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- Technology Assessment,1997 bb). A meta-meta-).A amitriptyline.The overall OR for dropping 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:

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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 criteria for depression. Nearly half of the corded. If the HDRS was not employed,we an intervention in units of standard devi- studies 47%) provided a comprehensive extracted the mean scores at end-point on ation so that scores from different outcome description of patients' side-effects,while the MADRS or on any other rating scale. scales can be combined into an overall 23 12%) trials gave inadequate details. Mean scores were recorded with the stand- estimate of effect. A random effects model, The outcome assessment was performed ard deviation s.d.) or standard error s.e.) which takes into consideration any with valid and reliable instruments in 70% of these values. When only the s.e. was re- between-studybetween-study variation,was adopted to of the sample; the use of valid instruments ported,it was converted into s.d. according combine the effect sizes. Calculations were in studies published before and after 1980 to Altman & Bland 1996). performed using the RevMan software pro- increased from 51 55%) to 81 86%). vided by the Cochrane Collaboration Statistical analysis Review Manager,1999). Efficacy data were analysed in the follow- Efficacy of amitriptyline ing way. Responders to treatment were RESULTSRESULTS Data extracted from 82 RCTs showed that calculated on an intention-to-treat ITT) the proportion of patients who responded basis: drop-outs were always included in Characteristics of included studies to amitriptyline was 2.4% higher than for this analysis. When data on drop-outs were We identified 352 potentially relevant control TCA/heterocyclic antidepressants carried forward and included in the efficacy studies: 186 RCTs met the inclusion criteria NNTB 42,95% CI NNTH 357 to ?? toto evaluation last observation carried for- and were considered in this review see NNTB 20) see Table 2). This difference ward,LOCF),they were analysed accord- Appendix),while 166 studies were corresponds to an overall odds ratio which ing to the primary studies; when drop- excluded for the reasons listed in Table 1. favoured amitriptyline Peto odds ratio outs were excluded from any assessment Of the 186 included studies,146 compared 1.11,95% CI 0.99±1.25),but with only in the primary studies they were considered amitriptyline with another TCA or hetero- borderline statistical significance. The esti- as `drug failures'. Scores from continuous cyclic antidepressant and 40 compared mate of the efficacy of amitriptyline and outcome scales could not be analysed on amitriptyline with one of the SSRIs. In six control TCAs/heterocyclic antidepressants an ITT basis. This approach was not studies amitriptyline was administered in on a continuous outcome,performed on feasible as most studies performed only combination with perphenazine; in two of 699 and 661 patients respectively,revealed an end-point or LOCF analysis,which these studies the experimental drug was an effect size which also significantly

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Ta b l e 11Tab Studies identified by the electronic search but excluded from the meta- Ta b l e 11Tab continued)continued) analysis, and reason for exclusion Study Reason for exclusion Study Reason for exclusion De Montigny et aletal,,1983 1983Lithium augmentation study Abou & Coppen, 1983Amitriptyline is not one of the randomised Denker, 1971Not randomised trial treatmentstreatments Elwan et aletal,,1976 1976Efficacy and safety data are not available AbramAbram et aletal, 1963Amitriptyline is not one of the randomised Fernstrom & Kupfer, Efficacy and safety data are not available treatmentstreatments 1988 Altamura et aletal,,1988 1988Subsample of Altamura et aletal ,1989aa)) Friedel et aletal,,1979 1979Efficacy and safety data are not available Angst, 1963 Not randomised trial Friedman et aletal, 1980Efficacy and safety data are not available Anonymous, 1971Efficacy and safety data are not available Ghose et aletal,,1976 1976Efficacy and safety data are not available Anton & Burch, 1993 Same efficacy/safety of Anton & Burch ,1990) Giedke et aletal, 1986Oxaprotiline as the experimental drug ArfwidssonArfwidsson et aletal,,1972 1972Amitriptyline is not one of the randomised Giedke et aletal,,1987 1987Oxaprotiline as the experimental drug treatmentstreatments Giller et aletal,1985, 1985 