68

27

44

69

73

25

59

64

27

15

84

39

49

13

38

11

3

15

15

574

14

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

976 947 1451 1466Mean rate Difference with TCAs

Mean rate Difference with Quaternary Amines

26

21

62

109

35

22

69

126

31

18

61

110

30

24

73

127

De Jonghe et al 1991b

Kuha et al 1991

Poelinger & Haber 1989

(Maprotiline)

(Maprotiline)

(Maprotiline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Cont.

17

16

20

37

26

35

15

18

20

36

26

35

12

15

17

24

19

33

14

13

15

26

17

33

Dick & Ferrero 1983

Klok et al 1981

Ottevanger 1995

Mullin et al 1988

Rahman et al 1991

Nolen et al 1988

(Clomipramine)

(Clomipramine)

(Clomipramine)

(Dothiepin)

(Dothiepin)

(Oxaproptiline)

530 546 723 733Mean rate difference with Tertiary Amines

(Clomipramine)

(Clomipramine)

(Clomipramine)

41

21

15

43

15

23

38

15

23

32

21

15

Coleman & Block 1982

De Wilde et al 1983a (1t/day)

De Wilde et al 1983a (3t/day)

186 196 228 231Mean rate difference with others Tert.Amines

(Desipramine)

(Maprotiline)

(Desipramine)

20

30

30

30

20

35

35

30

18

31

31

21

17

26

26

24

Nathan et al 1990

De Jonghe et al 1991a

Roth et al 1990

41

597

39

616

50

803

50

818

Mean rate difference with Secondary Amines

Mean rate difference with Quaternary Amines

Mean rate difference with TCAs

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

31

74

17

22

22

18

17

35

77

19

25

21

20

18

22

59

16

13

9

18

15

21

55

17

10

15

17

13

Feighner et al 1989b

Guelfi et al 1983

Guy et al 1984

Itil et al 1983

Lapierre 1987

Lydiard et al 1989

March et al 1983

Norton et al 1984 33 3029 29

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

15

30

50

35

50

15

30

50

35

50

10

29

21

24

25

15

28

20

18

22

Amore et al 1989

Bramanti et al 1988

Claghorn et al 1966

Dominguez et al 1985

Fabre 1996

Fig.18 Differences in rates of completion (Fluvoxamine vs. other antidepressants)

Fluvoxamine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

16 1713

Gasperini et al 1992 (Amitriptyline) 30 2628 25

Harris et al 1991 (Amitriptyline) 35 3423 24

11

81 7764 60

280 290 414 425Mean rate difference with Imipramine

Mean rate Difference with Amitriptyline

Remick et al 1994 (Amitriptyline)

Fig.18 Differences in rates of completion (Fluvoxamine vs. other antidepressants)

Fluvoxamine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

20

61

20

62

18

42

Phanjoo et al 1991 25 2520 15

Brunner 1994

Perez & Ashford 1990

(Mianserin)

(Mianserin)

(Mianserin)

20

24

29

33

18

21

17

30

19

47

150 160119 128Mean rate difference with others AD

Bocksberger et al 1993

Bougerol et al 1992

(Moclobemide)

(Moclobemide)

716 744 953 978Mean rate Difference with all comparators

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

136 1359691Dunner et al 1992 (Doxepin)

(Clomipramine)

(Clomipramine)

(Clomipramine)

(Clomipramine)

(Lofepramine)

42

56

40

41

43

46

39

42

27

27

27

32

31

44

31

29

Bourin 1990

Danish University ADG 1990

Gullibert et al 1989

Pelicier 1993

226 209 315 305Mean rate difference with others Tert.Amines

(Mianserin)

(Mianserin)

29

36

28

31

25

28

24

33

Dorman 1992

Mertens 1988

57 53 65 59Mean rate difference with others AD

51

795

54

729

60

1126

62

1089

Moon & Vince 1996

Mean rate difference with TCAs

852 782 1191 1148Mean rate difference with all comparators

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

16

74

40

40

15

77

40

40

6

58

28

10

9

61

29

26

Nielsen et al 1991

Ohrberg 1992

Peselow et al 1989a

Shrivastava 1992

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

25

35

39

39

32

31

37

40

17

18

16

16

12

19

16

23

Arminen et al 1994

Cohn et al 1992

Fabre 1992

Feighner & Boyer 1993

Fig.19 Differences in rates of completion (Paroxetine vs. other antidepressants)

Paroxetine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

56

20

21

112

21

32

20

23

110

19

44

14

16

75

16

Bascara 1989

Battegay et al 1985

Bignamini & Rapisarda 1992

Byrne 1989

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

27

11

156

35

23

10

153

35

25

8

125

23

20

2

133

26

Geretsegger 1995 (Amitriptyline) 44 4728 31

21

17

14

72

15

503 472374 351

195 169 308 312Mean rate difference with Imipramine

Mean rate difference with Amitriptyline

Hutchinson et al 1992

Kukhs & Rudolph 1989

Laursen et al 1985

Moller et al 1993

Staner et al 1995

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

(Clomipramine)

(Dothiepin)

51

99

150

55

108

163

45

96

141

47

83

130

Moon et al 1994

Doogan & Langdon 1994

Mean rate difference with others Tert.Amines

(Moclobemide) 28

28

27

27

17

17

19

19

Sibel et al 1995

Mean rate difference with others AD

350

331

313

296

514

486

453

426

Mean rate difference with all comparators

Mean rate difference with TCAs

Fig.20 Differences in rates of completion (Sertraline vs. other antidepressants)

Sertraline Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

141 14988

Bersani 1994 (Amitriptyline) 34 3431 30

Cohn et al 1990 (Amitriptyline) 161 8082 39

86

336 263201 155Mean rate difference with Amitriptyline

Reimherr et al 90a (Amitriptyline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fig.21 Differences in rates of drop-outs due to adverse events (Fluoxetine vs. TCAs)

Fawcett 1989

Feighner 1985

Judd et al 1993

Keegan et al 1991

Bremner 1984

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Ropert 1989

Remick et al 1989

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

()Doxepin

23 28

20

22

30

20

194

20

32

54

30

61

30

29

185

497

60

71

31

30

20

22

28

22

205

20

34

54

30

59

30

30

186

505

60

72

28

30

38 37

1

4

2

1

0

14

3

4

7

2

13

2

4

4

8

6

9

29

2

Beasley et al 1993a (Amitriptyline) 65 714 16

Altamura et al 1989 (Amitriptyline) 14 142 3

10

6

0

Beasley et al 1993b (Imipramine) 56 6212 14

3

38

24

9

18

0

4

28

104

6

12

0

1

8

18

65

0

3

4

27 159 155Mean rate difference with others Tert. Amines

Mean rate difference with Secondary Amines

Mean rate difference with Quaternary Amines

Mean rate difference with all TCAs

Mean rate difference with Amitriptyline

Mean rate difference with Imipramine

Stark & Hardison 1985

Feighner et al 1989a

Levine et al 1989

Nielsen et al 1993

South Wales ADTG 1988

Dowling et al 1990

Noguera et al 1991

Chouinard 1985 (Amitriptyline)

