Hostname: page-component-7c8c6479df-94d59 Total loading time: 0 Render date: 2024-03-28T12:11:02.394Z Has data issue: false hasContentIssue false

Predictive value of pharmacological activity for the relative efficacy of antidepressant drugs

Meta-regression analysis

Published online by Cambridge University Press:  02 January 2018

N. Freemantle*
Affiliation:
Medicines Evaluation Group, Centre for Health Economics, University of York
I. M. Anderson
Affiliation:
University of Manchester, Department of Psychiatry
P. Young
Affiliation:
Department of Health Science & Clinical Evaluation, University of York
*
Nick Freemantle, Reader in Epidemiology & Biostatistics, Medicines Evaluation Group, Centre for Health Economics, University of York, Heslington, York YO10 5DD, UK. Tel: 01904 434568; fax: 01904 433640; e-mail: meg@york.ac.uk
Rights & Permissions [Opens in a new window]

Extract

Background

There is uncertainty about the contribution of specific pharmacological properties to the efficacy of antidepressants.

Aims

To assess whether specific pharmacological characteristics of alternative antidepressants resulted in altered efficacy compared to that of selective serotonin reuptake inhibitors in the treatment of major depression.

Method

Meta-regression analysis of randomised trials that compare treatment with a selective serotonin reuptake inhibitor and an alternative antidepressant.

Results

One-hundred-and-five randomised trials were included. None of the factors identified a priori predicted a statistically significant improvement in outcome across the trials.

Conclusions

This analysis does not provide evidence that antidepressants acting at more than one pharmacological site differ in efficacy from drugs selective for serotonin reuptake in the treatment of major depression.

Type
Review Article
Copyright
Copyright © 2000 The Royal College of Psychiatrists 

About two-thirds of patients with a depressive disorder respond to antidepressant drugs. This proportion was described in the 1950s at the time it was discovered that monoamine oxidase inhibitors (MAOIs) and imipramine had antidepressant properties (Reference HealyHealy, 1997). In the four decades since, there has been enormous progress in neuroscience. The pharmacology of the first antidepressants is now known in greater detail and we have seen increasing development of new antidepressants with specific, designed pharmacological properties. In spite of these advances, there has been no convincing demonstration that an antidepressant has any greater efficacy than the first serendipitously discovered drugs, although progress has been made in improving side-effects and safety. However, for over a decade it has been recognised that combinations of drugs may be more effective than a single drug: the best combination established is the augmentation of antidepressants with lithium (Reference Austin, Souza and GoodwinAustin et al, 1991). This suggests that it should be possible to design a drug with more than one pharmacological action, which would be more effective than the selective, single-action drugs. Clinical belief in the greater effectiveness of clomipramine, and recent claims that some drugs, such as venlafaxine (Clerc et al, 1994), may be more effective than the selective serotonin reuptake inhibitor (SSRI) fluoxetine, have raised the issue of whether a joint action in inhibiting the reuptake of both 5-hydroxytryptamine (serotonin, 5-HT) and noradrenaline may confer added benefit. This has also been suggested by open studies of combined treatment with an SSRI and a tricyclic antidepressant (TCA) (Reference Nelson, Mazure and BowersNelson et al, 1991). Systematic reviews, using different methodologies, seeking to find out whether some antidepressants may be more effective than SSRIs, have reached differing conclusions. One overview of the effectiveness of various antidepressant drugs found statistical heterogeneity (systematic differences between studies) in treatment effects estimated in different studies, but not significant benefit for any one agent compared with others (Reference Geddes, Freemantle and MasonGeddes et al, 2000). Other systematic reviews have suggested that SSRIs may be less effective than amitriptyline (Reference AndersonAnderson, 2000), TCAs (in in-patients) (Reference AndersonAnderson, 1998) and venlafaxine (Reference Rudolph, Entsuah and ChitraRudolph et al, 1998).

One way to address these discrepancies is to ask whether particular pharmacological properties or their combination might increase efficacy. We used an extension of traditional meta-analytic methods - meta-regression - which provides a robust new way of exploring the factors which could explain differences between treatments. In addition, other potentially confounding factors which may affect relative efficacy were investigated.

METHOD

Objective

Our primary objective was to examine the predictive value of different pharmacological action for antidepressant drugs, singly and in combination, on outcome. The factors studied were noradrenaline reuptake inhibition, serotonin (5-HT) reuptake inhibition and 5-HT2 receptor antagonism. They were chosen because they have all, independently, been associated with antidepressant activity in specific drugs.

The important structural factors examined were: treatment setting (inpatient v. out-patient or family practice); dose of comparator (high v. low dose, based on the British National Formulary (British Medical Association & Royal Pharmaceutical Society of Great Britain, 1997), with a daily dose of < 100 mg of most comparators defined as a low dose, apart from 75 mg for nortriptyline and venlafaxine, 45 mg for mianserin, 150 mg for trazodone, 200 mg for nefazodone); method of analysis (last observation carried forward v. end-point analysis); age of patients (defined as over 65 or of mixed age); measurement scale used (either Hamilton Rating Scale for Depression (Reference HamiltonHamilton, 1960) or alternative scale); sponsor of the trial (where not stated, taken as SSRIs in comparisons with TCAs and older antidepressants, and the comparator in studies against drugs marketed since SSRIs).

Data-set and included trials

We analysed all available double-blind randomised trials which compared treatment of depression with an SSRI and with an alternative antidepressant drug that had a primary effect on 5-HT and/or noradrenaline reuptake and/or 5-HT2 antagonism. This data-set was chosen because it provides a large group of studies of antidepressants with a well-defined single pharmacological action (5-HT reuptake inhibition). Eligible trials had to include adult or elderly patients with a major depressive episode for which relevant data were available. As SSRIs are a relatively homogeneous group in terms of pharmacological action, the planned comparisons enabled us to examine the relative efficacy of other antidepressants with different single and combined sites of action against a common standard. Given the increasing pre-eminence of SSRIs in first-line treatment of depressive illness, this is also relevant to current practice.

Classification of drugs

Pharmacological classification of drugs was undertaken using the best available evidence. There are considerable difficulties in doing this, including availability of data in humans (species differences may be important), extrapolation from binding or in vitro data to activity in vivo (including the threshold at which an action becomes important) and the effect of metabolites. The classification used is described in Table 1 and is based, as far as possible, on recently available human binding data. Some generally accepted assumptions appeared less than well founded, from the available data, and there was uncertainty about the classification of some drugs. With regard to 5-HT reuptake inhibition, some drugs traditionally regarded, on the basis of studies in rats, as having minimal activity (especially dothiepin, but also nortriptyline and desipramine) may in fact have a significant degree of affinity for the human 5-HT transporter (Reference Tatsumi, Groshan and BlakelyTatsumi et al, 1997). In the case of desipramine and nortriptyline, dynamic studies in transfected cells or human platelets found low activity (Reference LingjaerdeLingjaerde, 1985; Reference Barker, Blakely, Bloom and KupferBarker & Blakely, 1995), but uncertainty remains about dothiepin. Trazodone and nefazodone are sometimes described as 5-HT reuptake inhibitors, but both animal and human data suggest low affinity for, and activity at, the 5-HT transporter (Reference Richelson and PfenningRichelson & Pfenning, 1984; Reference LingjaerdeLingjaerde, 1985; Reference Tatsumi, Groshan and BlakelyTatsumi et al, 1997). With regard to noradrenaline reuptake inhibition, the main uncertainty centred on venlafaxine, marketed as having both 5-HT and noradrenaline activity. However, the most comprehensive animal and human data indicate that it has low affinity for the noradrenaline transporter (Reference Bolden-Watson and RichelsonBolden-Watson & Richelson, 1993; Reference Tatsumi, Groshan and BlakelyTatsumi et al, 1997) and human functional data suggest that inhibition of noradrenaline reuptake only occurs at higher doses (Reference Abdelmawla, Langley and SzabadiAbdelmawla et al, 1999). Concerning antagonism of human 5-HT2 receptors, there is some uncertainty about the activity of clomipramine, which shows relatively low binding in animal studies (Reference Pälvimäki, Roth and MajasuoPälvimäki et al, 1996), higher affinity in the human brain (Reference Wander, Nelson and OkazakiWander et al, 1986), but intermediate binding and activity in platelets (Reference Ohsuka, Mashiko and KanekoOhsuka et al, 1995), raising uncertainty as to its effect in vivo, particularly at lower doses. The implication of this uncertainty was assessed in each case through a sensitivity analysis in which the initial classification excluded borderline properties, but separate analyses were performed in which they were included.