Amitriptyline v. placeboplacebo Bagheri et aletal, 1994Amitriptyline is not one of the randomised GlassmanGlassman et aletal,,1977 1977Not randomised trial treatmentstreatments Glatzel, 1967Not randomised trial Bagheri et aletal, 1997Amitriptyline is not one of the randomised GoldbergGoldberg et aletal,,1981 1981Same efficacy/safety data of Goldberg & Finnerty treatmentstreatments ,1980) and Rickels & Case ,1982) Baldini & Neary, 1970Amitriptyline is not one of the randomised GoodwinGoodwin et aletal,,1982 1982Non-responder patients treatmentstreatments GuyGuy et aletal,,1982 1982Efficacy and safety data are not available Ball & Kiloh, 1959Amitriptyline is not one of the randomised Hackett et aletal, 1967,1967Efficacy and safety data are not available treatmentstreatments Haider, 1967 Amitriptyline v. amitriptyline/chlordiazepoxide BanBan et aletal, 1982People without a primary diagnosis of depression Hanin, 1985 Same efficacy/safety data of Kocsis et aletal ,1986),1986) BaumannBaumann et aletal, 1985Amitriptyline is not one of the randomised Healy et aletal,,1984 1984Same efficacy/safety data of Carney et aletal ,1984) treatmentstreatments Herceg et aletal,,1979 1979Psychotherapy trial Bercel, 1967Not randomised trial Hoenig & Visram, 1964 Not randomised trial BeresewiczBeresewicz et aletal, 1991Not randomised trial Hollister et aletal, 1964,1964Efficacy and safety data are not available Bergener, 1968Amitriptyline v.v. Rd 292 Horden et aletal, 1963Same efficacy/safety data of Burt et aletal ,1962),1962) Bialos et aletal,1982, 1982 Amitriptyline v.v. placeboplacebo Horden et aletal, 1964Same efficacy/safety data of Burt et aletal ,1962),1962) Blaine, 1975 People without a primary diagnosis of depression Hutchinson & Efficacy and safety data are not available BlashkiBlashki et aletal,1971Amitriptyline v.v. amylobarbitone Smedberg, 1963 Bolzani & Slivar, 1967Not randomised trial Jakitowicz, 1991Not randomised trial trial Bowden et aletal,,1987 1987Same efficacy/safety data of Kocsis et aletal ,1986) Katz et aletal,,1987 1987Same efficacy/safety data of Kocsis et aletal ,1986),1986) Branconnier et aletal,,1981 1981Efficacy and safety data are not available Katz et aletal,1993, 1993 Amitriptyline v. oxaprotiline v. levoprotiline BrickBrick et aletal, 1965Crossover trial Kieback, 1982aa Efficacy and safety data are not available Brown et aletal, 1980Efficacy and safety data are not available Kieback, 1982bb Efficacy and safety data are not available Browne et aletal,1963, 1963 Amitriptyline v.v. placeboplacebo KilohKiloh et aletal, 1962Not randomised trial BurchBurch et aletal,,1988 1988Not randomised trial Klein et aletal, 1998Amitriptyline is not one of the randomised treatments BurgessBurgess et aletal,,1979 1979Efficacy and safety data are not available Koch, 1990 Efficacy and safety data are not available CasperCasper et aletal, 1994Same efficacy/safety data of Kocsis et aletal ,1986) Kocsis et aletal, 1990Same efficacy/safety data of Kocsis et aletal ,1986),1986) Chaplan, 1975People without a primary diagnosis of depression KonigKonig et aletal, 1994Amitriptyline is not one of the randomised treatments CharneyCharney et aletal,1984,1984aa Efficacy and safety data are not available Kopera, 1980Efficacy and safety data are not available CharneyCharney et aletal,1984,1984bb Amitriptyline is not one of the randomised Koszewska et aletal, 1994Not randomised trial treatmentstreatments KowalskiKowalski et aletal,,1985 1985People without a primary diagnosis of depression ClaghornClaghorn et aletal,,1984 1984Efficacy and safety data are not available Krakowski, 1968Not randomised trial Collard et aletal,,1978 1978Crossover trial KramerKramer et aletal,,1989 1989People without a primary diagnosis of depression CookeCooke et aletal, 1984Amitriptyline is not one of the randomised KupferKupfer et aletal,1977,1977Amitriptyline v. placeboplacebo treatmentstreatments KupferKupfer et aletal,1979,1979Amitriptyline v. placeboplacebo Coppen, 1978Not randomised trial KussKuss et aletal,1984, 1984 Amitriptyline v. amitriptyline-N-oxide CoppenCoppen et aletal,,1976 1976Efficacy and safety data are not available Lambourn & Rees, Efficacy and safety data are not available CoppenCoppen et aletal,,1987 1987Same efficacy/safety data of Coppen et aletal ,1976),1976) 1974 Croughan et aletal, 1988Efficacy and safety data are not available Leyburn, 1967Not randomised trial DavidsonDavidson et aletal, 1978Electroconvulsivetherapy v. amitriptylinephenelzine LiisbergLiisberg et aletal,1978, 1978 Amitriptyline v. sustained release amitriptyline