()Clomipramine

()Dothiepin

()Dothiepin

129 1039210 1027

28

26

30

20

Bowden et al 1993

Remick et al 1993

(Desipramine)

(Desipramine)

2

0

4

4

102

21

21

156

102

22

22

152

(Nortriptyline)

(Maprotiline)

17

2

2

19

Fabre et al 1991

Kuha et al 1991

29

4

4

37

Fluoxetine Comparator

N oftreated

patientsN of dropsComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

108 169 850 865Mean rate difference with Tertiary Amines

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

(Desipramine)

(Maprotiline)

20

20

30

30

20

20

35

35

2

2

1

1

0

0

1

1

Nathan et al 1990

De Jonghe et al 1991a

72 80 568 576

Mean rate difference with Secondary Amines

Mean rate difference with Quaternary Amines

Mean rate difference with TCAs

71 77 518 521Mean rate difference with Tertiary Amines

Fig.22 Differences in rates of drop-outs due to adverse events (Fluvoxamine vs. TCAs)

Fluvoxamine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

16 173

Gasperini et al 1992 (Amitriptyline) 30 261 1

Harris et al 1991 (Amitriptyline) 35 345 6

6

81 779 13Mean rate Difference with Amitriptyline

Remick et al 1994 (Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

31

74

22

22

18

35

77

25

21

20

13

5

7

1

2

7

2

9

1

1

Feighner et al 1989b

Guelfi et al 1983

Itil et al 1983

Lapierre 1987

Lydiard et al 1989

Norton et al 1984 33 303 0

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

30

50

35

50

30

50

35

50

1

13

8

9

0

12

10

7

Bramanti et al 1988

Claghorn et al 1996

Dominguez et al 1985

Fabre 1992

52 58 365 373Mean rate difference with Imipramine

37

35

36

35

6

0

9

1

Mullin et al 1988

Nolen et al 1988

(Dothiepin)

(Oxaproptiline)

10 6 72 71Mean rate difference with others Tert.Amines

136 1352633Dunner et al 1992 (Doxepin)

(Clomipramine)

(Clomipramine)

(Clomipramine)

(Clomipramine)

42

56

40

41

43

46

39

42

5

10

5

9

3

0

3

10

Bourin 1990

Danish University ADG 1990

Gullibert et al 1989

Pelicier 1993

49 55 315 305Mean rate difference with others Tert.Amines

191 252 1288 1280Mean rate difference with TCAs

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

16

74

40

40

15

77

40

40

3

14

3

19

1

10

4

7

Nielsen et al 1991

Ohrberg 1992

Peselow et al 1989a

Shrivastava 1992

(Imipramine)

(Imipramine)

(Imipramine)

25

35

240

32

31

237

7

9

85

6

11

55

Arminen et al 1994

Cohn et al 1992

Dunbar et al 1991

Fig.23 Differences in rates of drop-outs due to adverse events (Paroxetine vs. TCAs)

Paroxetine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

56

20

21

112

21

32

20

23

110

19

8

2

2

13

2

Bascara 1989

Battegay et al 1985

Bignamini & Rapisarda 1992

Byrne 1989

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

27

11

156

35

23

10

153

35

2

1

6

1

3

3

4

3

Geretsegger 1995 (Amitriptyline) 44 4711 13

6

0

4

19

2

503 47248 57

94 140 470 472Mean rate difference with Imipramine

Mean rate difference with Amitriptyline

Hutchinson et al 1992

Kukhs & Rudolph 1989

Laursen et al 1985

Moller et al 1993

Staner et al 1995

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

(Clomipramine)

(Dothiepin)

51

99

150

55

108

163

10

2

12

2

5

7

Moon et al 1994

Doogan & Langdon 1994

Mean rate difference with others Tert.Amines

81 73 512 451Mean rate difference with TCAs

Fig.24 Differences in rates of drop-outs due to adverse events (Sertraline vs. TCAs)

Sertraline Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

26

141

25

149

3

26

Bersani 1994 (Amitriptyline) 34 340 1

Cohn et al 1990 (Amitriptyline) 161 8045 28

4

28

362 28874 61Mean rate difference with Amitriptyline

Reimherr et al 1988

Reimherr et al 90a

(Amitriptyline)

(Amitriptyline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fig.25 Differences in rates of drop-outs due to lack of effect (Fluoxetine vs.TCAs)

Fawcett 1989

Feighner 1985

Judd et al 1993

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Remick et al 1989

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

()Doxepin

20

22

30

151

32

54

30

61

30

29

142

416

60

31

78

20

22

28

155

34

54

30

59

30

30

186

485

60

28

79

38 37

2

1

1

6

7

1

2

13

2

1

5

6

4

19

3

Beasley et al 1993a (Amitriptyline) 65 712 3

Altamura et al 1989 (Amitriptyline) 14 140 1

0

3

1

Beasley et al 1993b (Imipramine) 38 6215 10

8

4

2

8

1

1

15

47

0

4

0

2

19

60

6

14 129 125Mean rate difference with others Tert. Amines

Mean rate difference with Secondary Amines

Mean rate difference with all TCAs

Mean rate difference with Amitriptyline

Mean rate difference with Imipramine

Stark & Hardison 1985

Feighner et al 1989a

Levine et al 1989

Nielsen et al 1993

South Wales ADTG 1988

Feighner 1985b

Noguera et al 1991 ()Clomipramine

()Dothiepin

(Doxepin)

118 1011196 957

28

26

30

20

Bowden et al 1993

Remick et al 1993

(Desipramine)

(Desipramine)

3

0

2

1

102

24

24

156

102

24

24

152

(Nortriptyline) 2

1

1

19

Fabre et al 1991 5

3

3

37

Fluoxetine Comparator

N oftreated

patientsN of dropsComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

98 156 777 835Mean rate difference with Tertiary Amines

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

De Jonghe et al 1991a (Maproptiline)