Table 1 Selected pharmacological action of antidepressants in humans

5-HT reuptake Noradrenaline reuptake 5-HT2 antagonism
Tricyclic antidepressants
Amitriptyline + + +
Clomipramine + + ?
Desipramine - + -
Dothiepin ? + -
Doxepin - + +
Imipramine + + -
Lofepramine - + -
Nortriptyline - + +
Selective serotonin reuptake inhibitors
Citalopram + - -
Fluoxetine + - -
Fluvoxamine + - -
Paroxetine + - -
Sertraline + - -
Others
Amoxapine - + +
Buproprion - - -
Maprotiline - + -
Mianserin - - +
Nefazodone - - +
Nomifensine - + -
Trazodone - - +
Venlafaxine + ? -

Search strategy

We undertook an optimally sensitive electronic search for randomised trials meeting our entry criteria. We searched Medline (1966-1997 via OVID) and EMBASE (1974-1997 via DIALOG) and reviewed the reference list of each identified study. Existing bibliographies and reviews for relevant studies were also examined.

Data abstraction

For each study located, data on main outcome were abstracted. The Hamilton Depression Rating Scale (Reference HamiltonHamilton, 1960) was the preferred outcome scale, but where this was not available the Montgomery-Åsberg Depression Rating Scale (Reference Montgomery and ÅsbergMontgomery & Åsberg, 1979), or the Clinical Global Impression Scale (Reference GuyGuy, 1976) were abstracted. Where data were not available in published reports, we routinely contacted the principal author and, where necessary, the sponsor of the study, to request data.

Data synthesis

Standardised effect sizes for each arm of included trials were estimated from the data, using the final rating scale score and the pooled estimate of study variance as described by Hedges & Olkin (Reference Hedges and Olkin1985). The use of an effect size has the advantage of standardising the scores from different studies, which may adopt differing approaches to assessing treatment effect, on a common and thus comparable scale.

We used a meta-regression technique to examine the extent to which the value of individual factors such as specific pharmacological properties predicted a positive outcome in the trials. We have taken a similar approach in other meta-regression analyses (Reference Davis, Thomson O'Brien and FreemantleDavis et al, 1999; Reference Freemantle, Cleland and YoungFreemantle et al, 1999). BUGS software, described by Smith et al (Reference Smith, Spiegelhalter and Thomas1995), was used to specify the statistical model that attempted to explain variation in the results of different studies on the basis of a range of potentially important factors. This approach is analogous to standard regression analysis, but takes into account the fact that study results are estimated with measurement error (described by the confidence intervals), rather than known. The covariate terms for each factor applied to the model are multipliers which describe the positive or negative impact of different factors on the observed results. Where the estimated effect of a factor is not significantly different from zero, it does not contribute to an understanding of the differences in observed results, and so is not considered further in the analysis.

The statistical methods applied in this analysis have been developed relatively recently and are the subject of considerable interest. Further details of the general approach are available in the excellent introductory text by Gilks et al (Reference Gilks, Richardson and Spiegelhalter1996) and details of the software are available from http://www.mrc-bsu.cam.ac.uk/bugs/.

RESULTS

In total, 105 trials comparing SSRIs with alternative antidepressant drugs were included. These trials looked at 11 537 patients - 5937 treated with an SSRI contrasted with 5600 treated with an alternative antidepressant drug. The most commonly used SSRI was fluoxetine, while the most commonly used alternative was amitriptyline. Trials of five SSRIs and 12 comparator drugs were identified. The major characteristics of each trial included are described in Table 2.

Table 2 Major characteristics of included trials (references are listed in the Appendix)

