efficacy of fluvoxamine in severe depression
TRANSCRIPT
Drugs43 (Suppl. 2): 32·39, 19920012-6667/92/0200.0032/$4.00/0© Adis International Limited,All rights reserved.
DRSUP3400
Efficacy of Fluvoxamine in Severe Depression
J. MendlewiczClinique Universitaire de Bruxelles, Brussels, Belgium
Summary The therapeutic efficacy of fluvoxamine has been demonstrated in large numbers of patientsparticipating in comparative double-blind placebo-controlled studies using imipramine as theactive reference compound. Overall, patients treated with fluvoxamine for 4 to 6 weeks hadsignificant amelioration of their depression compared with placebo-treated patients, More importantly, the response rate in patients with severe depression was greater than in patients withmild or moderate depression. However, several investigators have observed high placebo responserates, and in some studies there has been a similar response rate to imipramine and placebotreatment. While the high placebo response rate may have resulted from methodological problems, the issue does raise some questions that can only be resolved by further investigation.
Selective serotonin reuptake inhibitors have thetheoretical advantages of being as effective as, andbetter tolerated than, tricyclic antidepressants,However, some investigators have suggested thatthe increased safety of selective serotonin reuptakeinhibitors is achieved at the expense of reduced efficacy when they are compared with tricyclic antidepressants (Bech 1988; Danish University Antidepressant Group 1986, 1990), Before anantidepressant agent can be considered to be trulyeffective, its activity has to be demonstrated inpatients with severe depression or melancholia.This review examines data from American andEuropean studies that compare the effects of fluvoxamine with those of other antidepressant agentsin severely depressed patients in order to determine whether fluvoxamine is indeed effective inpatients with severe depression. The efficacies of 2other selective serotonin reuptake inhibitors are alsodiscussed in this review,
1. Antidepressant Efficacies of OtherSelective Serotonin Reuptake Inhibitors
The efficacy of another new selective serotoninreuptake inhibitor, paroxetine, has been evaluatedin a meta-analysis of studies of its effects in patientswith DSM-III-defined melancholia and in patientswith severe depression [Hamilton Depression Rating Scale (HDRS) score> 25] (J. Dunbar, personalcommunication). In these studies, patients withmelancholia had received at least 6 weeks' treatment with either paroxetine, placebo or a referencecompound, while severely depressed patients received either paroxetine or the reference compound. American investigators usually used imipramine or doxepin as the reference compound,and amitriptyline, mianserin, clomipramine andmaprotiline were the usual reference compoundsused in European studies. An end-point total HDRS
Fluvoxamine in Severe Depression
score less than 10, an HDRS score change of atleast 50%, or an end-point Clinical Global Impression (CGI) score of I or 2 on a scale of 'normal','not ill' or 'borderline ill' were used to defineefficacy.
Results from these studies indicated that, overall, the antidepressant efficacy of paroxetine wassignificantly superior to that of placebo and the reference compounds, but there was no significantdifference between the response rates of the placebo and active control groups. More importantly,paroxetine and active controls were equally effective in treating hospitalised patients with very severe depression. However, the response rates in theseseverely depressed patients (about 30 to 40%) wererelatively low compared with the overall responserates of all patients (about 60 to 70%). Thus, thereremains a need for a more effective antidepressant.
Data from a separate controlled study comparing the effects of another selective serotonin reuptake inhibitor, fluoxetine, with those of clomipramine in patients with endogenous and melancholicdepression have shown that both treatments areequally effective (Ginestet et al. 1992). However,these findings require confirmation, as the studylacked placebo controls.
2. The Antidepressant Efficacy ofFluvoxamine
The therapeutic efficacy of fluvoxamine has nowbeen investigated in over 600 patients in comparative double-blind placebo-controlled studies usingimipramine as the reference compound (Amin etal. 1984; Cassano 1987; Feighner et al. 1989; Itil1983).