Mean rate difference with Quaternary. Amines

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

(Maprotiline) 24

24

24

24

3

3

1

1

De Jonghe et al 1991a

18 27 347 347

Mean rate difference with Quaternary Amines

Mean rate difference with TCAs

17 24 323 323Mean rate difference with Tertiary Amines

Fig.26 Differences in rates of drop-outs due to lack of effect (Fluvoxamine vs. TCAs)

Fluvoxamine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Harris et al 1991 (Amitriptyline) 35

35

34

34

5

5

6

6Mean rate Difference with Amitriptyline

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

74

22

22

77

25

21

3

1

6

0

0

2

Guelfi et al 1983

Itil et al 1983

Lapierre 1987

Norton et al 1984 33 301 0

(Imipramine)

(Imipramine)

30

35

30

35

0

1

2

0

Bramanti et al 1988

Dominguez et al 1985

5 11 215 218Mean rate difference with Imipramine

37

35

36

35

4

3

2

5

Mullin et al 1988

Nolen et al 1988

(Dothiepin)

(Oxaproptiline)

7 7 72 71Mean rate difference with others Tert.Amines

Phanjoo et al 1991 25 250 2

Perez & Ashford 1990 (Mianserin)

(Mianserin)

30 331 2

55 581 4Mean rate difference with others AD

19 31 402 405Mean rate Difference with all comparators

136 13564Dunner et al 1992 (Doxepin)

(Clomipramine)

(Clomipramine)

40

41

39

42

3

1

4

1

Gullibert et al 1989

Pelicier 1993

9 10 217 216Mean rate difference with others Tert.Amines

79 71 1167 1073Mean rate difference with TCAs

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

16

74

40

40

15

77

40

40

5

2

2

2

3

2

1

3

Nielsen et al 1991

Ohrberg 1992

Peselow et al 1989a

Shrivastava 1992

(Imipramine)

(Imipramine)

25

35

32

31

3

2

3

2

Arminen et al 1994

Cohn et al 1992

Fig.27 Differences in rates of drop-outs due to lack of effect (Paroxetine vs. TCAs)

Paroxetine Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

56

20

21

112

32

20

23

110

0

2

0

16

Bignamini & Rapisarda 1992 (Amitriptyline) 156 15311 9

Geretsegger 1995 (Amitriptyline) 44 473 0

1

2

1

15

409 38532 28

14 16 230 235Mean rate difference with Imipramine

Mean rate difference with Amitriptyline

Hutchinson et al 1992

Kukhs & Rudolph 1989

Laursen et al 1985

Moller et al 1993

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

22 19 328 254Mean rate difference with TCAs

Fig.28 Differences in rates of drop-outs due to lack of effect (Sertraline vs. TCAs)

Sertraline Comparator

N oftreated

patients

N of CompletersComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

26

141

25

149

0

11

Cohn et al 1990 (Amitriptyline) 161 8011 7

1

11

328 25422 19Mean rate difference with Amitriptyline

Reimherr et al 1988

Reimherr et al 90a

(Amitriptyline)

(Amitriptyline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Feighner 1985

Judd et al 1993

Young et al 1987

Beasley et al 1993b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Ropert 1989

1985bFeighner

Remick et al 1989

Beasley et al 1993a (Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

()Doxepin

()Doxepin

()Doxepin

(Lofepramine)

65

23

71

28

22

23

25

56

20

32

54

30

61

185

28

71

26

30

27

78

22

23

25

62

20

34

54

30

58

186

26

72

20

30

25

79

38

26

90

37

25

93

103 102

Poelinger & Haber 1989 (Maprotiline)

Remick et al 1993

Dowling et al 1990

Fabre et al 1996

(Desipramine)

(Dothiepin)

(Nortriptyline)

24

13

6

6

8

8

1

8

15

8

16

7

3

11

8

13

13

4

19

4

6

9

12

6

73

13

4

4

6

3

2

12

7

13

28

28

24

1

69

8

0

5

1

7

0

1

18

0

3

4

46

27

24

5

4

151 1237 1243Mean rate Difference Fluoxetine vs.TCAs 382

De Jonghe et al 1991b

Kuha et al 1991

Bremner 1984

Stark & Hardison 1985

Feighner et al 1989a

Tamminen & Lehtinen 1989

Robertson et al 1994

South Wales ADTG 1988

Ginestet 1989

Chouinard 1985 (Amitriptyline)

()Clomipramine

()Dothiepin

(Maprotiline)

(Maprotiline)

2

Fig.29 Differences in rates of nausea (SSRIs vs. TCAs) and method (right symbol) used to elicit AE

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI Fluoxetine Comparator

Cont.

Comparatorsdrugs

Check list

Indirect questions

Spontaneous report

TES

Unknown

Claghorn etal 1996

Fig.29 Differences in rates of nausea (SSRIs vs. TCAs) and method (right symbol) used to elicit AE

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

114 36 470 405Mean rate difference Sertraline vs. TCAs

Cohn et al 1990

Reimherr et al 1988

Reimherr et al 1990a

Moon et al 1994

Doogan & Langdon 1994

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

(Dothiepin)

Sertraline Comparator

161

26

149

51

83

80

25

149

55

96

44

8

53

8

1

2

2

15

11

6

750 323 2936 2868Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

33

68

113

66

81

397

774

1240

262

638

391

700

1152

264

658

Check list

Indirect questions

Spontaneous report

TES

Unknown

77

164

230

90

173

Hutchinson et al 1992

Kukhs & Rudolph 1989

Cohn et al 1992

Peselow et al 1989a

Shrivastava 1992

Pelicier 1993

Dunner et al 1992

Moon & Vince 1996

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Doxepin)

(Lofepramine)

Geretsegger 1995 (Amitriptyline)

Feighner et al 1989c (Imipramine)

Paroxetine Comparator

Mean rate difference Paroxetine vs. TCAs 94 48 697 668

3

56

20

35

40

40

26

136

60

32

20

31

36

40

28

135

62

7

1

11

8

10

4

34

4

4

0

4

7

10

2

9

0

44 470

240 23712 12

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

31

74

17

22

22

18

35

77

19

25

22

20

7

3

3

14

3

7

11

10

3

7

5

6

Feighner et al 1989b

Guelfi et al 1983

Guy et al 1984

Itil et al 1983

Lapierre 1987

Lydiard et al 1989

Norton et al 1984 33 3121 9

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

15

44

35

46

15

44

35

48

4

4

9

6

4

10

14

14

Amore et al 1988

Dominguez et al 1985

Fabre et al 1996

160 88 532 552Mean rate difference Fluvoxamine vs. TCAs

(Dothiepin)