Trial Effect size Number in comparator group Number in treatment group SSRI Comparator Setting Age Methods Scale Active treatment (weeks) Dose of SSRI Dose of comparator
Reference Ahlfors, Elovaara and HarmaAhlfors et al, 1988 0.63 34 37 Citalopram Mianserin Out-patients/family practice Adult End-point MADRS 4 38.6 61.1
Reference Amin, Anath and ColemanAmin et al, 1984 -0.11 106 105 Fluvoxamine Imipramine Out-patients/family practice Adult LOCF HAM-D 6 155 156
Arminen et al, 1982 -0.30 29 21 Paroxetine Imipramine In-patients Adult End-point HAM-D 12 20-40 100-200
Reference Baker, Dorian and SandorBaker et al, 1997 0.01 19 20 Fluoxetine Doxepin Out-patients Adult End-point HAM-D 6 97 169
Reference Baldwin, Halwy and AbedBaldwin et al, 1996 -0.08 100 95 Paroxetine Nefazodone Out-patients Adult LOCF HAM-D 8 32.7 472
Reference Battegay, Hager and RauchfleischBattegay et al, 1985 0.10 6 8 Paroxetine Amitriptyline Out-patients Adult LOCF HAM-D 6 30 75
Reference Beasley, Dornseif and PultzBeasley et al, 1991 0.11 57 63 Fluoxetine Trazodone Out-patients Adult LOCF HAM-D 6 20.9 244.1
Reference Beasley, Holman and PotvinBeasley et al, 1993a 0.47 60 54 Fluoxetine Imipramine In-patients Adult LOCF HAM-D 6 72 192
Reference Beasley, Sayler and PotvinBeasley et al, 1993b -0.08 71 65 Fluoxetine Amitriptyline Out-patients Adult LOCF HAM-D 5 65.2 201.4
Reference Berlanga, Arechavaleta and HeinzeBerlanga et al, 1997 -0.17 36 37 Fluoxetine Nefazodone Out-patients Adult LOCF HAM-D 8 24.0 400.0
Reference Bersani, Rapisarda and CianiBersani et al, 1994 0.00 30 31 Sertraline Amitriptyline Out-patients Adult End-point HAM-D 8 88 84
Reference Besançon, Cousin, Guitton and LavergneBesançon et al, 1993 0.63 32 33 Fluoxetine Mianserin Out-patients Adult End-point MADRS 8 26.7 72
Reference Bouchard, Dalaunay and DelisleBouchard et al, 1987 0.01 34 39 Citalopram Maprotiline In-patients Adult End-point MADRS 4 46 101
Reference Bramanti, Ricci and RoncariBramanti et al, 1988 0.58 29 28 Fluvoxamine Imipramine Not clear Adult LOCF HAM-D 4 100-120 100-135
Reference BremnerBremner, 1984 -1.32 19 16 Fluoxetine Imipramine Out-patients Adult End-point CGI 5 60 175-200
Reference Byerley, Reimherr and WoodByerley et al, 1988 -0.11 24 20 Fluoxetine Imipramine Out-patients Adult End-point HAM-D 6 40-80 150-300
Reference Christiansen, Behnke and BlackChristiansen et al, 1996 0.20 57 56 Paroxetine Amitriptyline Family practice Adult End-point HAM-D 8 28.1 112.7
Reference Clerc, Ruimy and Verdeau-PaillèsClerc et al, 1994 0.58 33 34 Fluoxetine Venlafaxine In-patients Adult LOCF HAM-D 6 40 200
Reference Cohn and WilcoxCohn & Wilcox, 1984 0.02 31 35 Fluoxetine Imipramine Out-patients Adult End-point HAM-D 6
Reference Cohn, Shrivastava and MendelsCohn, C. K. et al, 1990 -0.07 64 121 Sertraline Amitriptyline Out-patients Elderly End-point HAM-D 8 116.2 88.3
Reference Cohn, Crowder and WilcoxCohn, J. B. et al, 1990 0.24 31 35 Paroxetine Imipramine Out-patients Adult End-point HAM-D 6 65 275
Reference Corne and HallCorne & Hall, 1989 0.42 44 34 Fluoxetine Dothiepin Family practice Adult End-pont HAM-D 8 40± 75±
Reference Dalery, Rochat and PeyronDalery et al, 1992 0.09 68 73 Fluoxetine Amineptine Out-patients Adult End-point MADRS 13 20 200
Danish University, 1990 0.65 36 34 Paroxetine Clomipramine In-patients Adult End-point HAM-D 6 30 150
Reference de Jonghe, Ravelli and Tuynman-Quade Jonghe et al, 1991a 0.33 34 28 Fluoxetine Maprotiline In-patients Adult End-point HAM-D 6 40-80 50-150
Reference de Jonghe, Swinkels and Tuynman-Quade Jonghe et al, 1991b -0.01 21 21 Fluvoxamine Maprotiline Out-patients Adult End-point HAM-D 6 100-300 50-150
De Mendonça Lima, 1997 -0.02 20 20 Fluvoxamine Maprotiline In-patients Adult End-point MADRS 4 100 75
Reference De Wilde, Mertens and WakelinDe Wilde et al, 1983 -0.42 15 15 Fluvoxamine Clomipramine Out-patients Adult End-point HAM-D 4 259 231
Reference De Wilde, Mertens and OveroDe Wilde et al, 1985 -0.44 29 29 Citalopram Mianserin In-patients Adult LOCF CGI 6 53.1 94.1
Reference Dick and FerroDick & Ferro, 1983 0.30 13 13 Fluvoxamine Clomipramine In-patients Adult End-point HAM-D 4 130.9 132.8
Reference Dominguez, Goldstein and JacobsenDominguez et al, 1985 -0.26 19 16 Fluvoxamine Imipramine Out-patients Adult End-point CGI 4 100-300 100-300
Reference DormanDorman, 1992 -0.68 25 24 Paroxetine Mianserin Out-patients Elderly End-point HAM-D 6 15-30 30-60
Fabre, 1996 -0.62 48 46 Fluvoxamine Imipramine Out-patients Adult LOCF HAM-D 6 117 180
Reference Falk, Rosenbaum and OttoFalk et al, 1989 -0.75 12 13 Fluoxetine Trazodone Out-patients Elderly LOCF HAM-D 6 48 350
Reference Feighner, Boyer and MeridethFeighner et al, 1989 0.18 45 52 Fluoxetine Imipramine Out-patients Adult End-point HAM-D 6 NA NA
Reference Fudge, Perry and GarveyFudge et al, 1990 0.26 15 17 Fluoxetine Trazodone Out-patients Adult End-point HAM-D 6 20-60 50-400
Reference Geretsegger, Stuppaeck and MairGeretsegger et al, 1995 -0.19 31 28 Paroxetine Amitriptyline In-patients Elderly End-point HAM-D 6 22.7 109.6
Reference GinestetGinestet, 1989 0.89 26 28 Fluoxetine Clomipramine In-patients Elderly Not clear HAM-D 8 58 148
Reference Gonella, Baignoli and EcariGonella et al, 1990 -0.22 20 20 Fluvoxamine Imipramine Out-patients Adult LOCF HAM-D 4 140 130
Reference Gravem, Amthor and AstrupGravem et al, 1987 -0.27 14 12 Citalopram Amitriptyline Out-patients/Family practice Adult End-point CGI 6 36.1905 161.84211
Reference Guelfi, Dreyfus and PichotGuelfi et al, 1983 -0.24 68 59 Fluvoxamine Imipramine In-patients Not clear End-point HAM-D 4 221 112
Reference Guillibert, Pelicier and ArchambaultGuillibert et al, 1989 0.03 39 40 Paroxetine Clomipramine Out-patients Elderly Not clear HAM-D 6 30 75
Reference Harris, Szulecka and AnsteeHarris et al, 1991 0.63 26 24 Fluvoxamine Amitriptyline Out-patients Adult Not Clear HAM-D 6 100-150 100-150
Hutchinson, 1992 0.00 21 46 Paroxetine Amitriptyline Family practice Elderly End-point HAM-D 6 30 100
Reference Itil, Shrivastava and MukherjeeItil et al, 1983 0.31 14 9 Fluvoxamine Imipramine Out-patients Adult End-point HAM-D 4 101 127
Reference Judd, Moore and NormanJudd et al, 1993 -0.33 23 23 Fluoxetine Amitriptyline Out-patients/Family practice Adult End-point HAM-D 6 20 176
Reference Kasper, Voll and VieiraKasper et al, 1990 0.05 20 21 Fluvoxamine Maprotiline In-patients Adult LOCF HAM-D 4 229 236
Reference Kasper, Möller and MontgomeryKasper et al, 1995 -0.11 106 105 Fluvoxamine Imipramine Out-patients/Family practice Adult End-point HAM-D 4 50-300 50-300
Reference Kerkhofs, Rielaert and de MaertelaerKerkhofs et al, 1990 -0.25 10 9 Fluoxetine Amitriptyline In-patients Adult End-point HAM-D 6 60 150
Reference Klok, Brouwer and Van PraagKlok et al, 1981 0.36 15 13 Fluvoxamine Clomipramine In-patients Adult End-point HAM-D 4 150 150
Reference Kuhs and RudolfKuhs & Rudolf, 1989 0.08 17 14 Paroxetine Amitriptyline In-patients Adult End-point HAM-D 6 30 150