continued)continued) continued overleaf)

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TaTable b l e 1 continued)continued) Ta b l e 11Tab continued)continued)

StudyReason for exclusion Study Reason for exclusion

Lloyd et aletal,,1981 1981Efficacy and safety data are not available Renfordt & Bush, 1976Efficacy and safety data are not available LyonsLyons et aletal,,1985 1985Amitriptyline is not one of the randomised ReynoldsReynolds et aletal, 1969Not randomised trial treatmentstreatments Rickels et aletal,1974Amitriptyline v. placebo Maier et aletal,,1989 1989Efficacy and safety data are not available RobinsonRobinson et aletal, 1972Not randomised trial Marey et aletal, 1991,1991Not randomised trial RobinsonRobinson et aletal,1985, 1985 Amitriptyline v. phenelzine Marjerrison et aletal,, Efficacy and safety data are not available Rockcliffe, 1971Not randomised trial 19691969 Rouillon et aletal, 1989Amitriptyline is not one of the randomised Martin & Leahy,1968Same efficacy/safety data of Leahy & Martin ,1967) treatments Mathur, 1975Crossover design Rydzynski, 1966Amitriptyline is not one of the randomised Mattila et aletal, 1978Crossover design treatments McConaghy & Joffe, Same efficacy/safety data of McConaghy et aletal ,1965),1965) Saletu et aletal,,1979 1979Efficacy and safety data are not available 19681968 Sanger, 1969People without a primary diagnosis of depression McNair et aletal,,1984 1984aa Crossover design Schweizer, 1993People without a primary diagnosis of depression McNair et aletal,,1984 1984bb Crossover design Simpson et aletal,1972, 1972 Amitriptyline v. thiothixene Mindham, 1981Amitriptyline is not one of the randomised Sims, 1972 Sustained-release amitriptyline v. amitriptyline treatmentstreatments Snow & Rickels, 1964Crossover design design Montgomery et aletal,, Efficacy and safety data are not available StassenStassen et aletal, 1996Not randomised trial 1978 Stjean et aletal, 1966Amitriptyline Amitriptylineisnotone is not one ofthe therandomisedtreatments randomised treatments Moyes et aletal, 1980,1980Efficacy and safety data are not available Stratas, 1984Efficacy and safety data are not available Muck-Seler etaletal,1991,1991Efficacy and safety data are not available Stromberg et aletal, 1991People without a primary diagnosis of depression Murphy, 1975Efficacy and safety data are not available Sullivan et aletal,,1977 1977Efficacy and safety data are not available Myers & Calvert, Amitriptyline is not one of the randomised Swann et aletal, 1990Same efficacy/safety data of Kocsis et aletal ,1986) 19761976 treatmentstreatments Symes, 1967 Amitriptyline is not one of the randomised Myers & Efficacy and safety data are not available treatments Branthwaite, 1992 TaraganoTaragano et aletal, 1997People without a primary diagnosis of depression NahunekNahunek et aletal, 1964Not randomised trial Trick, 1975 Same efficacy/safety data of Trick ,1975) Oliver-Martin et aletal,, Amitriptyline is not one of the randomised Van De Merwe et aletal,, Efficacy and safety data are not available 1975 treatmentstreatments 1984aa Oltman & Friedman, Not randomised trial Van De Merwe et aletal,, Efficacy and safety data are not available 19631963 1984bb Oltman & Friedman, Not randomised trial VanVanScheyen&Van Scheyen & Van Efficacy and safety data are not available 19641964 Kammen, 1979 Ose, 1971 Noxiptiline as the experimental drug Vartanyan, 1984Efficacy and safety data are not available Pearce & Rees, 1974Amitriptyline is not one of the randomised VeithVeith et aletal,,1982 1982Efficacy and safety data are not available treatmentstreatments Vinar & Grof, 1964Not randomised trial Peet et aletal,,1977 1977Efficacy and safety data are not available Vogel et aletal,,1976 1976Efficacy and safety data are not available PennesePennese et aletal, 1993People without a primary diagnosis of depression VonArnold&Foitl,1961 Not randomised trial Peselow et aletal, 1986Not randomised trial Von Arnold & Heves, Not randomised trial Petrie et al,al, 1980Amitriptyline is not one of the randomised 1967 treatmentstreatments Von Bergener, 1968Efficacy and safety data are not available Post & Goodwin, Efficacy and safety data are not available Von Plavec & Not randomised trial 19741974 Steininger, 1968 Preskorn et aletal,,1984 1984Efficacy and safety data are not available Von Rosenberg,1974Rosenberg, 1974 Noxiptiline as the experimental drug Pressman & Weiss, Not randomised trial Weiss & Pressman,1961No random allocation 1961 Weissman, 1976Same efficacy/safety data of Weissman et aletal ,1975),1975) PrusoffPrusoff et aletal,,1976 1976Same efficacy/safety data of Weissman et aletal ,1975) Welner et aletal, 1980Not randomised trial Pugh, 1983Same efficacy/safety data of Pugh et aletal ,1982) Wheatley, 1967Imipramine v. phenobarbitone, amitriptyline RajotteRajotte et aletal, 1966Opipramol as the experimental drug v.v. amitriptyline/chlordiazepoxide RaoRao et aletal, 1996Same efficacy/safety data of Moller et aletal ,1995),1995) Wilkins et aletal,,1989 1989Efficacy and safety data are not available Rechlin, 1994Efficacy and safety data are not available Wilson et aletal, 1963Amitriptyline is not one of the randomised treatments Rees & Risdall, 1976Not randomised trial Wittenborn et aletal, 1973Efficacy and safety data are not available Reisby et aletal,,1977 1977Amitriptyline is not one of the randomised Yamamoto et aletal,,1972 1972Amitriptyline is not one of the randomised treatmentstreatments treatments

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favoured amitriptyline SMDˆ0.177,95% ratio 1.14,95% CI 0.92±1.38),but not sig- failed to complete the study,in com- CI 0.005±0.350). Head-to-head compari- nificantly. The estimate of the efficacy of parison with 21.5% of patients who sons indicated that amitriptyline,in com- amitriptyline and SSRIs on a continuous received another tricyclic/heterocyclic anti- parison with imipramine,is associated outcome,performed on 1041 and 1061 pa- depressant NNTBˆ69,95% CI NNTH with a greater proportion of responders; tients,respectively,revealed a small effect 385 to385to ?? to NNTB 32). This difference in comparison with dothiepin,however, size which significantly favoured amitripty- corresponded to an overall odds ratio the proportion of responders was signifi- line SMDlineSMDˆ0.106,95% CI 0.02±0.19). No non-significantly favouring amitriptyline cantly lower see Table 2). significant differences emerged from direct Peto odds ratio 1.09,95% CI 0.98±1.22) Data from 17 RCTs showed that the comparisons between amitriptyline and see Table 4). However,the estimate of proportion of patients who responded to one of the SSRIs see Table 3). the proportion of patients who experienced amitriptyline was 2.8% higher than for side-effects during the study was 13% high- SSRIs NNTB 35,95% CI NNTH 53 to er for amitriptyline than for control TCAs/ ?? to NNTB 13) see Table 3). This differ- Tolerability of amitriptyline heterocyclic antidepressants NNTHˆ7.6,7.6, ence corresponded to an overall odds ratio Data from 125 RCTs showed that 20% 95% CI NNTH 6 to NNTH 11) see Table which favoured amitriptyline Peto odds of patients treated with amitriptyline 4),corresponding to an odds ratio which

Ta b l e 22Tab Amitriptyline ,AMI) in comparison with tricyclic ,TCA) or heterocyclic antidepressants: proportion of responders, number of patients evaluated ona continuous outcome and estimates of efficacy

Responders/total randomised11 Patients evaluated on a continuous outcome22 RespondersMean score at end-point

44 ,No. of trials) TCA AMI ,No. of trials) TCA AMI ,intention to treat) SMDSMD ,95% CI)CI),95% Peto-odds ratio 33