(Clomipramine)

Mullin et al 1988

Coleman & Block 1982

Nolen et al 1988

De Jonghe et al 1991a

(Oxaproptiline)

(Maprotiline)

26

41

58

24

24

43

66

24

9

2

29

6

4

1

10

0

Fluvoxamine Comparator

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Feighner 1985

Judd et al 1993

Keegan et al 1991

Laakmann et al 1988

Young et al 1987

Beasley et al 1993b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Noguera et al 1991

Ropert 1989

1985bFeighner

Remick et al 1989

Altamura et al 1989

Beasley et al 1993a

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Clomipramine)

()Doxepin

()Doxepin

()Doxepin

(Maprotiline)

(Lofepramine)

14

65

23

19

14

71

28

19

22

23

18

25

63

56

20

32

54

30

61

186

28

60

71

26

27

30

78

22

23

19

65

25

62

20

34

54

30

58

186

26

60

72

20

25

30

79

38

26

21

90

37

25

28

93

103 102

Remick et al 1993

Fabre et al 1996

(Desipramine)

(Nortriptyline)

6

18

12

5

3

6

4

10

4

16

1

6

14

5

14

4

10

5

12

9

13

6

2

0

14

21

10

11

52

12

18

4

33

36

16

8

40

19

36

128

14

25

30

12

11

17

47

25

6

5

29

33

26

13

21

171 1288 1299Mean rate Difference Fluoxetine vs.TCAs 269

Bremner 1984

Stark & Hardison 1985

Feighner et al 1989a

Tamminen & Lehtinen 1989

De Jonghe 1991b

Robertson et al 1994

South Wales ADTG 1988

Dowling et al 1990

Ginestet 1989

Chouinard 1985

Fawcett et al 1989

(Amitriptyline)

(Amitriptyline)

()Clomipramine

()Dothiepin

()Dothiepin

34

Fig.30 Differences in rates of dry mouth (SSRIs vs. TCAs) and method (right symbol) used to elicit AE

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Cont.

Fig.30 Differences in rates of dry mouth (SSRIs vs. TCAs) and method (right symbol) used to elicit AE

Hutchinson et al 1992

Kukhs & Rudolph 1989

Cohn et al 1992

Peselow et al 1989a

Shrivastava 1992

Pelicier 1993

Dunner et al 1990

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Doxepin)

Bignamini & Rapisarda 1992

Geretsegger 1995

(Amitript.)

(Amitriptyline)

Feighner et al 1993 (Imipramine)

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

194 207 460 479Mean rate difference Fluvoxamine vs. TCAs

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Dothiepin)

(Clomipramine)

Fluvoxamine Comparator

31

74

17

22

18

35

77

19

22

20

17

65

10

10

10

5

57

6

9

7

Feighner et al 1989b

Guelfi et al 1983

Guy et al 1984

Lapierre 1987

Lydiard et al 1989

Norton et al 1984

Mullin et al 1988

Coleman & Block 1982

Nolen et al 1988 (Oxaproptiline)

33

26

41

58

31

24

43

66

12

1

4

15

19

9

5

20

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

15

44

35

46

15

44

35

48

9

10

17

6

4

28

5

32

Amore et al 1988

Claghorn et al 1996

Dominguez et al 1985

Fabre et al 1996

Mean rate difference Paroxetine vs. TCAs 93 221 782 762

4

Paroxetine Comparator

56

20

35

40

40

26

136

32

20

31

36

40

28

135

3

8

8

12

1

3

34

6

10

19

26

26

7

88

156

33

156

47

20 55

7

240 2370 26

104 211 478 414Mean rate difference Sertraline vs. TCAs

Bersani 1994

Cohn et al 1990

Reimherr et al 1990a

Doogan & Langdon 1994

Moon et al 1994

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Dothiepin)

(Clomipramine)

Sertraline Comparator

34

161

149

83

51

34

80

149

96

55

10

41

46

2

5

13

57

118

8

15

660 810 3008 2954Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

161

440

464

127

327

308

836

1173

236

720

311

754

1092

237

746

Check list

Indirect questions

Spontaneous report

TES

Unknown

63

235

178

54

179

Fig.31 Differences in rates of anorexia (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Dunbar et al 1991

Cohn et al 1990

Reimherr et al 1990a

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluvoxamine

Paroxetine

Sertraline

SSRIs

Comparator

Comparator

Comparator

TCAs

240

161

149

310

33

237

80

149

229

31

19

15

6

21

1

1

2

12

14

24

95 72 1030 940Mean rate difference SSRIs vs. TCAs

31 25 161 159Mean rate difference Fluvoxamine vs. TCAs

Mean rate difference Sertraline vs. TCAs

Norton et al 1984

(Imipramine)

(Imipramine)

(Imipramine)

46

47

35

48

45

35

5

1

7

1

3

3

Fabre 1996

Claghorn et al 1996

Dominguez et al 1985

Cohn et al 1989 (Imipramine)

(Imipramine)

30

185

78

26

30

186

79

20Remick et al 1993 (Desipramine)

3

3

24

11

17

12

2

0

7

31 319 315Mean rate Difference Fluoxetine vs.TCAs

Stark & Hardison 1985

Feighner 1985b (Doxepin)

10 361 284Mean rate difference Sertraline vs. TCAs 80

Fig.32 Differences in rates of diarrhea (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Feighner 1985

Beasley et al 1993b

Remick et al 1989

(Amitriptyline)

(Imipramine)

()Doxepin

22

56

27

22

62

25

38 37

1

6

1

6

1

4

2

0

South Wales ADTG 1988 ()Dothiepin

7 143 146Mean rate difference Fluoxetine vs. TCAs 14

5 149 147Mean rate difference Fluvoxamine vs. TCAs 27

Pelicier 1993 (Clomipramine) 26 282

Dunner et al 1992

Cohn et al 1992

Peselow et al 1989a

(Doxepin)

(Imipramine)

(Imipramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluvoxamine

Paroxetine

Comparator

Comparator

135

35

40

136

31

36

5

2

Mullin et al 1988 (Dothiepin) 26 244 0

16

3

2

0

135

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1994

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

Sertraline Comparator

161

149

51

80

149

55

45

35

0

1

8

1

43 889 718Mean rate difference SSRIs vs. TCAs

(Imipramine) 44 4418Claghorn et al 1996

(Imipramine) 46 4827Fabre et al 1996

(Imipramine) 33 3128Norton et al 1984

SSRIs TCAs

21 236 141Mean rate difference Paroxetine vs. TCAs 14

5

Fawcett 1989

Feighner 1985

Judd et al 1993

Keegan et al 1991

Beasley et al 1993b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Ropert 1989