Reference La Pia, Giorgio and CirielloLa Pia et al, 1992 -0.31 16 19 Fluoxetine Mianserin Out-patients/Family practice Elderly End-point HAM-D 6 20 40
Laakmann et al, 1988 0.53 46 39 Fluoxetine Amitriptyline Out-patients Adult End-point HAM-D 5 20-60 50-150
Laakmann, 1991 0.02 62 62 Fluoxetine Amitriptyline In-patients Adult End-point HAM-D 6 40 100
Reference Lapierre, Browne and HornLapierre et al, 1987 -1.17 2 7 Fluvoxamine Imipramine In-patients Adult End-point HAM-D 6 207.1 191.7
Reference Laursen, Mildcelson and RasmussenLaursen et al, 1985 0.07 14 16 Paroxetine Amitriptyline In-patients Adult End-point HAM-D 6 38.75 160.71429
Reference Lydiard, Laird and MortonLydiard et al, 1989 0.31 15 17 Fluvoxamine Imipramine Out-patients Adult End-point HAM-D 6 240 180
Reference Lydiard, Stahl and HertzmanLydiard et al, 1997 0.16 104 119 Sertraline Amitriptyline Out-patients Adult LOCF HAM-D 8 90.8 91.3
Reference Manna, Martucci and AgnoliManna et al, 1989 -0.30 15 15 Fluoxetine Clomipramine In-patients Adult LOCF HAM-D 6 20 75
Reference Mertens and PintensMertens & Pintens, 1988 -0.39 31 36 Paroxetine Mianserin In-patients Adult LOCF HAM-D 6 30 60
Reference Moller, Berzewski and EckmannMoller et al, 1993 0.30 68 72 Paroxetine Amitriptyline In-patients Not clear End-point HAM-D 6 30 150
Reference Muijen, Roy and SilverstoneMuijen et al, 1988 -0.45 14 14 Fluoxetine Mianserin Out-patients Adult End-point HAM-D 6 60-80 60-80
Reference Mullin, Pandita-Gunawardena and WhiteheadMullin et al, 1988 -0.04 24 26 Fluvoxamine Dothiepin Out-patients Adult End-point HAM-D 6 100-300 75-225
Reference Nathan, Perel and PollackNathan et al, 1990 -0.08 18 17 Fluvoxamine Desipramine In-patients Adult Not clear HAM-D 4 203 206
Reference Nielsen, Morsing and PetersenNielsen et al, 1991 0.00 12 11 Paroxetine Imipramine Not clear Adult End-point HAM-D 4 30 150
Reference Noguera, Altuna and AlvarezNoguera et al, 1991 -0.35 60 60 Fluoxetine Clomipramine Out-patients Adult LOCF HAM-D 6 40 100
Reference Norton, Sireling and BhatNorton et al, 1984 0.02 30 33 Fluvoxamine Imipramine Out-patients Adult End-point HAM-D 4 132.8 153.3
Reference Ohrberg, Christiansen and SeverinOhrberg et al, 1992 -0.07 59 61 Paroxetine Imipramine Out-patients Adult End-point HAM-D 6 32.2973 166.88312
Reference OttevangerOttevanger, 1995 0.12 20 20 Fluvoxamine Clomipramine In-patients Adult LOCF HAM-D 4 204 106
Reference Pakesch and DossenbachPakesch & Dossenbach, 1991 0.01 48 91 Fluoxetine Clomipramine Out-patients Adult LOCF HAM-D 4 30.1 50
Reference Peters, Lenhard and MetzPeters et al, 1990 0.13 41 40 Fluoxetine Amitriptyline Out-patients Adult End-point HAM-D 5 20 100
Reference Phanjoo, Wonnacott and HodgsonPhanjoo et al, 1991 0.35 15 16 Fluvoxamine Mianserin Out-patients/family practice Elderly End-point MADRS 6 170 60
Reference Poelinger and HaberPoelinger & Haber, 1989 -0.25 69 73 Fluoxetine Maprotiline Out-patients/family practice Adult LOCF HAM-D 4 NA NA
Rahman et al, 1991 0.13 19 17 Fluvoxamine Dothiepin In-patients Elderly End-point MADRS 6 157 159
Reference Ravindran, Teehan and BakishRavindran et al, 1995 0.16 30 34 Sertraline Desipramine Out-patients Adult End-point HAM-D 8 50-200 50-225
Reference Ravindran, Judge and HunterRavindran et al, 1997 -0.02 502 500 Paroxetine Clomipramine Family practice Adult LOCF MADRS 8 28.2 99.75
Reference Reimherr, Chouinard and CohnReimherr et al, 1990 0.13 144 142 Sertraline Amitriptyline Out-patients Adult LOCF HAM-D 8 145 104
Reference Remick, Claman and ReesalRemick et al, 1993 0.82 15 24 Fluoxetine Desipramine Out-patients/family practice Adult End-point HAM-D 6
Reference Remick, Reesal and OakanderRemick et al, 1994 -0.10 17 16 Fluvoxamine Amitriptyline Out-patients Adult LOCF HAM-D 7 175 135
Reference Robertson, Abou-Saleh and HarrisonRobertson et al, 1994 0.13 77 76 Fluoxetine Lofepramine Out-patients/family practice Adult LOCF HAM-D 6 20 140-210
Reference RopertRopert, 1989 -0.29 48 55 Fluoxetine Clomipramine Out-patients Adult End-point HAM-D 6 20 75
Reference Rosenberg, Damsbo and FuglumRosenberg et al, 1994 -0.02 85 187 Citalopram Imipramine Family practice Adult LOCF HAM-D 6 25 120
Reference Rosenberg, Damsbo and FuglumRosenberg et al, 1994 0.00 85 193 Citalopram Imipramine Family practice Adult LOCF HAM-D 6 48 120
Reference Roth, Mattes and SheehanRoth et al, 1990 -0.13 24 27 Fluvoxamine Desipramine Out-patients Adult End-point HAM-D 6 218.2 224.6
Reference Rush, Armitage and GillinRush et al, 1998 0.03 62 60 Fluoxetine Nefazodone Out-patients Adult LOCF HAM-D 8 20 200
Reference Schnyder and Koller-LeiserSchnyder & Koller-Leiser, 1996 0.09 34 37 Paroxetine Maprotiline Out-patients/family practice Adult LOCF HAM-D 4 32.2 107.4
Reference Shaw, Thomas and BriscoeShaw et al, 1986 -0.08 20 24 Citalopram Amitriptyline Out-patients/family practice Adult LOCF HAM-D 6 46 148
South Wales Antidepressant Drug Trial Group, 1988 -0.06 21 16 Fluoxetine Dothiepin Out-patients/family practice Adult End-point HAM-D 6 67 172
Reference Staner, Kerkhofs and DetrouxStaner et al, 1995 0.72 19 21 Paroxetine Amitriptyline In-patients Adult LOCF HAM-D 5 30 150
Reference Stark and HardisonStark & Hardison, 1985 0.03 186 185 Fluoxetine Imipramine Out-patients Adult LOCF HAM-D 6 69.2 219.1
Reference Stott, Blagden and AitkenStott et al, 1993 -0.01 262 243 Paroxetine Amitriptyline Family practice Adult Not clear MADRS 8 20 75
Reference Stratta, Bolino and CupillariStratta et al, 1991 -0.04 9 14 Fluoxetine Imipramine Not clear Adult End-point HAM-D 6 20 NA
Reference Stuppaeck, Geretsegger and WhitworthStuppaeck et al, 1994 -0.05 66 68 Paroxetine Amitriptyline In-patients Adult End-point HAM-D 6 33.3 166
Reference Szegedi, Wetzel and AngersbachSzegedi et al, 1997 -0.01 260 257 Paroxetine Maprotiline Out-patients Adult LOCF HAM-D 6 35.3 109.9
Reference Timmerman, de Beurs and TanTimmerman et al, 1987 0.20 13 14 Citalopram Maprotiline In-patients Adult End-point HAM-D 4 40-60 75-150
Reference Tollefson, Greist and JeffersonTollefson et al, 1994 -0.08 62 62 Fluoxetine Imipramine Out-patients Adult LOCF HAM-D 8 43 165
Reference Tylee, Beaumont and BowdenTylée et al, 1997 -0.11 147 156 Fluoxetine Venlafaxine Family practice Adult LOCF HAM-D 12 20 75
Unpublished, 1998a 1 0.34 75 80 Paroxetine Venlafaxine Out-patients Adult LOCF HAM-D 12 20 150
Unpublished, 1998b 1 0.45 82 80 Paroxetine Venlafaxine Out-patients Adult LOCF HAM-D 12 20 75
Unpublished, 1998c 1 0.10 175 161 Paroxetine Venlafaxine Family practice Adult LOCF HAM-D 12 20 75
Unpublished, 1998d 1 0.20 44 52 Paroxetine Venlafaxine Out-patients/family practice Adult LOCF HAM-D 6 36.3 269
Unpublished, 1998e 1 0.02 196 186 Fluoxetine Venlafaxine Out-patients Adult LOCF HAM-D 8 20-40 75-150
Unpublished, 1998f 1 0.21 95 103 Fluoxetine Venlafaxine Out-patients Adult LOCF HAM-D 8 20-40 75-150
Unpublished, 1998g 1 0.06 122 119 Fluoxetine Venlafaxine Out-patients Adult LOCF HAM-D 12 39.9 140.8
Reference Young, Coleman and LaderYoung et al, 1987 0.11 25 25 Fluoxetine Amitriptyline Out-patients Adult End-point HAM-D 6 73 122