2.1 Findings from a WorldwideMulticentre Study
One multicentre study involving a total of 481patients was conducted in 3 European and 5 NorthAmerican centres (Amin et al. 1984; Cassano et al.1986). All centres followed a standard protocol,which included patients severely depressed for atleast 2 weeks prior to entry, meeting DSM-III cri-
33
teria for major depressive disorders (single or recurrent episode) and having a score of at least 15on the 17-item HDRS. After a washout period of4 to 7 days, patients were randomised to treatmentwith fluvoxamine [50 to 300 rug/day (mean 155.4mg/day) after an initial tapering-on over the first3 days], imipramine (mean 156.3 mg/day), or placebo. Each patient's dose was adjusted accordingto response. Both the lowest (imipramine 122mg,fluvoxamine 136mg) and the highest (imipramine223mg, fluvoxamine 240mg) daily doses were administered in the European centres. Europeanpatients were treated for 4 weeks and those in NorthAmerica for 6 weeks. The HDRS and CGI scalesfor severity and change in condition were the major instruments for investigator ratings of efficacy.The Brief Psychiatric Rating Scale (BPRS) was alsoused.
There were no significant differences in demographic characteristics between the 3 groups ofpatients although 58% of European patients received concomitant benzodiazepines (mainlychloral-hydrate or flurazepam as hypnotics) [vs 15%of North American patients]. In the Europeancentres 49% of the fluvoxamine group, 39% of theimipramine group and 48% of the placebo groupused night-time sedatives (Norton et al. 1984).During the first 4 weeks' therapy, active treatmentwas withdrawn from 34% of participants after thedevelopment of adverse events. These were mainlynausea in the fluvoxamine group and confusion inthe imipramine group. There was a clear differencein overall type of adverse effect between the 2 active treatments in the European centres. Gastrointestinal symptoms such as nausea, diarrhoea andanorexia were more frequent in the fluvoxaminegroup, and postural hypotension and anticholinergic effects were observed only in the imipraminegroup (Norton et al. 1984).
A meta-analysis of the results from the 8 centres(Amin et al. 1984; Cassano et al. 1986)showed that,overall, both fluvoxamine- and imipramine-treatedpatients had significant amelioration of theirdepression after 4 weeks' therapy (table I). This significant effect is also evident if the analysis is limited to the North American data. More import-
34 Drugs 43 (Suppl. 2) 1992
Table I. Comparative antidepressant activity of f1uvoxamine, imipramine and placebo after 4 weeks' therapy in a multicentre study
of 481 patients with depression [Wakelin JS, Coleman BS. Fluvoxamine: a multicentre placebo and imipramine controlled study in
depression. Medical Report (1984)]
Improvement in HDRS score (%J Responders· (% of patients)
fluvoxamine imipramine placebo f1uvoxamine imipramine placebo
All centres 48** 45* 34 68** 56** 42North America 53** 46* 32 73**t 57* 38Europe 40 43 37 55 55 50
a Defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression change scale.
Abbreviation: HDRS = Hamilton Depression Rating Scale.
* p < 0.01: statistically significant difference vs placebo; ** p < 0,001: statistically significant difference vs placebo; t p < 0.05:statistically significant difference vs imipramine.
antly, in the North American studies, the effects offluvoxamine were shown to be significantly greaterthan those of placebo from the second week oftreatment (figs I & 2), indicating an early onset ofaction.
In the European centres, there was a trend toimprovement in total HDRS and BPRS scores inall 3 treatment groups. Since 50% of patients responded to placebo, a significantly greater effect ofactive treatment was difficult to discern. The only
significant difference was observed at 3 weeks whenimipramine-treated patients had a significantlygreater (p < 0.05) improvement on the BPRS thanplacebo patients, although there was a trend for fluvoxamine to be more effective than placebo atweeks 3 and 4 (Norton et al. 1984). A similar nonsignificant trend was observed in changes assessedusing the HDRS. In contrast, in patients with nonsituational depression there were significant differences between fluvoxamine and placebo and flu-
Fig. 1. The comparative antidepressant efficacies offluvoxamine, imipramine and placebo in a total of 308 patients in North
American centres. HDRS = Hamilton Depression Rating Scale. * p < 0.05 vs placebo.
Fluvoxamine in Severe Depression 35
Fig. 2. The comparative effects of fluvoxamine, imipramine and placebo on mood depression in a total of 308 patients inNorth American centres. * p < 0.05 vs placebo.
voxamine and imipramine in factors assessed usingthe BPRS and CGI (table II).