1985bFeighner

Remick et al 1989

Robertson et al 1994

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

()Doxepin

()Doxepin

(Lofepramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

23 28

19

22

23

18

20

32

54

30

61

185

28

60

71

26

27

78

19

22

23

19

62

34

54

30

58

186

26

60

72

20

25

79

38

93

37

90

103 102

Remick et al 1993

Fabre et al 1991

(Desipramine)

(Nortriptyline)

13

3

2

1

0

8

3

5

2

15

3

0

5

5

0

3

2

10

112

5

1

Beasley et al 1993a (Amitriptyline) 65 718 26

Altamura et al 1989 (Amitriptyline) 14 145 8

7

3

11

6

2

10

8

15

41

28

11

7

14

8

4

19

10

18

0

13

27

5

8

258 1117 1159Mean rate difference Fluoxetine vs. TCAs

De Jonghe et al 1991b

Stark & Hardison 1985

Feighner et al 1989a

South Wales ADTG 1988

Ginestet 1989

Noguera et al 1991

Chouinard 1985 (Amitriptyline)

()Clomipramine

()Clomipramine

()Dothiepin

(Maprotiline)

17

Fig.33 Differences in rates of constipation (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

87 150 434 453Mean rate difference Fluvoxamine vs. TCAs

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

Fluvoxamine Comparator

31

74

17

22

18

35

77

19

22

20

9

41

5

2

17

5

31

1

7

0

Feighner et al 1989b

Guelfi et al 1983

Guy et al 1984

Lapierre 1987

Lydiard et al 1989

Norton et al 1984

Coleman & Block 1982

Nolen et al 1988 (Oxaproptiline)

33

41

58

31

41

66

8

6

5

7

6

24

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

15

44

35

46

15

44

35

48

6

10

8

15

5

6

6

5

Amore et al 1989

Claghorn et al 1996

Dominguez et al 1985

Fabre 1996

Cont.

Fig.33 Differences in rates of constipation (SSRIs vs. TCAs)

Paroxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

76 137 760 764Mean rate difference Paroxetine vs. TCAs

40 69 478 414Mean rate difference Sertraline vs. TCAs

Bignamini & Rapisarda 1992

Geretsegger 1995

Kukhs & Rudolph 1989

Cohn et al 1992

Feighner et al 1993

Peselow et al 1989a

Shrivastava 1992

Dunner et al 1992

Moon & Vince 1996

Bersani 1994

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1994

Doogan & Langdon 1994

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

(Dothiepin)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Doxepin)

(Lofepramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Sertraline Comparator

156

33

20

35

240

40

40

136

60

34

161

149

51

83

156

47

20

31

237

36

40

135

62

34

80

149

55

96

14

3

3

2

7

9

8

27

3

4

18

17

0

1

5

22

32

9

1

27

6

6

10

12

21

8

41

6

315 614 2789 2790Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

Chouinard 1985

Feighner 1985

Beasley et al 1993b

Feighner et al 1989a

Dowling et al 1990

Beasley et al 1993a (Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Dothiepin)

65 71

23

22

56

59

30

28

22

62

58

30

18

12

1

4

9

2

10

13

0

4

5

5

Fig.34 Differences in rates of anxiety (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Fluvoxamine

Tamminen & Lehtinen 1989

Feighner & Cohn 1985

Robertson et al 1994

Kuha et al 1991

South Wales ADTG 1988 (Dothiepin)

(Doxepin)

(Doxepin)

(Lofepramine)

(Maprotiline)

27 25

26

78

90

24

25

79

93

24

51 500 517Mean rate Difference Fluoxetine vs. TCAs

3

1

25

7

2

1

2

8

2

1

84

Paroxetine Comparator

20 3 104 102Mean rate difference Fluvoxamine vs.TCAs

Claghorn 1996

Wagner 1986

Mullin et al 1988

(Imipramine)

(Imipramine)

(Dothiepin)

Comparator

44

34

26

44

34

24

5

13

2

1

1

1

9 8 221 222Mean rate difference Paroxetine vs. TCAs

Bignamini & Rapisarda 1992

Geretsegger 1995

Staner et al 1995

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

156

44

21

156

47

19

2

4

3

8

0

0

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

113 62 825 841Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

Byerley et al 1988

Cohn & Wilcox 1985

Kuha et al 1991

(Imipramine)

(Imipramine)

(Imipramine)

32

54

24

34

54

24

8

3

2

0

0

0

0 110 112Mean rate Difference Fluoxetine vs. TCAs 13

Fig.35 Differences in rates of agitation ( SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Geretsegger 1995

Cohn et al 1992

Cohn et al 1990

Reimherr et al 1990a

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluvoxamine

Paroxetine

Comparator

Comparator

Sertraline Comparator

SSRIs TCAs

44

35

161

149

31

22

47

36

80

149

35

25

5

1

20

18

8

23

5

0

2

1

8

6

76 44 613 543Mean rate difference SSRIs vs. TCAs

19 10 114 119Mean rate difference Fluvoxamine vs. TCAs

6 3 79 78Mean rate difference Paroxetine vs. TCAs

38 31 310 229Mean rate difference Sertraline vs. TCAs

Feighner et al 1989b

Itil et al 1983

Mullin et al 1988 (Dothiepin) 26 240 3

(Imipramine) 35 3525Dominguez et al 1985

Feighner 1985

Judd et al 1993

Beasley et al 1993b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Dowling et al 1990

Ropert 1989

1985bFeighner

Remick et al 1989

South Wales ADTG 1988

Beasley et al 1993a (Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Dothiepin)

()Doxepin

()Doxepin

65 71

22

23

56

32

54

30

30

71

26

78

22

23

62

34

54

30

30

72

20

79

38 37

103 102

Poelinger & Haber 1989

Kuha et al 1991

Robertson et al 1994

(Maprotiline)

(Maprotiline)

(Lofepramine)

Remick et al 1993

Fabre et al 1991

(Desipramine)

(Nortriptyline)

55 842 847Mean rate Difference with TCAs

12

1

5

4

4

11

9

4

6

4

11

11

13

7

8

1

73

24

90

2

2

2

5

6

2

1

6

3

4

2 25

0

3

7

69

24

93

10

2 27

0

0

113

Fig.36 Differences in rates of insomnia (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