The predictive value of each factor was assessed in turn. None of the factors achieved a statistically significant predictive effect upon outcome and thus all coefficients reflect the predictive value of a factor alone in the model. As expected, 5-HT reuptake inhibition on its own did not predict any difference in efficacy; the coefficient was - 0.003 (95% CI - 0.064 to 0.048). For the presence of activity on noradrenaline reuptake, the coefficient was 0.006 (95% CI ‒0.042 to 0.082). The coefficients examining the predictive value of 5HT2 antagonism did not predict the outcome in the included trials (see Table 3 and Fig. 1).

Fig. 1 Coefficient values for predictive value of receptor site activity.

For each coefficient described, the vertical line describes the point estimate of effect, and the diamond describes the limits of the 95% confidence intervals. The approach to estimation does not force assumptions of symmetry for confidence intervals. For pharmacological activity, a coefficient value less than zero implies an advantage for the presence of the factor described.

For the structural factors examined:

  • Setting: a positive value would suggest an increased efficacy for selective serotonin reuptake inhibitors (SSRIs) in in-patients

  • Age: a positive value would imply an increased efficacy for SSRIs where only those over 65 years are included

  • Method: a positive value would imply an increased efficacy for SSRIs in studies that used last observation carried forward instead of end-point analysis

  • Scale: a positive value would imply an advantage for SSRIs where the Hamilton Depression Rating Scale was used

  • Dose: a positive result would imply an advantage for SSRIs when a higher dose comparator was used

  • Funding: a positive result would imply an advantage for the sponsor's drug.

Table 3 Predictive effects of pharmacological action and other study factors

Covariate Coefficient 95% Credibility limits
Lower limit Upper limit
Dual action 0.011 -0.025 0.096
Dual action (sensitivity) -0.007 -0.086 0.034
Triple action -0.05 -0.172 0.067
Triple action (sensitivity) -0.040 -0.15 0.065
Noradrenaline reuptake 0.006 -0.042 0.082
Noradrenaline reuptake (sensitivity) -0.016 -0.134 0.039
5HT reuptake -0.003 -0.064 0.048
5HT reuptake (sensitivity) -0.006 -0.070 0.033
5HT2 antagonism -0.001 -0.060 0.055
5HT2 antagonism (sensitivity) 0.002 -0.042 0.057
Setting -0.069 -0.176 0.041
Age 0.080 -0.113 0.28
Method 0.032 -0.065 0.13
Scale -0.049 -0.175 0.088
Dose 0 > 0.0010 <0.001
Funding 0.097 -0.03 0.23

We also examined the predictive value of the presence of dual action (5-HT and noradrenaline reuptake inhibition) and triple action (dual action plus 5-HT2 antagonism) on the model. Neither predicted an increase in effectiveness.

None of the identified structural factors that may have confounded the results of the analyses had statistically significant predictive value and, perhaps surprisingly, the dose of the comparator had no influence, with the results being particularly precise (very narrow confidence interval). The most important structural predictor of outcome was trial sponsorship, which demonstrated a trend towards increased efficacy of the sponsor's drug, although this did not reach statistical significance.

DISCUSSION

We have shown that, in this data-set, there is no evidence to support the increased efficacy of specific combinations of actions at 5-HT and noradrenaline transporter and 5-HT2 receptor sites, compared to a single action in inhibiting the reuptake of 5-HT. The results of our review suggest that great caution needs to be taken in ascribing any possible efficacy advantages of particular antidepressants over SSRIs to acute pharmacological properties.

Scope

We did not examine the efficacy of MAOIs, moclobemide or mirtazapine because their actions to increase 5-HT and noradrenaline function, while presynaptic, cannot be compared directly with single or dual action reuptake inhibition. Neither did we examine effects at other receptors, based on the principle of limiting the analysis to factors for which there is evidence of involvement in antidepressant efficacy. Our results indicate that the argument that a dual action (in inhibiting 5-HT and noradrenaline reuptake) could account for the results of selected trials in which superior efficacy is shown by one drug over another should be accepted with caution, and emphasise the difficulty in establishing the superiority of one antidepressant over another in studies such as these. The term ‘dual action’ has become a marketing concept for a number of antidepressants, and this study raises the question as to whether it has a legitimate scientific basis, in considering mechanisms behind antidepressant efficacy.

The role of 5-HT2 receptor antagonism in antidepressant action is unclear, but is suggested because it is the principal pharmacological property of the antidepressants trazodone and nefazodone. The picture is further complicated by the differentiation of this receptor into 5-HT2A and 5-HT2C subtypes. Our analysis is based on antagonism of the 5-HT2A subtype, and there is a lack of good data on the binding of antidepressants to the human 5-HT2C receptor. Animal studies suggest that most, but not all, antidepressants bind with similar affinity to the two subtypes (Reference Pälvimäki, Roth and MajasuoPälvimäki et al, 1996). However, this analysis has not made a specific examination of the role of 5-HT2C receptor antagonism.

Issues in the analysis of the data

Our findings show that appropriate meta-regression techniques can be useful in examining the importance of different factors across a range of trials examining a common goal, but differing in potentially important characteristics. Standard ordinary least-squares regression is inadequate in an analysis such as this, as the method assumes that the observed outcomes in the trials (the estimate of the size of effect) are the true outcomes. It is important to recognise that the outcomes in clinical trials involve considerable uncertainty, and that standard statistical techniques would fail to include an adequate estimate of measurement error.

Each of the factors was entered individually in the analysis, and only if a significant predictive effect had been found would its influence on other factors have been examined. A potential limitation of our study is that factors without a uniform influence on outcome could have been missed. For instance, the effect of in-patient treatment setting could be to favour one group of comparators but disadvantage others, giving no overall effect. Addressing this type of limitation requires strong a priori hypotheses, such as that for the category of ‘dual action’, and goes beyond this analysis.

The pharmacological classification of antidepressants we used needs comment. A difficulty permeating our analysis, and relatively unrecognised, is how limited our knowledge of even the acute pharmacology of antidepressants remains. Commonly held views about the pharmacology of antidepressants, at least in vivo, and in humans, probably go beyond the evidence. We are uncertain about whether many of the putative pharmacological properties of drugs are translated into effects in the human brain for many reasons, including continuing advances in our understanding of how neurotransmission may be modified, the lack of true selectivity of drugs (including the action of metabolites), lack of knowledge of the pharmacology of drugs in humans as opposed to other animals, and ignorance about neuronal concentrations of drugs and their metabolites at doses employed clinically. This suggests that the scientific question of whether particular putative actions or combinations of putative actions of drugs may relate to efficacy still awaits better understanding of what the actions really are. We have tried to use the best data available, including those obtained in experiments with human tissues, but these are relatively limited. Uncertainties about the classification of some drugs are inevitable, and for some there is evidence of a dose relationship across the doses used in the studies, which could not easily be accounted for in the analysis (for example, noradrenaline reuptake inhibition occurring only at a higher venlafaxine dose). A final important point is the recognition that the acute effects of antidepressants do not directly account for antidepressant action, which is believed to be due to secondary changes arising as a consequence of the primary effects. The acute pharmacology, even if it can be known, therefore stands as a crude proxy for as yet unknown changes that are crucial for antidepressant action. It is quite possible that it is not simply the presence or absence of an acute pharmacological effect but the balance between different ones that is important in determining later changes and, finally, response to antidepressants.