Results from the North American centres werealso reanalysed separately to determine the response of patients with different HDRS scores. Ofthe 338 patients enrolled in the 5 centres, 181women and 127 men (aged 19 to 70 years) wereavailable for evaluation. 100 patients were classified as having mild depression (HDRS score 15 to20), 105 were moderately depressed (HDRS score21 to 25) and 103 had severe depression (HDRSscore ~ 26). Stratification of the North American
results for the severity of patients' depressionshowed that the response rate to fluvoxaminetherapy was greater in patients with severe depression than in patients with moderate or milddepression (Ottevanger 1991) [fig. 3]. In the latteranalysis, a comparison of the treatment effects inseverely depressed patients showed that fluvoxamine was superior to placebo (p < 0.02) whereasthere was no significant difference between the effects of imipramine and placebo (p =0.08). A similar trend for greater fluvoxamine efficacy in moreseverely depressed patients was also observed in
Table II. Mean symptom scores in patients with nonsituational depression treated in UK centres for 4 weeks with fluvoxamine,
imipramine or placebo
Fluvoxamine Imipramine Placebo
(n = 21) (n = 16) (n = 11)
HDRS total 11.03 14.07 13.75BPRS total 32.20· 26.32t 26.53Clinical Global Impression
Global severity 2.66* 3.30t 3.31Global change 2.05* 2.75tt 3.09
Abbreviations: HDRS =Hamilton Depression Rating Scale; BPRS = Brief Psychiatric Rating Scale. * p < 0.05: statistically significant
difference vs placebo; t p < 0.05: statistically significant difference vs fluvoxamine; tt p < 0.01: statistically significant difference vs
fluvoxamine.
36 Drugs 43 (Suppl. 2) 1992
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2.2 Therapeutic Efficacy of Fluvoxamine inPatients with Severe Depression
Fig. 3. The mean decrease in Hamilton Depression RatingScale (HDRS)scores in North American patients with mild(n = 100), moderate(n = 105) or severe (n = 103) depressiontreated with fluvoxamine, imipramineor placebo.
Summarising the data according to the globalresults, it is apparent that the selective serotoninreuptake inhibitors fluvoxamine, paroxetine andfluoxetine are effective antidepressants. Overallfindings from the studies discussed here suggestthatfluvoxamine is particularly effectivein patients withsevere depression, with definite advantages overimipramine and placebo. However, in several investigating centres there has been a high placeboresponse rate. This may have been a result ofmethodological problems such as an undetected assessment bias. In addition, some studies lack placebo controls. It is also possible that patients recruited for placebo-eontrolled studies have different
3. Conclusion
were randomly assigned to treatment with fluvoxamine, imipramine or placebo in the ratio of2 : 2 : 1. Improvements were measured using theobserver-rated scales, HDRS, COl and BPRS, andthe patient-rated scales the Zung Depression Scaleand the 90 item Symptom Checklist (SCL-90).There were no significant differences in demographic characteristics between the 3 groups. 60 ofthe 81 enrolled patients completed at least 2 weeks'treatment and were included in the efficacy analysis. Actual drug dosages used were fluvoxamine 85to 280 (median 145) rug/day and imipramine 50to 280 (median 159) mg/day,
Statistical analysis of the results revealed thatthere were significant differences (p ~ 0.05) in CGImeasures of severity of illness and total BPRSscores between active treatment and placebo. Therewas also a trend to significance for improvementsassessed using the HDRS (p = 0.08 for active treatment vs placebo). More importantly, there weresignificant differences between fluvoxamine andplacebo on all 3 measures (p ~ 0.02). As was thecase in the European centres of the multicentrestudy, there was a similar response to treatmentwith imipramine and placebo, which may havebeen due to the very high placebo response rate(approximately 40%) [fig.4]. However, despite thishigh placebo response rate fluvoxamine treatmentremained significantly more effective than placebo.
End-point
- Fluvoxamine- - Imipramine•••• Placebo
Pretreatment
Mild
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the European patients. However, this trend was notsignificant (Norton et al. 1984).
It is possible that the differences in findings between the North American and European centresarises from either the smaller population size [moreNorth American (n =308) than European (n =91)patients completed the study)] or the higher consumption of concomitant sedatives or hypnoticagents by patients in the European centres. It isalso possible that the shorter treatment duration inthe European studies (4 weeks vs 6 for the NorthAmerican studies), or that the lower doses used insome patients compared with those used in theNorth American centres, may have resulted in alack of response in some patients.