36 32 219 226Mean rate difference Fluvoxamine vs. TCAs

(Imipramine)

(Imipramine)

(Clomipramine)

Fluvoxamine

Paroxetine

Comparator

Comparator

31

22

41

35

25

41

6

6

5

4

8

5

Feighner et al 1989b

Itil et al 1983

Coleman 1982

(Imipramine)

(Imipramine)

(Imipramine)

44

35

46

44

35

46

4

9

2

3

9

7

Claghorn et al 1996

Dominguez et al 1985

Fabre et al 1996

28 22 481 482Mean rate difference Paroxetine vs. TCAs

55 20 361 274Mean rate difference Sertraline vs. TCAs

Geretsegger 1995

Cohn et al 1992

Feighner et al 1993

Øhrberg 1992

Pelicier et al 1993

Moon & Vince 1996

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1994

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Lofepramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Sertraline Comparator

44

35

240

74

26

60

161

149

51

47

31

237

77

28

62

80

149

55

3

7

7

7

2

2

28

26

1

6

14

0

3

3

7

2

3

4

232 129 1903 1829Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

Feighner 1985

Cohn et al 1989

Ropert 1989

(Amitriptyline)

(Imipramine)

(Clomipramine)

22

30

71

27

22

30

72

25

0

2

3

3

2

3

3

1

9 150 149Mean rate Difference Fluoxetine vs. TCAs 8

South Wales ADTG 1988 ()Dothiepin

Mullin et al 1988 (Dothiepin)

Fluvoxamine Comparator

26 242 1

Bignamini & Rapisarda 1992

Dunbar et al 1991

Øhrberg et al 1992

(Amitriptyline)

(Imipramine)

(Imipramine)

Paroxetine Comparator

146

240

74

460

156

237

77

570

2

7

1

10

8

17

5

30

Cohn et al 1990

Reimherr et al 1990a

Doogan & Langdon 1994

(Amitriptyline)

(Amitriptyline)

(Dothiepin)

Sertraline Comparator

161

149

83

393

80

149

96

325

8

7

3

18

4

9

1

14

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

38 54 1029 1068Mean rate difference SSRIs vs. TCAs

Mean rate difference Sertraline vs. TCAs

Mean rate difference Paroxetine vs. TCAs

Fig.37 Differences in rates of palpitations (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

SSRIs TCAs

Fawcett 1989

Masco et al 1986

Beasley et al 1993b

Claghorn et al 1996

Guelfi et al 1983

Dunbar et al 1991

Øhrberg et al 1992

Mean rate difference Paroxetine vs.TCAs

Cohn et al 1990

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Oxaproptiline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluoxetine

Fluvoxamine

Paroxetine

Sertraline

Comparator

Comparator

Comparator

Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatients

22

20

20

44

74

240

74

314

161

185

58

149

26

27

19

20

62

44

77

237

77

314

80

186

66

149

20

25

Remick et al 1993 (Desipramine)

ControlSSRI

0

0

5

0

14

17

1

18

0

0

4

19

Beasley et al 1993a (Amitriptyline) 65 716 0

3

1

5

7

14

14

7

21

3

11

14

11

6

2

Fig.38 Differences in rates of urinary disturbance (SSRIs vs. TCAs)

4

16

0

28 365 403Mean rate difference Fluoxetine vs. TCAs

30 35 176 187Mean rate difference Fluovoxamine vs.TCAs

0 14 310 229Mean rate difference Sertraline vs.TCAs

67 98 1165 1133Mean rate difference SSRIs vs. TCAs

Stark & Hardison 1985

Nolen et al 1988

Reimherr et al 1990a

South Wales ADTG 1988 ()Dothiepin

SSRIs TCAs

Feighner 1985

Laakman et al 1988

Beasley et al 1993b

Bremner 1984

Byerley et al 1988

Cohn & Wilcox 1985

Dowling et al 1990

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Dothiepin)

()Doxepin

()Doxepin

22

63

56

20

32

54

30

22

65

62

62

34

54

30

26

26

37

25

0

2

2

1

6

7

0

6

0

1

8

4

0

5

3

15

3

4

43 329 391Mean rate Difference Fluoxetine vs.TCAs 24

Remick et al 1989

Tamminen & Lehtinen 1989

18 23 153 155Mean rate difference Fluvoxamine vs. TCAs

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

Fluvoxamine Comparator

44

46

22

44

48

22

1

6

3

3

4

0

Claghorn et al 1996

Fabre et al 1996

Lapierre 1987

Coleman & Block 1982 41 4111 13

Fig.39 Differences in rates of fatigue (SSRIs vs. TCAs)

Fluoxetine Comparator

Paroxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

38 21 441 432Mean rate difference Paroxetine vs. TCAs

Cohn et al 1992

Feighner 1993

Peselow et al 1989a

Pelicier 1993

Moon & VInce 1996

Shrivastava 1992

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Lofepramine)

(Imipramine)

35

240

40

26

60

40

31

237

36

28

62

40

8

7

12

2

4

5

2

7

11

0

1

0

(Clomipramine)

Bersani 1994

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1990a

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

Sertraline Comparator

34

161

149

51

395

34

80

149

55

318

0

35

13

0

48

2

18

35

1

56Mean rate difference Sertraline vs. TCAs

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

128 147 1318 1296Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Feighner 1985

Judd et al 1993

Laakman et al 1988

Beasley et al 1993b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Ropert 1989

1985bFeighner

Remick et al 1989

Beasley et al 1993a (Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

()Doxepin

()Doxepin

()Doxepin

65

23

71

28

22

23

63

56

32

54

30

186

28

60

71

26

27

78

22

23

65

62

34

54

30

186

26

60

72

20

25

79

38

26

37

25

Remick et al 1993 (Desipramine)

16

11

3

1

3

6

3

12

9

6

5

12

9

5

2

0

3

21

5

5

12

8

14

6

24

28

24

9

7

7

0

3

8

0

2

3

2

22

11

3

21

24

15

7

De Jonghe et al 1991b

Kuha et al 1991

Stark & Hardison 1985

Tamminen & Lehtinen 1989

South Wales ADTG 1988

Ginestet 1989

Noguera et al 1991

Chouinard 1985 (Amitriptyline)

()Clomipramine

()Clomipramine

()Dothiepin

(Maprotiline)

(Maprotiline)

158 953 971Mean rate Difference TCAsFluoxetine vs. 142

94 78 458 411Mean rate difference Fluvoxamine vs.TCAs

Mean rate difference Paroxetine vs.TCAs

(Imipramine)

(Imipramine)

(Dothiepin)

Fluvoxamine Comparator

31

74

35

77

7

21

6

28

Feighner et al 1989b

Guelfi et al 1983

Mullin et al 1988

Nolen et al 1988 (Oxaproptiline)

26

58

24

66

1

22

(Imipramine)

(Clomipramine)

Norton et al 1984

Coleman & Block 1982

33

41

31

41

16

11

12

14

3

7

(Imipramine)

(Imipramine)

(Imipramine)

44

35

46

44

35

48

3

6

5

1

8

1

Claghorn et al 1996

Dominguez et al 1985

Fabre et al 1996

Fig.40 Differences in rates of tremor (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Cont.