Quality of data

Our data-set is both large and systematically assembled, which means that the power to detect significant effects is high and that bias is minimised, although in interpreting our results it is important to recognise the limitations inherent in the data. The quality of the trials was variable and likely to have added ‘noise’ to the results. In addition, there is uncertainty about optimum doses for the comparators in relation to SSRIs, which will influence the analysis of dose; this may be particularly true for the comparator drugs in which there is uncertainty about pharmacological activity at specific sites, as discussed above. In our model there was strong evidence that the dose of comparator antidepressant had no effect on the relative effectiveness compared with that of an SSRI. Hence we believe it is unlikely that a major effect attributable to the chosen pharmacological actions, singly or in combination, has been obscured in the data, although we cannot exclude an effect of dose for some individual drugs or an interaction between factors. For example, as discussed above, drugs such as venlafaxine may cross from single to dual reuptake inhibition with increasing dose.

Most studies involved TCAs, and the lack of effect of dose on efficacy potentially adds to the debate about the supposed dangers of ‘subtherapeutic’ prescribing of TCAs, which has been seen as a factor influencing choice between antidepressants (Reference Donaghue and TyleeDonaghue & Tylee, 1996). In clinical practice, it is not uncommon to see individual patients, often with more severe illness, whose depression only responds to higher doses of TCAs. The evidence that this is generally true is extremely limited (Reference Blashki, Mowbray and DaviesBlashki et al, 1971; Reference Thompson and ThompsonThompson & Thompson, 1989) and should not be accepted uncritically. The trials included in this analysis were not designed to look at the effect of dose, and differed as to whether a fixed or variable dose was employed. Nevertheless, not only was no effect of dose on relative efficacy detected, but the precision of the estimate was extremely high, making it very unlikely that a true effect was obscured, taking the cut-off between high and low dose that we employed. As nearly all ‘low-dose’ studies used TCA doses of 75 mg or above, this suggests that one needs to keep an open mind about whether the minimum therapeutic dose of TCAs may be 75 mg or below in populations such as these.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

  • Currently, there is uncertainty about whether some antidepressants display superior efficacy.

  • In our present state of knowledge of the pharmacology of individual drugs, there does not seem to be a simple relationship between acute pharmacological properties and efficacy.

  • When choosing antidepressants on the basis of efficacy, clinicians should consider the properties of individual drugs rather than make assumptions about efficacy based on their acute pharmacological actions. Safety, tolerability and patients' preference are likely to be more important for most patients.

LIMITATIONS

  • Differences in the reporting of outcomes between studies require standardisation of many outcomes, resulting in a reduction in interpretation of the practical importance of the results.

  • Data on the relative effectiveness of different antidepressants remain limited for individual agents.

  • Our knowledge of the acute pharmacology of individual antidepressants in humans is limited; this is even more true of the secondary effects believed to underlie the antidepressant action.

ACKNOWLEDGEMENTS

We are grateful to Wyeth UK for supporting this research, and to those investigators and sponsors who provided unpublished data. The views expressed are those of the investigators and not necessarily those of the sponsor. We are grateful also to Anne Burton, for her assistance in retrieving relevant studies and her persistent attempts to locate unpublished data.

Footnotes

Declaration of interest

Study sponsored by an unrestricted grant from Wyeth Laboratories. N.F. has previously received funding from the Department of Health to investigate the effectiveness and cost-effectiveness of antidepressants. I.M.A. has received research funding and honoraria from a number of pharmaceutical companies.