The antidepressant efficacy of fluvoxamine hasalso been investigated in a 6-week double-blindstudy of severely ill patients aged 18 to 71 yearswith a DSM-III diagnosis of depression. All but 1patient also met the criteria for melancholic subtype. After a 3-day placebo washout phase, patients
Fluvoxamine in Severe Depression 37
Fig. 4. Mean percentage improvement in total HamiltonDepression Rating Scale (HDRS) and BriefPsychiatric Rating Scale (BPRS) scores in patients with severe depressiontreated with fluvoxamine (n = 21), imipramine (n = 27)orplacebo (n = 12) [after Feighner et al. 1989].
60
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o Placebo• Fluvoxamineo Imipramine
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selective serotonin reuptake inhibitor showing bettertolerance, but weakerantidepressanteffectthan clomipramine in a controlled multicentre study. Journal ofAffective Disorders 18: 284-299, 1990
FeighnerJ, BoyerWF, Meredith CH, Hendrickson GG.A placebo-eontrolled inpatients comparisonof fluvoxamine maleate and imipramine in major depression.InternationalClinical Psychopharmacology 4: 239-244,1989
Ginestet D, et al. Etude de la fluoxetine dans Ie traitement des depressions endogenes et des melancolics,International Clinical Psychopharmacology, in press,1992
Itil T. A double-blind placebo controlled study of fluvoxamine and imipramine in out-patients with primary depression. British Journal of Clinical Pharmacology 15: 433S-438S, 1983
Norton K, Sireling LI, Bhat AV, Rao B, Paykel ES. Adouble-blindplacebocontrolled study of fluvoxamine,imipramine and placeboin depressed patients.Journalof Affective Disorders 7: 297-308, 1984
Ottevanger E.The efficacy offluvoxaminein patientswithseveredepression. BritishJournal of Clinical Research2: 125-132, 1991
symptoms from those presenting in general practice. What is known is that the population in themulticentre study was a very heterogeneous groupand included patients from different diagnosticsubgroups and patients with situational depression.With this in mind and the lack of significant differences between the efficacies of both fluvoxamine and the active reference compound comparedwith placebo in patients with mild and moderatedepression, some questions that can only be answered by further investigations are raised.
References
Amin MM, Anath JV, Coleman BS, Darcourt G, FarkasT, et al. Fluvoxamine: antidpressant effect confirmedin a placebo controlled international study. ClinicalNeuropharmacology 7 (Suppl. I): S312-S319, 1984
Bech P. A review of the antidepressant propertyofSSRI's.In Advanced biological psychiatry, Vol. 17, pp. 58-69,Karger, Basel, 1988
Cassano GB, Conti L, MassimettiG, Mengali F, WakelinJS, et al. Use of a standardizeddocumentation system(BLIPSjBPD) in the conduct of a multicenter international trial comparingfluvoxamine, imipramine andplacebo. Psychopharmacology Bulletin 22: 52-58, 1986
Danish University Antidepressant Group. Citalopram:clinical effect profile in comparison with clomipramine. A controlled multicentre study. Psychopharmacology 90: 131-299, 1986
Danish University Antidepressant Group. Paroxetine: a
Correspondence and reprints: Prof. J. Mendlewicz, Clinique Universitaire de Bruxelles, Hopital Erasme, Service de Psychiatric,Route de Lennik 808, 1070 Brussels, Belgium.
Discussion
Dr Y. Lecrubier: Before I ask a question I wishto make a brief comment for those unfamiliar withthe different definitions of depressed patients. Someof the studies presented here have defined melancholic patients according to DSM-III criteria.However, many investigators in different European countries use a definition of melancholiacloser to that of endogenous depression and thisshould be kept in mind when interpreting someresults.
There is a very high response rate with placeboin studies evaluating the efficacy of paroxetine orfluvoxamine, and some of the reference compounds were not superior to placebo. Dr Mendlewicz, could the lack of efficacy of the active therapybe due to the adverse effects of tricyclic antidepressants, or would the adverse effects have resulted inwithdrawal of some patients who may have responded later?