Pelicier 1993 (Clomipramine) 26

145

28

142

2

13

Geretsegger 1995

Cohn et al 1992

Peselow et al 1989a

(Amitriptyline)

(Imipramine)

(Imipramine)

Paroxetine Comparator

44

35

40

47

31

36

0

4

7

2

6

5

0

13

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

47 36 444Mean rate difference Sertraline vs. TCAs

Cohn et al 1990

Reimherr et al 1990a

Moon & Lane 1993

Doogan & Langdon 1994

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

(Dothiepin)

Sertraline Comparator

161

149

51

83

80

149

55

96

23

24

0

0

10

20

3

3

296 285 2000 1904Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

Fig.40 Differences in rates of tremor (SSRIs vs. TCAs)

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Judd et al 1993

Beasley et al 1993b

Cohn et al 1989

Noguera1991

Ropert 1989

Remick et al 1989

Beasley et al 1993a (Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Clomipramine)

()Doxepin

()Doxepin

65

23

71

28

23

56

30

61

60

71

26

30

27

23

62

30

58

60

72

20

30

25

38

26

37

25

Remick et al 1993

Dowling et al 1990

(Desipramine)

(Dothiepin)

19

9

10

7

3

13

4

5

12

4

11

13

2

14

8

14

5

10

7

2

6

7

5

8

2

9

100 581 593Mean rate difference Fluoxetine vs. TCAs 120

Feighner et al 1989a

Tamminen & Lehtinen 1989

South Wales ADTG 1988

Chouinard 1985 (Amitriptyline)

()Dothiepin

3

5

28

24

0

3

21

24

De Jonghe et al 1991b

Kuha et al 1991

(Maprotiline)

(Maprotiline)

Fig.41 Differences in rates of headache (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

63 51 265 278Mean rate difference Fluvoxamine vs. TCAs

58 38 355 351Mean rate difference Paroxetine vs. TCAs

56 30 448 376Mean rate difference Sertraline vs. TCAs

Geretsegger 1995

Cohn et al 1992

Peselow et al 1989a

Shrivastava 1992

Dunner et al 1992

Moon & Vince 1996

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1994

Doogan & Langdon 1994

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

(Dothiepin)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluvoxamine

Paroxetine

Sertraline

Comparator

Comparator

Comparator

44

35

40

40

136

60

161

149

55

83

31

22

47

31

36

40

135

62

80

149

51

96

35

25

1

4

8

8

33

4

27

24

2

3

8

16

2

4

5

0

3

6

4

8

15

2

9

3

297 219 1649 1598Mean rate difference SSRIs vs. TCAs

Feighner et al 1989b

Lapierre 1987

Mullin et al 1988

Nolen et al 1988

(Dothiepin)

(Oxaproptiline)

26

58

24

66

3

5

3

3

(Imipramine)

(Imipramine)

(Imipramine)

47

35

46

45

35

48

18

2

20

15

4

24

Claghorn et al 1996

Dominguez et al 1985

Fabre et al 1996

SSRIs TCAs

Chouinard 1985

Beasley et al 1993b

Bremner 1984

Cohn & Wilcox 1985

Cohn et al 1989

Feighner et al 1989a

Noguera 1991

1985Feighner

1985bFeighner

Beasley et al 1993a (Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

(Doxepin)

65 71

23

56

20

54

30

28

62

20

54

30

61

60

78

58

60

79

67 469 484Mean rate Difference Fluoxetine vs. TCAs

Mean rate Difference Fluvoxamine vs. TCAs

12

4

4

6

3

14

3

23

9

8

5

12

11

2

9

2

12

4

6

224 22

86

Fig.42 Differences in rates of nervousness (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Claghorn et al 1996

Fabre et al 1996

(Imipramine)

(Imipramine)

44

46

90

44

48

92

7

3

10

4

0

4

Rate Difference with 95% Confidence Interval

Mean rate difference SSRIs vs. TCAs

Cohn et al 1990

- 0.5 0- 1 10.5

104 72 755 687

SSRIs TCAs

Sertraline Comparator

(Amitriptyline) 161 806 1

Cohn et al 1992

Paroxetine Comparator

(Imipramine) 35 312 0

Fluvoxamine Comparator

Feighner 1985

Judd et al 1993

Beasley et al 1993b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

1985bFeighner

Beasley et al 1993a (Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

()Doxepin

65

23

71

28

22

23

56

32

54

30

61

26

30

27

78

22

23

62

34

54

30

58

20

30

25

79

Remick et al 1993

Dowling et al 1990

(Desipramine)

(Dothiepin)

7

4

2

6

8

5

7

2

3

5

2

6

6

19

6

10

10

8

3

9

4

3

8

13

11

2

106 527 536Mean rate Difference Fluoxetine vs. TCAs 63

14 84 90Mean rate Difference Fluoxetine vs. TCAs 16

Feighner et al 1989a

South Wales ADTG 1988

Chouinard 1985 (Amitriptyline)

()Dothiepin

Remick et al 1989 ()Doxepin 38 3713 0

Mullin et al 1988

Dunbar et al 1991

Moon & Vince 1996

Mean rate Difference Paroxetine vs. TCAs

Cohn et al 1990 (Amitriptyline)

(Dothiepin)

(Imipramine)

(Lofepramine)

(Oxaprotiline)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluvoxamine

Paroxetine

Sertraline

Comparator

Comparator

Comparator

26

240

60

161

58

24

237

62

80

66

1

12

1

10

2

21

0

300 29913 21

0

1215

102 141 1072 1005Mean rate difference SSRIs vs. TCAs

Nolen et al 1988

Fig.43 Differences in rates of blurred vision (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

SSRIs TCAs

Laakman 1988

Judd et al 1993

Beasley et al 1993b

Cohn & Wilcox 1985

Cohn et al 1989

1985bFeighner

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Dothiepin)