Control TCA/heterocyclic drug Amineptine ,1) 21/26 14/25 ,2),2) 42 4747 0.32 ,0.10^1.04) 0.397 ,,0.397 772.78 to3.58) AmoxapineAmoxapine ,11),11) 180/298 199/303 ,1) 17 21 1.28 ,0.91^1.81) 0.099 ,,0.099 770.54 to0.74) Clomipramine ,1) 20/3520/35 13/3713/37 ,1) 35 3737 0.42 ,0.17^1.05) 770.236 ,,0.236 770.70 to0.23) Desipramine ,3),3) 41/77 39/6939/69 ,2),2) 43 3939 1.20 ,0.62^2.31) 0.422 ,,0.422 770.01 to0.86) DothiepinDothiepin ,5) 87/114 74/11674/116 ,2),2) 46 4747 0.54 ,0.31^0.96) 0.015 ,,0.015 770.39 to0.42) Doxepin ,8),8) 100/161 103/170 ,^) 1.00 ,0.63^1.59) 77 ImipramineImipramine ,9),9) 141/285 177/293 ,^) 1.71 ,1.20^2.43) 77 Lofepramine ,6),6) 129/189 116/187 ,3),3) 57 5454 0.75 ,0.49^1.16) 770.002 ,770.48 to0.47) Maprotiline ,12) 217/343 207/340207/340 ,5) 71 6868 0.90 ,0.65^1.26) 0.324 ,770.06 to0.71) MianserinMianserin ,5) 70/133 65/109 ,3),3) 39 3838 1.37 ,0.82^2.29) 0.252 ,,0.252 770.20 to0.71) MinaprineMinaprine ,1) 15/3015/30 17/3017/30 ,1) 2828 3030 1.30 ,0.48^3.56) 0.173 ,770.34 to0.69) Nortriptyline ,4),4) 55/104 55/93 ,2),2) 33 32 1.36 ,0.77^2.40) 770.140 ,770.63 to0.35) Protriptyline ,1) 17/5117/51 27/4927/49 ,^) 2.40 ,1.09^5.26) 77 Tianeptine ,2),2) 204/285204/285 218/280218/280 ,1) 103 108 1.40 ,0.95^2.06) 0.180 ,770.09 to0.45) Trazodone ,7),7) 149/271 149/276149/276 ,4),4) 145 98 0.94 ,0.66^1.33) 0.273 ,0.01 to0.54) Trimipramine ,1) ,/13,/13 7/13 ,1) 17 1717 0.54 ,0.11^2.52) 0.251 ,,0.251 770.42 to0.93) Viloxazine ,3),3) 25/5725/57 35/60 ,1) 23 2525 1.76 ,0.84^3.67) 0.379 ,,0.379 770.19 to0.95) Combination ,2),2) 25/6825/68 17/3717/37 ,^) 1.59 ,0.69^3.71) 77 Overall comparison 1.11 ,0.99^1.25)0.177 ,0.005^0.350) Test of heterogeneity ww22ˆ108.4 ,d.f.ˆ81), ww22ˆ63.2 ,d.f.,d.f.63.2 ˆ28),28), ZZˆ1.78, PP550.050.05 ZZˆ2.01, PP550.050.05

1. The following studies were included in this analysis: Aberg & Holmberg ,1977); Amin et al ,1973);Anton&Burch,1990);Ather,1973); Anton & Burch ,1990); Atheret al ,1985); Beckman & Goodwin ,1975); Bianchi et aletal ,1971); Browne ,1969); Burke et al ,1967); Burrows et aletal ,198,1980); 0); BurtBur t et aletal ,1962); Carney et aletal ,1984); Click & Zisook ,1982); Deering & Valle-JonesValle© -Jones ,1974); Del Zompo et aletal ,1990 ^91); Delaunay & Meynard ,1978); Donlon et aletal ,1981); Doongaji et al ,1993); Dorn ,1980); Feighner et aletal ,1983); Forrest et al ,1964); Fruensgaard et aletal ,1979); Goldberg & Finnerty ,1977, 1980);19 8 0); Goldstein & Pinosky ,1969); ,1969); Gomez-MarGomez-Martinez tinez ,1968); ,1968); Guelfi Guelfi et al ,1989); Guy et al ,1983); Invenizzi et al ,1994); James ,1982); Kampman et al ,1978); Kaumier & Haase ,1980); KerrKerr et aletal ,1984); Kilohet al ,1979); Klieser & Lehmann ,1988); Kocsis et al ,1986); Lauritsen & Madsen ,1974); Levin ,1974); Lipsedge & Rees ,1971); Marais ,1974); Mariategui et al ,1978); Marneros & Philipp ,1979); Mason et al ,1990); McClelland et aletal ,1979); McConaghy et al ,1965); Mendlewicz et aletal ,1980); Mendlewicz et aletal ,1982); Metha et al ,1980); Mindham ,1977); Moises et al ,1981); Moller et aletal ,1995); Montbrun & Obermair ,1976); Montgomeryet al ,1980); Naftulin & Ware ,1972); Nieto& Rincon,1973); Okasha Okasha & & Sadek Sadek ,1976); ,1976); Petrie Petrie et aletal ,1982); Prusoff et aletal ,1981); Quadri et al ,1980); Querol ,1970); Rees & Cryer ,1976); Rego & Sanchez DeVega ,1974); Richels & Case ,1982); Richmond & Roberts ,1964); Roseet aletal ,1965); Rush et aletal ,1988,1989);,1988,1989);Rybakowskiet Rybakowski etalal ,1991); Sandifer et al ,1965); Sedman ,1977); Sethi et al ,1979); Shipleyet al ,1985); Solis et aletal ,1970); Stier et al ,1982); Straker et al ,1966); Tor uToru et aletal ,1972); Trick ,1975); Van Amerongen ,1979); Veith et al ,1983);VonBauer&Nowak,1969);Waiteet al ,1986); Watanabe et aletal ,1978); Ziegler et al ,1977).,1977). 2. The following studies were included in this analysis: Altamura et al ,1989,1989aa); Anton & Burch ,1990); Bennie & Schiff ,1976); Blacker et aletal ,1988); Cournoyeret aletal ,1987); Deering & ValleValle-Jones© -Jones ,1974); Del Zompo et al ,1990,1990^91); ^91); Dorman ,1980); ,1980); Dorn Dorn ,1980); ,1980); Guelfi Guelfiet al ,1989); Kampman et al ,1978); Kay & Davies ,1974); KlieserKlieser& & Lehmann ,1988); Lehmann et aletal ,1982); Mariategui et aletal ,1978); McCallum & Meares ,1975); McClelland et al ,1979); Metha et aletal ,1980); Moises et al ,1981); Monteleone & Fabrazzo ,1994); Montgomeryet al ,1980); Nugent ,1979); Rabkin et al ,1984); Rampello et al ,1995); Shipley et al ,1985); Sims ,1980); Stier et al ,1982); Van Amerongen ,1979); Veith et aletal ,1983). 3. Odds ratio 441favours amitriptyline, odds ratio 5511favourscontroldrug. favours control drug. 4. SMD, standardised mean difference; SMD 440favoursamitriptyline,SMD550 favours control drug. drug.