References

APPENDIX — REPORTS OF TRIALS INCLUDED IN THE META-ANALYSIS

Ahlfors, U. G., Elovaara, S., Harma, P., et al (1988) Clinical multicentre study of citalopram compared double-blindly with mianserin in depressed patients in Finland. Nordisk Psykiatrisk Tidsskrift, 42, 201-210.CrossRefGoogle Scholar
Amin, M. M., Anath, J. V., Coleman, B. S., et al (1984) Fluvoxamine; antidepressant effects confirmed in a placebo controlled international study. Clinical Neuropharmacology, 7, 580-581.Google Scholar
Arminen, S. L., Ikonen, U., Pulkkinen, M., et al (1992) Paroxetine and imipramine: a 12-week, double-blind multicentre study in hospitalised depressed patients. Nordisk Psykiatrisk Tidsskrift Suppl. 46, 27-31.Google Scholar
Baker, B., Dorian, P., Sandor, P., et al (1997) Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder. Journal of Clinical Psychopharmacology, 17, 15-21.Google Scholar
Baldwin, D. S., Halwy, C. J., Abed, R. T., et al (1996) A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate to severe depression. Journal of Clinical Psychiatry, 57 (suppl. 2), 46-52.Google ScholarPubMed
Battegay, R., Hager, M. & Rauchfleisch, U. (1985) Double-blind comparative study of paroxetine and amitriptyline in depressed patients of a university psychiatric out-patient clinic (pilot study). Neuropsychobiology, 13, 31-37.Google Scholar
Beasley, C. M. Jr, Dornseif, B. E., Pultz, J. A., et al (1991) Fluoxetine versus trazodone: efficacy and activating-sedating effects. Journal of Clinical Psychiatry, 52, 294-299.Google ScholarPubMed
Beasley, , Holman, S. L. & Potvin, J. H. (1993a) Fluoxetine compared with imipramine in the treatment of inpatient depression. A multicenter trial. Annals of Clinical Psychiatry, 5, 199-207.CrossRefGoogle ScholarPubMed
Beasley, , Sayler, M. E. & Potvin, J. H. (1993b) Fluoxetine versus amitriptyline in the treatment of major depression: a multicenter trial. International Clinical Psychopharmacology, 8, 143-149.CrossRefGoogle ScholarPubMed
Berlanga, C., Arechavaleta, B., Heinze, G., et al (1997) A double-blind comparison of nefazodone and fluoxetine in the treatment of depressed outpatients. Salud Mental, 20, 1-8.Google Scholar
Bersani, G., Rapisarda, V., Ciani, N., et al (1994) A double-blind comparative study of sertraline and amitriptyline in outpatients with major depressive episodes. Human Psychopharmacology, 9, 63-68.Google Scholar
Besançon, G., Cousin, R., Guitton, B. & Lavergne, F. (1993) Etude en double aveugle de la mianserine et de la fluoxetine chez des patients déprimés traités en ambulatoire. Encéphale, 19, 341-345.Google Scholar
Bouchard, J. M., Dalaunay, J., Delisle, J. P., et al (1987) Citalopram versus maprotiline: a controlled, clinical multicentre trial in depressed patients. Acta Psychiatrica Scandinavica, 76, 583-592.Google Scholar
Bramanti, P., Ricci, R. M., Roncari, R., et al (1988) An Italian multicenter experience with fluvoxamine, a new antidepressant drug, versus imipramine. Current Therapeutic Research, 43, 718-725.Google Scholar
Bremner, J. D. (1984) Fluoxetine in depressed patients: a comparison with imipramine. Journal of Clinical Psychiatry, 45, 414-419.Google ScholarPubMed
Byerley, W. F., Reimherr, F. W., Wood, D. R., et al (1988) Fluoxetine, a selective serotonin uptake inhibitor, for the treatment of outpatients with major depression. Journal of Clinical Psychopharmacology, 8, 112-15.CrossRefGoogle ScholarPubMed
Christiansen, P. E., Behnke, K., Black, C. H., et al (1996) Paroxetine and amitriptyline in the treatment of depression in general practice. Acta Psychiatrica Scandinavica, 93, 158-163.Google Scholar
Clerc, G. E., Ruimy, P., Verdeau-Paillès, J. on behalf of the Venlafaxine French Inpatient Study Group (1994) A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. International Clinical Psychopharmacology, 9, 139-143.Google Scholar
Cohn, C. K., Shrivastava, R., Mendels, J., et al (1990) Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. Journal of Clinical Psychiatry, 51 (suppl. B), 28-33.Google Scholar
Cohn, J. B. & Wilcox, C. (1984) A comparison of fluoxetine, imipramine and placebo in patients with depressive disorder. Journal of Clinical Psychiatry, 45, 414-419Google Scholar
Cohn, J. B., Crowder, J. E., Wilcox, C. S., et al (1990) A placebo- and imipramine-controlled study of paroxetine. Psychopharmacology Bulletin, 26, 185-189.Google Scholar
Corne, S. J. & Hall, J. R. (1989) A double-blind comparative study of fluoxetine and dothiepin in the treatment of depression in general practice. International Clinical Psychopharmacology, 4, 245-254.CrossRefGoogle ScholarPubMed
Dalery, J., Rochat, C., Peyron, E., et al (1992) Etude comparative de l'efficacité et de l'acceptabilité de l'amineptine et de la fluoxetine chez des patients dépressifs majeurs. Encéphale, 18, 257-262.Google Scholar
Danish University Antidepressant Group (1990) Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Journal of Affective Disorders, 18, 289-299.Google Scholar
de Jonghe, F., Ravelli, D. P. & Tuynman-Qua, H. (1991a) A randomized, double-blind study of fluoxetine and maprotiline in the treatment of major depression. Pharmacopsychiatry, 24, 62-67.CrossRefGoogle ScholarPubMed
de Jonghe, F., Swinkels, J. & Tuynman-Qua, H. (1991b) Randomized double-blind study of fluvoxamine and maprotiline in treatment of depression. Pharmacopsychiatry, 24, 21-27.CrossRefGoogle ScholarPubMed
De Mendonça Lima, C. A., Vandel, S., Bonin, B., et al (1997) Maprotiline versus fluvoxamine: comparison entre leurs actions sur l'ace hypothalamo-hypophysothryoïdien. Encéphale, 23, 48-55.Google Scholar
De Wilde, J. E., Mertens, C. & Wakelin, J. S. (1983) Clinical trials of fluvoxamine vs chlorimipramine with single and three times daily dosing. British Journal of Clinical Pharmacology, 15 (suppl. 3), 427s-431s.CrossRefGoogle ScholarPubMed
De Wilde, J. E., Mertens, C., Overo, K. F., et al (1985) Citalopram versus mianserin: a controlled, double-blind trial in depressed patients. Acta Psychiatrica Scandinavica, 72, 89-96.Google Scholar
Dick, P. & Ferro, E. (1983) A double-blind comparative study of the clinical efficacy of fluvoxamine and chlorimipramine. British Journal of Clinical Pharmacology, 15 (suppl. 3), 419s-4125s.CrossRefGoogle ScholarPubMed
Dominguez, R. A., Goldstein, B. J., Jacobsen, A. F., et al (1985) A double-blind controlled study of fluvoxamine and imipramine in depression. Journal of Clinical Psychiatry, 46, 84-87.Google ScholarPubMed
Dorman, T. (1992) Sleep and paroxetine: a comparison with mianserin in elderly depressed patients. International Clinical Psychopharmacology, 6 (suppl 4), 53-58.CrossRefGoogle ScholarPubMed
Fabre, L., Birkhimer, L. J., Zaborny, B. A., et al (1996) Fluvoxamine versus imipramine and placebo: a double-blind comparison in depressed patients. International Clinical Psychopharmacology, 11, 119-127.Google Scholar
Falk, W. E., Rosenbaum, J. F., Otto, M. W., et al (1989) Fluoxetine versus trazodone in depressed geriatric patients. Journal of Geriatric Psychiatry and Neurology, 2, 208-214.Google Scholar
Feighner, J. P., Boyer, W. F., Merideth, C. H., et al (1989) A double-blind comparison of fluoxetine, imipramine and placebo in outpatients with major depression. International Clinical Psychopharmacology, 4, 127-134.Google Scholar
Fudge, J. L., Perry, P. J., Garvey, M. J., et al (1990) A comparison of the effect of fluoxetine and trazodone on the cognitive functioning of depressed outpatients. Journal of Affective Disorders, 18, 275-280.Google Scholar
Geretsegger, C., Stuppaeck, C. H., Mair, M., et al (1995) Multicenter double-blind study of paroxetine and amitriptyline in elderly depressed inpatients. Psychopharmacology, 119, 277-281.Google Scholar
Ginestet, D. (1989) Fluoxetine in endogenous depression and melancholia versus clomipramine. International Clinical Psychopharmacology, 4 (suppl 1), 37-40.Google Scholar
Gonella, G., Baignoli, G., Ecari, U. (1990) Fluvoxamine and imipramine in the treatment of depressive patients: a double-blind controlled study. Current Medical Research and Opinion, 12, 177-184.CrossRefGoogle ScholarPubMed
Gravem, A., Amthor, K. F., Astrup, C., et al (1987) A double-blind comparison of citalopram (Lu 10-171) and amitriptyline in depressed patients. Acta Psychiatrica Scandinavica, 75, 478-486.Google Scholar
