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CANADIAN COORDINATING OFFICE FOR HEALTH TECHNOLOGY ASSESSMENT
SELECTIVE SEROTONINREUPTAKE INHIBITORS (SSRIS)
FOR MAJOR DEPRESSION
PART 1
EVALUATION OF THECLINICAL LITERATURE
CCOHTA REPORT 1997: 3E
Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is givento CCOHTA.
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
Additional copies are available from CCOHTA.
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Vous pouvez aussi vous procurer la version française a l'OCCETS.
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
51
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2
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
ntid
epre
ssan
nts)
-1.2
-0.8
-0.4
0.0
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0.8
1.2
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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611
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2 54 50 0.372
0
0.115
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8 265 269
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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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0.0661
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Fig.8 Differences in effect size by age categories
1404
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1E-04
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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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0.126 0.318
0.102
7
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21
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.
16
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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)
14 479 480
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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)
82
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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)
64
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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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22
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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
10
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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2
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
28 22 481 482
55 20 361 274
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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11
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)
9
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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)
23
4
9
6
4
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)
23
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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)
32
7
15
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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)
2
1
10 67 469 48486
90
35 31
9210
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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)
19
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1
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)
27
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3
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)
37
9
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7
5
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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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Dunbar, G. C., Claghorn, J. L., Kiev, A., Rickels, K., Smith, W. T. (1993). A comparison of paroxetine and placebo indepressed outpatients. Acta Psychiatrica Scandinavica, 87 (5) : 302-305.
Emrich, H. M., Berger, M., Riemann, D., von Zerssen, D. (1987). Serotonin reuptake inhibition vs. norepinephrine reuptakeinhibition: A double-blind differential-therapeutic study with fluvoxamine and oxaprotiline in endogenous and neuroticdepressives. Pharmacopsychiatry, 20 (2) : 60-63.
Feighner, J. P. (1992). A double-blind comparison of paroxetine, imipramine and placebo in depressed outpatients.International Clinical Psychopharmacology, 6 (Suppl 4) : 31-35.
Feighner, J. P., Cohn, J. B., Fabre, L. F., Fieve, R. R., Mendels, J., Shrivastava, R. K., et al. (1993). A study comparingparoxetine, placebo and imipramine in depressed patients. Journal of Affective Disorders, 28 : 71-79.
Fieve, R. R., Goodnick, P. J., Peselow, E. D., Barouche, F., Schlegel, A. (1986). Pattern analysis of antidepressant responseto fluoxetine. Journal of Clinical Psychiatry. 47 (11) : 560-562.
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.
Judd, F. (1991). Preliminary report of a double-blind study comparing fluoxetine and amitriptyline in the treatment ofdepression. JAMA, (SEA Suppl) : 31-33.
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Koran, L. M., Hamilton, S. H., Hertzman, M., Meyers, B. S., Halaris, A. E., Tollefson, G. D., et al. (1995). Predicting re-sponse to fluoxetine in geriatric patients with major depression. Journal of Clinical Psychopharmacology, 15 (6) : 421-427.
Lauritzen, L., Odgaard, K., Clemmesen, L., Lunde, M., Öhrström, J., Black, C., et al. (1996) . Relapse prevention by meansof paroxetine in ECT-treated patients with major depression: A comparison with imipramine and placebo in medium-termcontinuation therapy. Acta Psychiatrica Scandinavica, 94 (4) : 241-251.
Levine, S., Deo, R., Mahadevan, K. (1989). A comparative trial of a new antidepressant, fluoxetine. International ClinicalPsychopharmacology, 4 (Suppl 1) : 41-45.
Lonnqvist, J., Sihvo, S., Syvälahti, E., Kiviruusu, O. (1994). Moclobemide and fluoxetine in atypical depression: Adouble-blind trial. Journal of Affective Disorders, 32 (3) : 169-177.
Lonnqvist,J., Sihvo, S., Syvälahti, E., Sintonen, H., Kiviruusu, O., Pitkanen, H. (1995). Moclobemide and fluoxetine in theprevention of relapses following acute treatment of depression. Acta Psychiatrica Scandinavica, 91 (3) : 189-194.
Moller, S. E., Bech, P., Bjerrum, H., Bojholm, S., Butler, B., Folker, H., et al. (1990). Plasma ratio tryptophan / neutral aminoacids in relation to clinical response to paroxetine and clomipramine in patients with major depression. Journal of Affec-tive Disorders, 18 (1) : 59-66.Moon, C. A., Wood, K., Lane, R. M., Jago, W. (1993). Sertraline and clomipramine in mixed anxiety depression. Journal ofPsychopharmacology, (Suppl) : A14.
Montgomery, S. A., Dunbar, G. C. (1993). Paroxetine is better than placebo in relapse prevention and the prophylaxis ofrecurrent depression. International Clinical Psychopharmacology, 8 : 189-195.
Ottevanger, E. A. (1991). The efficacy of fluvoxamine in patients with severe depression. British Journal of ClinicalPractice, 2 : 125-132.
Reimherr, F. W., Wood, D. R., Byerley, B., Brainard, J., Grosser, B. I. (1984). Characteristics of responders to fluoxetine.Psychopharmacology Bulletin, 20 (1) : 70-72.
Reimherr, F. W., Byerley, W. F., Ward, M. F., Lebegue, B. J., Wender, P. H. (1988). Sertraline, a selective inhibitor ofserotonin uptake, for the treatment of outpatients with major depressive disorder. Psychopharmacology Bulletin, 24 (1) :200-205.
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Skausig, O. B., Nielsen, O. A., Morsing, I., Petersen, J. S., Larsen, T., Moller, S., et al. (1992). Paroxetine and imipraminetreatment of depressed patients in a controlled, multicentre study wih plasma amino acid measurements. Nordic Journalof Psychiatry, 46 (Suppl 27) : 23-26.
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Thompson, C. (1991). Sertraline in a primary care setting. In G. Racagni, et al, (Eds.), Biological psychiatry: Proceedingsof the 5th World Congress of Biological Psychiatry, Florence, 9-14 June 1991. Amsterdam: Elsevier Science. (Interna-tional Congress Series; no. 968) 2 : 863-865.
Usher, R. W., Beasley, C. M., Bosomworth, J. C. (1991). Efficacy and safety of morning versus evening fluoxetine adminis-tration. Journal of Clinical Psychiatry, 52 (3) : 134-136.
Wade, A., Aitken, C. (1993). Efficacy, tolerability and effect on sleep of morning and evening doses of paroxetine indepressed patients. British Journal of Clinical Research, 4 : 105-111.
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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.