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TaTable b l e 3 Amitriptyline ,AMI) in comparison with selective serotonin reuptake reuptake inhibitors inhibitors ,SSRIs): ,SSRIs): proportion proportion of of responders, responders, number number of of patients patients evaluated evaluated o on a continuous outcome and estimates of efficacy

Responders/total randomised11 Patients evaluated on a continuous outcome22 RespondersMean score at end-point ,intention to treat) SMD44 ,95% CI)CI),95% ,No. of trials)SSRI AMI ,No. of trials)SSRI AMI Petoodds ratio 33 ,95% CI)CI),95%

Control SSRI Fluoxetine ,5) 77/14677/146 70/145 ,9),9) 336336 341341 0.83 ,0.52^1.33) 0.113 ,770.04 to0.27) Fluvoxamine ,1),1) 16/35 22/3422/34 ,2),2) 4040 43 2.13 ,0.83^5.46) 0.291 ,770.41 to0.99) Sertraline ,^),^) ,2),2) 173 174174 ^^ 0.109 ,770.10 to0.32) Paroxetine ,9),9) 266/487266/487 267/455267/455 ,7) 468 483 1.21 ,0.93^1.58) 0.114 ,,0.114 770.04 to0.27) Citalopram ,2),2) 104/206104/206 112/210112/210 ,1),1) 2424 2020 1.11 ,0.76^1.63) 770.077 ,770.67 to0.52) Overall comparison 1.14 ,0.94^1.38)0.106 ,0.02^0.19) Testof heterogeneity ww22ˆ11.27 ,d.f.,d.f.11.27 ˆ16),16), ww22ˆ19.65 ,d.f.ˆ20),20), ZZˆ1.31, PPˆ0.79 ZZˆ2.42, PPˆ0.480.48

1. The following studies were included in this analysis: Bascara ,1989); Battegay et al ,1985); Bignamini & Rapisarda ,1992); Christiansen et aletal ,1996); Demyttenaere et al ,1998); Faw- cettcett et aletal ,1989); Geretsegger et al ,1995); Gravem et aletal ,1987); Harris et al ,1991); Hutchinson et al ,1992); Keegan et al ,1991); Kyle et al ,1998); Laursen et al ,1985); Masco& Sheetz ,1985); Peters et aletal ,1990); Staner et al ,1995); Stuppaek et al ,1994). 2. The following studies were included in this analysis: Bersani et al ,1994); Christiansen et al ,1996); De Ronchiet al ,1998); Demyttenaere et al ,1998); Fawcett et al ,1989); Harris et al ,1991); Judd et aletal ,1993); Kuhs & Rudolf ,1989); Laakmann ,1991); Laakmann et al ,1988); Laursen et aletal ,1985); Marchesi et al ,1998); Moller et al ,1993); Peters et aletal ,1990); Reimherr et al ,1990); Remick et al ,1994); Shaw et al ,1986); Staner et al ,1995); Stott et al ,1993); Stuppaek et aletal ,1994); Young et al ,1987).,1987). 3. Odds ratio 441favours1 favours amitriptyline, odds ratio ratio 5511favourscontroldrug. favours control drug. 4. SMD, standardised mean difference; SMD 4400favoursamitriptyline,SMD favours amitriptyline, SMD 5500favourscontroldrug. favours control drug.

significantly favoured the control TCAs/ of amitriptyline in comparison to TCAs/ included in the analysis ± we estimated that heterocyclic antidepressants. Head-to-head heterocyclic drugs and SSRIs showed a amitriptyline is slightly more efficacious comparisons failed to detect statistically 2.5% difference in the proportion of respon- than all other antidepressants grouped significant differences in terms of drop-outs ders in favour of amitriptyline NNTBˆ40,40, together. The same applied when the analy- between amitriptyline and one of the TCA/ 95% CI NNTB 21 to NNTB 694) see Fig. sis was subdivided according to pharmaco- heterocyclic antidepressants see Table 4). 2),which corresponded to an intention to logical class of the comparison drug ± However,amitriptyline was associated treat odds ratio of 1.12 95% CI 1.01± although the comparison with SSRIs failed with more side-effects than dothiepin, 1.24). The estimate of the efficacy of ami- to reach statistical significance. This mea- maprotiline,mianserin,minaprine and nor- triptyline and control antidepressants on a sure of outcome takes into consideration triptyline see Table 4). continuous outcome confirmed the slightly drop-outs from therapy,so it cannot be Data from 40 RCTs comparing amitrip- superior efficacy profile of amitriptyline: explained by differential completion of the tyline and SSRIs showed that 29.8% of the estimate of the SMD significantly favours study protocol. The additional efficacy out- patients treated with amitriptyline failed to amitriptyline see Fig. 2). come ± using effect sizes of continuous out- complete the study,in comparison with The drop-out rate in patients taking comes ± showed a similar picture,but now 27.7% of patients treated with SSRIs amitriptyline and the control antidepres- with a statistically significant difference NNTHNNTHˆ49,95% CI NNTB 180 to ?? toto sants was very similar,yielding an overall against the SSRIs. The tolerability data con- NNTH 22). This difference corresponds to odds ratio of 0.99 95% CI 0.91±1.08). firm that amitriptyline is associated with an overall odds ratio of 0.86 95% CI However,the estimate of the proportion more side-effects than,but similar drop- 0.75±0.98),which significantly favoured of patients who experienced side-effects outs to,other TCAs,and more side-effects SSRIs see Table 5). The estimate of the during the study was 13.1% higher for and more drop-outs than SSRIs. proportion of patients who experienced amitriptyline than control antidepressants side-effects during the study was 11.6% NNTHNNTHˆ7.6,95% CI NNTH 6 to NNTH higher for amitriptyline than for SSRIs 10),corresponding to an odds ratio which Methodological concerns NNTHNNTHˆ8.6,95% CI NNTH 6 to NNTH significantly favoured the control anti- There are reasons for interpreting these 15) see Table 5),corresponding to an odds depressantsdepressantsseesee Fig. 2). results with caution. Included studies are ratio which significantly favoured the heterogeneous in terms of selection criteria, SSRIs.SSRIs. allocation concealment,setting and out- DISCUSSION come measures. A certain variability in the overall quality of the primary research Overall efficacy and tolerability Implications for research might therefore have influenced the overall of amitriptyline in comparison This systematic review suggests that ami- comparison. This systematic review did not with all antidepressant drugs triptyline should remain in its position as investigate heterogeneity by grouping trials A funnel plot Fig. 1) showed no evidence of the gold-standard antidepressant. Using a according to patient characteristics or trial publication bias being a problem in the data highly conservative approach to estimate quality and performing subgroup analyses. collected. The overall estimate of the efficacy efficacy ± in which drop-outs were This approach was not adopted because it