Prof J. Mendlewicz: The occurrence of side ef-
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fects can certainly interfere with the end result.There do seem to be more early adverse event-related withdrawals from the tricyclic antidepressantgroups than the selective serotonin reuptake inhibitor groups. However, it is also apparent that insome studies subtherapeutic doses of tricyclicswereused, and this could explain the absence of efficacyof the reference compounds compared with placebo. One other factor is that some of the patientsdid not have very high Hamilton Depression Rating Scale scores, and it is clear that patients withonly mild depression had a poor response to thereference compounds.
Prof H.M. van Praag: I would like to suggestan alternative explanation. Over the past years, wehave tended to give insufficient emphasis topatients' symptoms and symptom patterns. I donot think that it is appropriate to distinguish different forms of depression solely by severity andtalk only of mild, moderate, and severe depression.In doing so, a large number of data are confounded, as the more one investigates symptomsof 'endogenous' depression, the more difficulties innomenclature arise. In addition, the more closelysymptoms of nonendogenous depression are examined, the higher the rate of side effects evinced.It is therefore possible that patients with nonendogenous depression were included in the studygroups.
Dr S. Montgomery: It is indeed an importantissue that the efficacy of imipramine may not bediscerned because subtherapeutic doses are used.It is also possible that the comparatively low patientnumbers used could have resulted in atypical findings. However, there is some evidence that imipramine is not effective in patients with severedepression. Is it possible that the selective serotonin reuptake inhibitors might possess the advantage of efficacy in patients who have severe depression?
Prof Mendlewicz: There are 2 important issueshere. In principle, I agree that we have been oversimplistic in looking at Hamilton scores, theirthresholds, or the definition of melancholia, andhave ignored all other parameters when analysingthe data from such large collaborative studies of
Drugs 43 (Suppl. 2) 1992
patients with personality problems and situationaldepression. We need behavioural psychology toprovide other dimensional typologies and instruments in order to objectively evaluate these factors, and such reliable instruments are not available. I agree with you that there is a lack ofsophistication in the way analyses of data are made.
As Dr Montgomery mentioned, there is someevidence that tricyclic antidepressants are ineffective in severe psychotic depression, and it is clearthat selective serotonin reuptake inhibitors havesome efficacy in this indication.
Dr D. Olagide: I would like to raise the issue ofthe chronicity of patients entering clinical trials. Theoutcome measures I currently use suggest that thelonger the duration ofthe patient's depression, theless the likelihood of a marked improvement during the study, In addition, the longer patients havebeen depressed, the more likely it is that they willhave been treated with tricyclic antidepressants atsome time in the past. Could there be a methodological problem in that some patients enteringclinical trials evaluating the effects of fluvoxaminewere refractory to tricyclic antidepressant agents?
Prof Mendlewicz: From the patient profiles Ihave seen, there do not appear to be any markeddifferences in chronicity between the imipramineand selective serotonin reuptake inhibitor groups,but further analysis are ongoing.
Dr G. Beaumont: During early evaluations oftricyclic antidepressants, we observed that they hadno effect in patients with delusions, so that thetreatment of choice for patients with delusionaldepression was frequently ECT rather than a tricyclic. Is there any evidence that the new serotoninreuptake inhibitors have any effect on delusions indepression?
Prof van Praag: On the contrary, there is someevidence from case history reports that serotoninreuptake inhibitors may exacerbate the situation,particularly as hyperactivity of serotonergic systems may be involved in the development of schizophrenia or psychosis.
Dr Montgomery: I would like to comment thatthere was a higher incidence of emergent psychoticsymptoms in patients treated with reference com-
Fluvoxamine in Severe Depression
pounds than in those treated with the selectiveserotonin reuptake inhibitors, sertraline and paroxetine. On the surface, this finding suggests thatselective serotonin reuptake inhibitors may suppress psychotic symptoms more effectively thantricyclic antidepressants but retrospective analysisof the results will not establish whether this is so.
39
A prospective study would be required to confirmthis hypothesis.
Dr Lecrubier: What would you recommend asan initial dosage of fluvoxamine for severely depressed patients?
Prof Mendlewicz: I would suggest initiatingtherapy with the standard recommended dose.