()Doxepin

()Doxepin

(Maprotiline)

63

23

56

20

54

30

185

30

27

78

65

23

62

20

54

30

186

30

25

79

26

24

25

24

5

4

3

1

16

7

8

10

2

1

16

2

0

1

22

4

30

1

4

6

2

2

15

3

90 616 653Mean rate Difference Fluoxetine vs. TCAs 75

Bremner 1984

Stark & Hardison 1985

Dowling et al 1990

Tamminen & Lehtinen 1989

Kuha et al 1991

South Wales ADTG 1988 ()Dothiepin

Fig.44 Differences in rates of sweats (SSRIs vs. TCAs)

Fluoxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

40 63 313 321Mean rate difference Fluvoxamine vs. TCAs

35 59 359 351Mean rate difference Paroxetine vs. TCAs

23 13 365 280Mean rate difference Sertraline vs. TCAs

Geretsegger 1995

Cohn et al 1992

Dunbar et al 1991

Peselow et al 1989a

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1994

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluvoxamine

Paroxetine

Sertraline

SSRIs

Comparator

Comparator

Comparator

TCAs

44

35

240

40

161

149

55

31

22

47

31

237

36

80

149

51

35

22

2

5

26

2

10

11

2

3

5

5

9

6

3

8

45

3

2

1

173 225 1653 1605Mean rate difference SSRIs vs. TCAs

Feighner et al 1989b

Lapierre 1987

Norton et al 1984

Coleman & Block 1982

Nolen et al 1988 (Oxaproptiline)

33

41

58

31

41

66

7

6

18

14

1

12

(Imipramine)

(Imipramine)

(Imipramine)

47

35

46

45

35

48

5

6

10

3

3

0

Claghorn et al 1996

Dominguez et al 1985

Fabre 1996

Feighner 1985

Laakman et al 1988

Beasley et al 1993b

Byerley et al 1988

Cohn & Wilcox 1985

Cohn et al 1989

Ropert 1989

1985bFeighner

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Clomipramine)

()Doxepin

()Doxepin

(Lofepramine)

(Maprotiline)

23 28

22

63

56

32

54

30

61

185

71

27

78

22

65

62

34

54

30

58

186

72

25

79

26

90

24

25

93

24

103 102Fabre et al 1991 (Nortriptyline)

15

1

0

8

3

15

13

3

3

3

8

1

3

0

0

9

9

13

28

5

17

43

10

5

17

4

7

2

2

21

6

212 945 959Mean rate Difference Fluoxetine vs.TCAs 78

Stark & Hardison 1985

Feighner et al 1989a

Tamminen & Lehtinen 1989

Robertson et al 1994

Kuha et al 1991

South Wales ADTG 1988

Chouinard 1985 (Amitriptyline)

()Dothiepin

16

79 115 372 383Mean rate difference Fluvoxamine vs. TCAs

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Dothiepin)

Fluvoxamine Comparator

31

74

22

35

77

22

9

17

5

3

33

2

Feighner et al 1989b

Guelfi et al 1983

Lapierre 1987

Norton et al 1984

Mullin et al 1988

Nolen et al 1988 (Oxaprotiline)

33

26

58

31

24

66

11

4

15

21

5

20

(Imipramine)

(Imipramine)

(Imipramine)

47

35

46

45

35

48

7

7

24

2

2

7

Claghorn et al 1996

Dominguez et al 1985

Fabre et al 1996

Fig.45 Differences in rates of dizziness (SSRIs vs. TCAs)

Fluoxetine Comparator

Paroxetine Comparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

73 100 491 458Mean rate difference Paroxetine vs. TCAs

Hutchinson et al 1992

Kukhs & Rudolph 1989

Cohn et al 1992

Dunbar et al 1991

Peselow et al 1989a

Shrivastava 1992

Moon & Vince 1996

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Imipramine)

(Imipramine)

(Lofepramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

56

20

35

240

40

40

60

32

20

31

237

36

40

62

3

1

3

43

16

4

3

4

5

6

55

13

11

6

Cont.

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

81 87 421 414Mean rate difference Sertraline vs. TCAs

Bersani 1994

Cohn et al 1990

Reimherr et al 1990a

Moon et al 1994

Doogan & Langdon 1994

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Clomipramine)

(Dothiepin)

Sertraline Comparator

34

161

149

51

83

34

80

149

55

96

4

49

22

2

4

3

30

46

5

3

311 514 2229 2214Mean rate difference SSRIs vs. TCAs

SSRIs TCAs

Fig.45 Differences in rates of dizziness (SSRIs vs. TCAs)

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Beasley et al 1993a

Chouinard 1985

Young et al 1987

Remick et al 1993

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Amitriptyline)

(Imipramine)

(Imipramine)

(Clomipram.)

(Clomipramine)

(Doxepin)

65

23

25

28

38

71

28

25

26

37

4

0

5

4

6

9

7

3

7

9

35 179 187Mean rate Difference Fluoxetine vs. TCAs 19

Ginestet 1989

Fig.46 Differences in rates of hypotension (SSRIs vs. TCAs)*

FluoxetineComparator

N oftreated

patientsN of casesComparators

drugsAuthor/s and year

of study publication

N ofcontrolpatientsControlSSRI

Mean rate difference Fluvoxamine vs. TCAs

Mean rate difference Paroxetine vs. TCAs

11 18 56 54

Mean rate difference Sertraline vs. TCAs

Mean rate difference SSRIs < 20 vs. TCAs

Mean rate difference SSRIs vs. TCAs

Pelicier & Schaefer 1993

Moon et al 1990 (Clomipramine)

(Clomipramine)

- 0.5 0- 1 10.5Rate Difference with 95% Confidence Interval

Fluvoxamine

Paroxetine

Sertraline

SSRIs

Comparator

Comparator

Comparator

TCAs

26

26

51

51

345

28

28

55

55

355

4

4

1

1

38

0

0

65

1

1

0

0

3

19

1

11

7

3

3

7

35

3

15

5

14

14

15

179

10

42

17

14

14

15

187

10

40

15

Altamura et al 1990 Fluox<20

Fluoxetine sub-total/ trials <20 patients/drug

Fluoxetine sub-total/ trials 20 patients/drug>

Fluvoxamine sub-tot/ trials <20 patients/drug

Amore et al 1989 Fluvox<20

Gonella et al 1990 Fluvox<20

Dick & Ferrero 1983Fluvox<20

(Imipramine) 33

33

31

31

11

11

3

3

Norton et al 1984

* without and with trials having less than 20 patients treated with each drug.