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Ta b l e 44Tab Amitriptyline ,AMI) in comparison with tricylcic/heterocyclic antidepressants ,TCAs): proportion of drop-outs, proportion of patients with side-effects and estimates of tolerability

Responders/total randomised11 Patients evaluated on a continuous outcome22 Drop-outs33 Patients with side-effects Petoodds ratio 44 Petoodds ratio 44 ,95% CI)CI),95% ,No. of trials) TCA AMI ,No. of trials) TCA AMI ,95% CI)CI),95%

Control TCA/heterocyclic Amineptine ,2),2) 8/488/48 7/477/47 ,1) 6/26 10/25 1.14 ,0.38 ^ 3.39) 0.46 ,0.14^1.49) AmoxapineAmoxapine ,13),13) 94/359 89/36389/363 ,3),3) 59/9759/97 63/9563/95 1.09 ,0.77^1.54) 0.77 ,0.41^1.44) Clomipramine ,3),3) 73/14873/148 59/15159/151 ,1) 18/3518/35 16/3716/37 1.52 ,0.95^2.41) 1.38 ,0.55^3.47) Desipramine ,4),4) 10/82 13/74 ,^) 0.72 ,0.28^1.84) ^^ DothiepinDothiepin ,8),8) 12/196 18/20018/200 ,5) 51/11551/115 70/119 0.68 ,0.32^1.47) 0.51 ,0.29^0.88) Doxepin ,13),13) 88/427 103/433103/433 ,4),4) 46/76 61/9261/92 0.84 ,0.60^1.17) 0.77 ,0.39^1.50) ImipramineImipramine ,6),6) 25/17225/172 24/177 ,2),2) 17/7117/71 25/85 1.34 ,0.71^2.51) 0.73 ,0.35^1.50) Lofepramine ,8),8) 54/236 61/234 ,2),2) 12/31 19/3119/31 0.85 ,0.55^1.32) 0.39 ,0.14^1.08) Maprotiline ,18) 86/55786/557 88/55088/550 ,7),7) 136/224136/224 154/212 0.97 ,0.69^1.35) 0.59 ,0.40^0.88) MianserinMianserin ,12) 123/410123/410 96/37796/377 ,3),3) 73/135 101/13110 1/131 1.27 ,0.91^1.77) 0.34 ,0.20^0.57) MinaprineMinaprine ,2),2) 115/429 31/162 ,2),2) 117/429117/429 67/162 1.50 ,0.98^2.29) 0.55 ,0.37^0.82) Nomifensine ,1) 1/171/17 1/12 ,^) 0.69 ,0.04^12.1) ^^ Nortriptyline ,8),8) 27/235 26/23226/232 ,4),4) 42/124 52/10252/102 1.01 ,0.56^1.83) 0.51 ,0.30^0.87) Protriptyline ,^) ,1) 38/5138/51 33/4933/49 ^^ 1.41 ,0.60^3.33) Tianeptine ,3),3) 80/34980/349 65/34565/345 ,^) 1.28 ,0.89^1.85) ^^ Trazodone ,10) 79/35779/357 72/362 ,2),2) 53/113 54/110 1.14 ,0.79^1.65) 0.92 ,0.54^1.55) Trimipramine ,2),2) 11/5811/58 13/5713/57 ,1) 3/213/21 5/205/20 0.76 ,0.30^1.97) 0.51 ,0.11^2.36) Viloxazine ,7),7) 24/14024/140 21/148 ,1) 14/1914/19 16/2216/22 1.32 ,0.69^2.55) 1.05 ,0.27^4.12) Combinations ,5) 84/40984/409 32/164 ,1) 68/8968/89 37/4637/46 1.05 ,0.66^1.69) 0.79 ,0.34^1.86) Overall comparison 1.09 ,0.98^1.22)0.62 ,0.53^0.73) Test of heterogeneity ww22ˆ118.1 ,d.f.,d.f.118.1 ˆ109)109) ww22ˆ53.3 ,d.f.ˆ39)39) ZZˆ1.60, PP550.05 ZZˆ5.90, PPˆ0.06

