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Still the Leading Antidepressant After 40 Years of Randomised Controlled Trials CORRADO BARBUI and MATTHEW HOTOPF BJP 2001, 178:129-144

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Still the Leading Antidepressant After 40 Years of Randomised Controlled Trials CORRADO BARBUI and MATTHEW HOTOPF BJP 2001, 178:129-144 BRITISH JOURNAL OF PSYCHIATRY "2001), 178, 129^144 REVIEW ARTICLE Amitriptyline vv.therest:stilltheleading METHOD Inclusion criteria antidepressant after 40 years of randomised All RCTs comparing amitriptyline with any y other tricyclic,heterocyclic or SSRI were in- controlled trials cluded. Crossover studies were excluded. Studies adopting any criteria to define CORRADO BARBUI and MATTHEW HOTOPF patients suffering from depression were included; a concurrent diagnosis of another psychiatric disorder was not considered an exclusion criterion. Trials in patients with depression with a concomitant medical ill- Background Tricyclic antidepressants Amitriptyline is one of the first `reference' ness were not included in this review. have similar efficacy and slightly lower tricyclic antidepressants TCAs). Over the past 40 years a number of newer tricyclics, tolerability than selective serotonin Search strategy heterocyclics and selective serotonin re- Relevant studies were located by searching reuptakeinhibitorsreuptake inhibitors SSRIs).However, uptake inhibitors SSRIs) have been intro- the Cochrane Collaboration Depression, there are no systematic reviews assessing duced Garattini et aletal,1998). Despite Anxiety and Neurosis Controlled Trials several large systematic reviews comparing amitriptyline, the reference tricyclic drug, Register CCDANCTR). This specialised tricyclics and SSRIs there is no clear agree- vv. other tricyclics and SSRIs directly. register is regularly updated by electronic ment over first-line treatment of depression Medline,Embase,PsycINFO,LILACS, SongSong et aletal,1993; Anderson & Tomenson, Aims ToreviewTo review the tolerability and Psyndex,CINAHL,SIGLE) and non-electro- 1995; Montgomery & Kasper,1995; efficacy of amitriptyline inthe nicnicliterature searches. The register was HotopfHotopf et aletal,1996; Canadian Coordinating management of depression. searched using the following terms: Office for Health Technology Assessment, AMITRIPTYLIN**AMITRIPTYLIN oror AMITRILAMITRIL oror ELA-ELA- 19971997aa). Grouped as a whole,tricyclics MethodMethod Asystematic review of TROLTROL oror ELAVILELAVIL oror EMITRIPEMITRIP oror ENDEPENDEP appear to have similar efficacy to SSRIs, oror ENOVILENOVIL oror LAROXYL oror LENTIZOL randomised controlled trials RCTs) but are slightly less well tolerated. If toler- oror LEVATELEVATE oror MEVARILMEVARIL oror NOVOTRIP- comparing amitriptyline with other ability is measured according to the TYNTYN oror SAROTENSAROTEN oror TRYPTALTRYPTAL oror numbers of drop-outs occurring in random- tricyclics/heterocyclics or with an SSRI. TRYPTIZOL oror TRIPTAFEN*.TRIPTAFEN*. A specific ised controlled trials RCTs),the number electronic search was also performed with ResultsResults Wereviewed186 RCTs.The needed to treat NNT) with SSRIs to Medline and Embase from 1966 to 1998. prevent one tricyclic-related drop-out is overallestimate ofthe efficacy of We used the search term: AMITRIP-AMITRIP- estimated at 33 Anderson & Tomenson, amitriptyline revealed a standardised TYLINETYLINE andand RANDOMISED CON- 1995). This modest advantage has to be mean difference of 0.147 95% CI 0.05^ TROLLED TRIAL oror RANDOM ALLO- set against the increased cost of SSRIs CATIONCATION oror DOUBLE-BLIND METHOD..METHOD 0.243), significantly favouring Canadian Coordinating Office for Health Reference lists of relevant papers and pre- amitriptyline.The overall OR for dropping Technology Assessment,1997 bb). A meta-meta-).A vious systematic reviews were hand analysis which subdivided TCAs according out was 0.99 95% CI 0.91^1.08) and that searched for published reports and citations to whether they were reference compounds for side-effects was 0.62 95% CI 0.54^ of unpublished research. Finally,attempts e.g. the oldest TCAs,amitriptyline and were made to obtain data through direct 0.70), favouring the control drugs.With imipramine) or newer tricyclics or hetero- contact with the pharmaceutical industry. drop-outsincluded as treatmentfailures, cyclics,suggested that the higher drop-out thetheestimateoftheeffectivenessof estimate ofthe effectiveness of rates associated with tricyclics could be Outcomes amitriptyline vv. tricyclics/heterocyclics and attributed to the effect of amitriptyline and imipramine ± newer tricyclics and Efficacy was evaluated using the following SSRIs showed a 2.5% difference in the heterocyclics were no worse than the SSRIs outcome measures: proportion of responders in favour of HotopfHotopf et aletal,1997). However,there have a)a)NumberNumber of patients who responded to amitriptyline number needed to treat 40, not been any