1. The following studies were included in this analysis: Aberg & Holmberg ,1977); Altamura et al ,1989aa); Amin et al ,1973); Amin et al ,1978); AntonAnton& & Burch Burch ,1990); ,1990); Ather Atheret aletal ,1985);,1985); BalestrieriBalestrieri et aletal ,1971); Beckmann & Goodwin ,1975); Bennie & Schiff ,1976); Bianchi et al ,1971); Blacker et al ,1988); Botros et al ,1989); Browne ,1969); ,1969); Burrows Burrowset al ,1980); Carman et aletal ,1991); Carney et al ,1984); Click & Zisook ,1982); Cournoyeret al ,1987); Dahl et al ,1981);,1981);Daly&Browne,1979);Deering&Valle-Jones,1974);DelZompo Daly & Browne ,1979); Deering & Valle© -Jones ,1974); Del Zompo et al ,1990 ^91); Delaunay & Meynard ,1978); Dell ,1977); Donlon et al ,1981); Doongaji et al ,1993); Dorman ,1980); Dorn ,1980); ,1980); Edwards Edwards et aletal ,1996); Feighner et al ,1983); Ferrari et aletal ,1987); Forrest ,1975); Fruensgaard et al ,1979); Goldberg & Finnerty ,1980); Goldstein & Pinosky ,1969); Gomez-Martinez ,1968); Grof et al ,1974); Guelfi et al ,1989); Guyet al ,1983); Harding ,1973); Hekimian et aletal ,1978); Invenizzi et al ,1994);James,1994); James ,1982); Jaskariet aletal ,1977); Kampman et aletal ,1978); Kaumier et al ,1980); Kay & Davies ,1974); Kerr et al ,1984);Khan,1984); Khan ,1981);Khan,1981); Khanet al ,1982); Kiloh et al ,1979); Klieser & Lehmann ,1988); Kocsis et al ,1986); Lapierre et al ,1980); Lauritsen & Madsen ,1974); Leahy & Martin ,1967); Lehmann et al ,1982); Lennox et al ,1978); Levin ,1974); Logaet al ,1992); Loo et al ,1988); Lopez-Ibor Alinoet al ,1979); Magnus & Schiff ,1977); Marais ,1974); Mariategui et al ,1978); Marneros & Philipp ,1979); Mason etet alal ,1990); McCallum & Meares ,1975); McClelland et al ,1979); Melode Paula et al ,1977); Mendels ,1968); Mendlewicz et al ,1980); Mendlewicz et al ,1982); Metha et al ,1980); Mindham ,1977); Moises et al ,1981); Moller et al ,1995); Montbrun & Obermair ,1976); Monteleone & Fabrazzo ,1994); Montgomeryet al ,1980); Muller-Oerlinghausen et al ,1979); Murphy & Ankier ,1980); Murphy & Bridgman ,1978); Naftulin & Ware ,1972); Nelson et al ,1982); Nieto& Rincon,1973); Nugent ,1979); Okasha & Sadek ,1976); Petrie et al ,1982); Prusoff et al ,1981); Pugh et al ,1982); Quadri et aletal ,1980);,1980);Querol,1970);Rampello Querol ,1970); Rampello et al ,1995); Rees & Cryer ,1976); Richels & Case ,1982); Richels et aletal ,1982); Richels et aletal ,1970,1972,1974,1985); RoseRose et aletal ,1965); Rush et al ,1989); Sandifer et aletal ,1965); Sedman ,1977); Sethi et al ,1979); Shipleyet al ,1985); Silverstone ,1977); Sims ,1980); Sinclair et al ,1975); Soliset al ,1970); Stier et aletal ,1982); Straker et al ,1966); Toru et al ,1972); Trappe ,1973);Trick,1973); Trick ,1975); Van Amerongen ,1979); Veith et al ,1983);VonBauer&Nowak,1969);Waiteet al ,1986); Watanabe et aletal ,1978); Weissman et al ,1975); Wilcoxet al ,1994); Wright & Hermann ,1976); Ziegler et al ,1977).,1977). 2. The following studies were included in this analysis: Aberg & Holmberg ,1977); Ather et al ,1985); Balestrieri et al ,1971); Browne ,1969); Click & Zisook ,1982); Deering & ValleValle-© - Jones ,1974); Del Zompo et al ,1990 ^91); Delaunay & Meynard ,1978); Dorman ,1980); Edwards et al ,1996); Feighner et aletal ,1983); Forrest et al ,1964); Goldberg & Finner ty ,1977, 1980); Goldstein & Pinosky ,1969); Gomez-Martinez ,1968); ,1968); Kampman Kampmanet al ,1978);,1978);Khan,1981);Kline,1982);Lauritsen&Madsen,1974);Leahy&Martin,1967);Lennox Khan ,1981); Kline ,1982); Lauritsen & Madsen ,1974); Leahy & Martin ,1967); Lennoxet al ,1978); Magnus & Schiff ,1977); Marais ,1974); Marneros & Philipp ,1979); McConaghy et aletal ,1965); Molnar ,1977); Murphy & Bridgman ,1978); Okasha & Sadek ,1976); Querol ,1970); Rees & Cryer ,1976); Rose et aletal ,1965); Sethi et aletal ,1979); Silverstone ,1977); ,1977); Toru Toruet al ,1972); Trick ,1975); Tsaras & Ambrus ,1981); Van Amerongen ,1979); Wheatley ,1975); Wright & Her- mann ,1976). 3. Including 15 studies without drop-outs. 4. Odds ratio 441favours amitriptyline, odds ratio 551favours1 favours control drug.

would have inevitably decreased the power can be applied to a very diverse range of good as ± if not better than ± the other of the analysis,thus providing ambiguous patients Oxman et aletal,1994).,1994). TCAs and heterocyclic antidepressants, results; in addition,increasing the number with the possible exception of dothiepin of comparisons would have increased the EcclesEccles et aletal,1999). It seems reasonable to possibility of detecting significant differ- Implications for practice suggest that either amitriptyline or encesencesonly by chance. The present analysis, dothiepin should remain the first-line which pools data from different trials car- How should these data be translated into TCA. More controversial is the role of ried out in many populations,has the ad- clinical practice? It certainly seems reason- TCAs alongside SSRIs. The results from vantage of generating information which able to conclude that amitriptyline is as randomised trials suggest that amitriptyline

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TaTable b l e 5 Amitriptyline ,AMI) in comparison with selective serotonin reuptake inhibitors ,SSRIs): proportion of drop-outs, proportion of patients with side-effects and estimates of tolerability

Drop-outs/total randomised11 Patients with side-effects/total randomised22 Drop-outsPatients with Petoodds ratio 33 side-effects ,No. of trials)SSRI AMI ,No. of trials)SSRI AMI 33 ,95% CI)CI),95% Petoodds ratio ,95% CI)CI),95%

SSRISSRI Fluoxetine ,15),15) 124/540124/540 148/551148/551 ,1) 7/207/20 16/21 0.79 ,0.59^1.04) 0.20 ,0.06^0.66) Fluvoxamine ,3),3) 17/81 19/7719/77 ,^) 49/115 52/11352/113 0.84 ,0.39^1.83) ^^ Sertraline ,6),6) 264/650264/650 228/568228/568 ,2),2) 221/366221/366 251/360251/360 0.97 ,0.76^1.23) 0.87 ,0.50^1.50) Paroxetine ,13),13) 205/897205/897 217/882217/882 ,4) 131/206131/206 169/210 0.89 ,0.71^1.12) 0.70 ,0.51^0.96) Citalopram ,3),3) 55/23055/230 75/230 ,2),2) 0.64 ,0.42^0.96) 0.43 ,0.28^0.66) Overall comparison 0.86 ,0.75^0.98)0.61 ,0.48^0.76) Test of heterogeneity ww22ˆ49.6 ,d.f.ˆ39),39), ww22ˆ14.7 ,d.f.ˆ8),8), ZZˆ2.27, PPˆ0.11 ZZˆ4.35, PPˆ0.06

1. The following studies were included in this analysis: Altamura et aletal ,1989bb); Bascara ,1989); Battegay et al ,1985); Bersani et al ,1994); Bignamini & Rapisarda ,1992); Byrne ,1989); Chouinard ,1985); Christiansen et al ,1996); Cohnet al ,1990); De Ronchi et al ,1998); Demyttenaere et al ,1998); Fawcett et al ,1989); Gasperini et al ,1992); Geretsegger et al ,1995); Gravem et aletal ,1987); Harris et al ,1991); Hutchinson et aletal ,1992); Judd et aletal ,1993); Kamijima et al ,1997); Keegan et al ,1991); Kuhs & Rudolf ,1989); Kyle et al ,1998); Laakmann ,1991); LaakmannLaakmann et al ,1988); Laursen et al ,1985); Lydiard et al ,1997); Marchesi et al ,1998); Masco& Sheetz ,1985); Moller et al ,1993,1998),1993, 1998) Peters et al ,1990); Preskorn et al ,1991); Reimherr et aletal ,1990); Remick et al ,1994); Shaw et al ,1986); Staner et aletal ,1995); Stott et al ,1993); Stuppaek et aletal ,1994); Upward et al ,1988);Younget al ,1987,1987). ). 2. The following studies were included in this analysis: Bersani et al ,1994); Geretsegger et al ,1995); Gravem et aletal ,1987);,1987 ); Hutchinson et al ,1992); Kyle et aletal ,1998); Masco& Sheetz ,1985); Moller et aletal ,1998); Staner et al ,1995); Stott et al ,1993). 3. Odds ratio 441favours amitriptyline, odds ratio 551favourscontroldrug.

probably has the edge in terms of efficacy showing that the widespread use of SSRIs over SSRIs. Given that publication bias is decreases suicide rates are lacking Barbui likely to work in favour of newer com- et aletal,1999). The advice should probably pounds,it is possible that unpublished data remain that SSRIs are the first-line treatment would further improve amitriptyline's to be given to patients at high risk of com- position. Those who advocate first-line mitting deliberate self-harm. The problems use of an SSRI point to two additional of TCAs being prescribed in low doses has strands of evidence ± the danger of TCAs attracted considerable attention,as evidence in overdose and the fact that they are oftenareoften suggests that in real situations TCAs are in practice prescribed at sub-therapeutictherapeuticsub- rarely taken appropriately. However,the Fig. 11Fig. Funnel plot of estimated logarithmic odds doses. Although the widespread prescribing guidelines on `adequate' dosing ± which ratioagainst the size ofthe study.Broken of SSRIs has to be viewed as a public health suggest at least 125 mg of amitriptyline have horizontal line represents the overall estimate of measure to prevent suicide,it is likely to be to be prescribed for it to be effective ± are the logarithmic odds ratio ,0.11). prohibitively expensive; in addition,data themselves based on inadequate research.

Fig. 22Fig. Overall estimate of the efficacy and tolerability of amitriptyline ,AMI) in comparison to all other antidepressant drugs.

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Recent systematic reviews indicate that low-dose TCAs are as effective as SSRIs in CLINICAL IMPLICATIONS treating depression Canadian Coordinating Office for Health Technology Assessment, && Amitriptyline is at least as effective as the other tricyclic and heterocyclic 19971997aa),and studies directly comparing antidepressants. low- and high-dose TCAs show only very modest benefits of high doses Bollini etet && Slightly more patients treated with amitriptyline make a recovery than with alal,1999).,1999). selective serotonin reuptake reuptake inhibitors. inhibitors.

ACKNOWLEDGEMENTS && Amitriptyline is less well tolerated than selective serotonin reuptake inhibitors.

LIMITATIONS We would like to thank Hugh McGuire,McGuire,CCDANCTR CCDANCTR Trial Search Coordinator, for assisting in developing the search strategy of this research. Thanks in addi- && Included trials are heterogeneous in terms of patients, settings and outcome tion to Nick Freemantle for sharing relevant refer- measures. ences and to Jennifer Hillebrand for assistance in extracting data from non-English articles. && Heterogeneity has not been investigated by performing subgroup analyses.

&& The variability in the quality of the original studies might have influenced the REFERENCES overall comparison.

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Nieto, D. & Rincon, H. P."19 "1973) 73) Un nuevo __ , Hutchinson, J. C.,Weise, C. C., et aletal "19 72) Staner, L., Kerkhofs, M., Detroux, D., et aletal "19 95) antidepresivo: el C 34,276^Ba o maprotilina, primer Doxepin and amitriptylineamitriptyline^perphenazine ^ perphenazine in mixed Acute, subchronic and withdrawal sleep EEG changes

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