systematic reviews assessing treatment out of the total number of CI 21^694;21^694;OR1.12 OR1.12 95% CI1.01^1.24)). amitriptyline v.v. other tricyclics and hetero- randomised patients. cyclics directly. We therefore aimed to test Conclusions Amitriptyline is less well the hypothesis that amitriptyline would be b)b)GroupGroup mean scores at the end of the trial on Hamilton Depression Rating tolerated thantricyclics/heterocyclics and less well tolerated than other tricyclics and SSRIs,and also to assess its effective- Scale HDRS; Hamilton,1960),or SSRIs, but slightly more patients treated Montgomery and AAsbergÊ sberg Depression ness compared with the alternatives. on it recover than on alternative Scale MADRS; Montgomery & Ê antidepressants. AAsberg,1979),orsberg,1979),or any other depression scale.scale. Declaration of interest None.None. Tolerability was evaluated using the ySee editorial, pp. 99^100, thisissue. following outcome measures: 129129 BARBUI & HOTOPF a)a)NumberNumber of patients failing to complete inevitably excluded most drop-out patients. nortriptyline in combination with fluphena- the study as a proportion of the total Therefore,scores from continuous out- zine. One trial compared amitriptyline with number of randomised patients. comes were analysed on an end-point basis, nortriptyline plus fluphenazine. including only patients with a final assess- Although all trials reported that b)b)NumberNumber of patients complaining of ment or with an LOCF to the final assess- patients had been randomly allocated,in side-effects out of the total number of ment. Tolerability data were analysed by six cases the concealment of allocation randomised patients. calculating the proportion of patients who was inadequate with some bias possible. failed to complete the study and who In four studies only physicians,but not Data extraction experienced adverse reactions out of the patients,were blind to treatments,in nine total number of randomised patients. For cases neither physicians nor patients were Using a standard form two reviewers inde- each outcome measure three separate blind,while the other 173 studies were pendently extracted information on the year meta-analyses were planned. The firstThefirst double-blind. The median sample size was of publication,concealment of allocation, compared amitriptyline with tricylic/hetero- 50 patients 10% percentile 24,25% per- blindness,length of treatment,inclusion cri- cyclic antidepressants,the second amitripty-amitripty- centile 40,75% percentile 80,90% percen- teria,age range,country and setting of the line with SSRIs and the third analysis tile 153; range 10±531). The median length study and type of pharmacologicalpharmacological interven- summarised the overall comparison of ami- of trials was four weeks 25% percentile 4, tion. The number of patientsundergoing the triptyline with both tricyclic/heterocyclic 50% percentile 4,75% percentile 6; range randomisation procedure,the number of drugs and SSRIs. 3±12); the number of studies with more patients who failed to complete the study Dichotomous outcomes were sum- than four weeks of follow-up increased drop-outs) and that of patients complain- marised by calculating a Peto-weighted from 28 30%) to 62 67%) after 1980. ing of side-effects were recorded. For odds ratio for each study,together with In 67 trials 36%) authors adopted diag- dichotomous outcomes the number of the 95% CI. An overall odds ratio was then nostic criteria and a specification of severity patients showing a 50% reduction in score calculated as a summary measure. The of depression to enrol patients; in 55 trials on the HDRS or MADRS scale was ex- number of patients who need to be treated 30%) authors adopted only a specification tracted; if these figures were not available, NNT) with amitriptyline rather than the of severity,while in the remaining 34% of we extracted the number of patients cate- control antidepressants for one additional studies patients were enrolled on the basis gorised as `much improved' and `improved' patient to benefit NNTB) or be harmed of physicians' implicit criteria to define on the Clinical Global Impression scale NNTH) was calculated with the 95% CI patients with depression or because they CGI; Guy,1976),or the number of patients Altman,1998). Heterogeneity of treatment were judged to require antidepressant in the corresponding categories of any other effects between studies was tested using the therapy. Fifty-nine per cent of studies pub- rating scale if the CGI was not used. For ww22 statistic. Continuous outcomes were lished before 1980 used implicit criteria vv.. continuous outcomes the mean scores at analysed by calculating a standardised 9.6% of those published after this date. end-point on the HDRS and the number weighted mean difference SMD) for each Overall,108 trials 60%) used operational of patients included in this analysis were re- study. This measure gives the effect size of
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