Guelfi, J. D., Dreyfus, J. F., Pichot, P., et al (1983) A double-blind placebo controlled clinical trial comparing fluvoxamine with imipramine. British Journal of Clinical Pharmacology, 15 (suppl. 3), 411s-417s.Google Scholar
Guillibert, E., Pelicier, Y., Archambault, J. C., et al (1989) A double-blind, multicentre study of paroxetine versus clomipramine in depressed elderly patients. Acta Psychiatrica Scandinavica Supplementum, 350, 132-134.Google Scholar
Harris, B., Szulecka, T. K. & Anstee, J. A. (1991) Fluvoxamine versus amitriptyline in depressed hospital out patients: a multicentre double-blind comparative trial. British Journal of Clinical Research, 2, 89-99.Google Scholar
Hutchinson, D. R., Tong, S., Moon, C. A., et al (1992) Paroxetine in the treatment of elderly depressed patients in general practice: a double-blind comparison with amitriptyline. International Clinical Psychopharmacology, 6 (suppl 4), 43-51.Google Scholar
Itil, T. M., Shrivastava, R. K., Mukherjee, S., et al (1983) A double-blind placebo-controlled study of fluvoxamine and imipramine in out patients with primary depression. British Journal of Clinical Pharmacology, 15 (suppl. 3), 433s-438s.CrossRefGoogle ScholarPubMed
Judd, F. K., Moore, K., Norman, T. R., et al (1993) A multicentre double-blind trial of fluoxetine versus amitriptyline in the treatment of depressive illness. Australian and New Zealand Journal of Psychiatry, 27, 49-55.CrossRefGoogle ScholarPubMed
Kasper, S., Voll, G., Vieira, A., et al (1990) Response to total sleep deprivation before and during treatment with fluvoxamine or maprotiline in patients with major depression — results of a double-blind study. Pharmacopsychiatry, 23, 135-142.Google Scholar
Kasper, S., Möller, H. J., Montgomery, S. A., et al (1995) Antidepressant efficacy in relation to item analysis and severity of depression: a placebo controlled trial of fluvoxamine versus imipramine. International Clinical Psychopharmacology, 9 (suppl 4), 3-12.CrossRefGoogle ScholarPubMed
Kerkhofs, M., Rielaert, C., de Maertelaer, V., et al (1990) Fluoxetine in major depression: efficacy, safety and effects on sleep polygraphic variables. International Clinical Psychopharmacology, 5, 253-260.CrossRefGoogle ScholarPubMed
Klok, C. J., Brouwer, G. J., Van Praag, H. M., et al (1981) Fluvoxamine and clomipramine in depressed patients: a double-blind clinical study. Acta Psychiatrica Scandinavica, 64, 1-11.Google Scholar
Kuhs, H. & Rudolf, G. A. (1989) A double-blind study of the comparative antidepressant effect of paroxetine and amitriptyline. Acta Psychiatrica Scandinavica Supplementum, 350, 145-146.Google Scholar
La Pia, S., Giorgio, D., Ciriello, R., et al (1992) Double-blind controlled study to evaluate the effectiveness and tolerability of fluoxetine versus mainserin in the treatment of depressive disorders among the elderly and their effects on cognitive behavioural parameters. New Trends in Experimental Clinical Psychiatry, 8, 139-146.Google Scholar
Laakman, G. (1991) Selective re-uptake-hemmung und ihre Bedeutung für die Depression. Berlin: Springer.CrossRefGoogle Scholar
Laakman, G., Blaschke, D., Engel, R., et al (1988) Fluoxetine vs amitriptyline in the treatment of depressed out-patients. British Journal of Psychiatry, 153 (suppl. 3), 64-68.Google Scholar
Lapierre, Y. D., Browne, M., Horn, E., et al (1987) Treatment of major affective disorder with fluvoxamine. Journal of Clinical Psychiatry, 48, 65-68.Google ScholarPubMed
Laursen, A. L., Mildcelson, P. L., Rasmussen, S., et al (1985) Paroxetine in the treatment of depression: a randomised comparison with amitriptyline. Acta Psychiatrica Scandinavica, 71, 249-255.CrossRefGoogle ScholarPubMed
Lydiard, R. B., Laird, L. K., Morton, W. A. Jr, et al (1989) Fluvoxamine, imipramine, and placebo in the treatment of depressed outpatients: effects on depression. Psychopharmacology Bulletin, 25, 68-70.Google ScholarPubMed
Lydiard, R. B., Stahl, S. M., Hertzman, M., et al (1997) A double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression. Journal of Clinical Psychiatry, 58, 484-490.CrossRefGoogle ScholarPubMed
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.Google Scholar
Mertens, C. & Pintens, H. (1988) Paroxetine in the treatment of depression. A double-blind multicenter study versus mianserin. Acta Psychiatrica Scandinavica, 77, 683-688.CrossRefGoogle ScholarPubMed
Moller, H. J., Berzewski, H., Eckmann, F., et al (1993) Double-blind multicenter study of paroxetine and amitriptyline in depressed inpatients. Pharmacopsychiatry, 26, 75-78.CrossRefGoogle ScholarPubMed
Muijen, M., Roy, D., Silverstone, T., et al (1988) A comparative clinical trial of fluoxetine, mianserin and placebo in depressed outpatients. Acta Psychiatrica Scandinavica, 78, 384-390.CrossRefGoogle ScholarPubMed
Mullin, J. M., Pandita-Gunawardena, V. R. & Whitehead, A. M. (1988) A double-blind comparison of fluvoxamine and dothiepin in the treatment of major affective disorder. British Journal of Clinical Practice, 42, 51-55.Google Scholar
Nathan, R. S., Perel, J. M., Pollack, B. G., et al (1990) The role of neuropharmacologic selectivity in antidepressant action: fluvoxamine versus desipramine. Journal of Clinical Psychiatry, 51, 367-372.Google Scholar
Nielsen, O. A., Morsing, I., Petersen, J. S., et al (1991) Paroxetine and imipramine treatment of depressive patients in a controlled multicentre study with plasma amino acid measurements. Acta Psychiatrica Scandinavica, 84, 233-241.Google Scholar
Noguera, R., Altuna, R., Alvarez, E., et al (1991) Fluoxetine vs clomipramine in depressed patients: a controlled multicentre trial. Journal of Affective Disorders, 22, 119-124.Google Scholar
Norton, K. R. W., Sireling, L. I., Bhat, A. V., et al (1984) A double-blind comparison of fluvoxamine, imipramine and placebo in depressed patients. Journal of Affective Disorder, 7, 297-308.CrossRefGoogle ScholarPubMed
Ohrberg, S., Christiansen, P. E., Severin, B., et al (1992) Paroxetine and imipramine in the treatment of depressive patients in psychiatric practice. Acta Psychiatrica Scandinavica, 86, 437-444.CrossRefGoogle ScholarPubMed
Ottevanger, E. A. (1995) Fluvoxamine and clomipramine in depressed hospitalised patients: results from a randomised, double-blind study. Encéphale, 21, 317-321.Google Scholar
Pakesch, G. & Dossenbach, M. (1991) Wirkung und Sicherheit von Fluoxetin versus Clomipramin bei ambulanten Patienten mit einem depressiven Syndrom in einer klinischen Prüfung bei niedergelassenen Arzten. Wiener Klinische Wochenschrift, 103, 176-182.Google Scholar
Peters, U. H., Lenhard, P. & Metz, M. (1990) Therapy of depression in the psychiatrist's office — A double-blind multicenter study. Nervenheikunde, 9, 28-31.Google Scholar
Phanjoo, A. L., Wonnacott, S. & Hodgson, A. (1991) Double-blind comparative multicentre study of fluvoxamine and mianserin in the treatment of major depressive episode in elderly people. Acta Psychiatrica Scandinavica, 83, 476-479.CrossRefGoogle ScholarPubMed
Poelinger, W. & Haber, H. (1989) Fluoxetine 40 mg vs maprotiline 75 mg in the treatment of out-patients with depressive disorders. International Clinical Psychopharmacology, 4 (suppl 1), 47-50.Google Scholar
Rahman, M. K., Aktar, M. J., Salva, N. C., et al (1999) A double-blind randomised comparison of fluvoxamine with dothiepin in the treatment of depression in elderly patients. British Journal of Clinical Practice, 4, 255-258.Google Scholar
Ravindran, A. V., Teehan, M. D., Bakish, D., et al (1995) The impact of sertraline, desipramine, and placebo on psychomotor functioning in depression. Human Psychopharmacology, 10, 273-281.CrossRefGoogle Scholar
Ravindran, A. V., Judge, R., Hunter, B. N., et al (1997) A double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Journal of Clinical Psychiatry, 58, 112-118.Google Scholar
Reimherr, F. W., Chouinard, G., Cohn, C. K., et al (1990) Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. Journal of Clinical Psychiatry, 51 (suppl B), 18-27.Google Scholar
Remick, R. A., Claman, J., Reesal, R., et al (1993) Comparison of fluoxetine and desipramine in depressed outpatients. Current Therapeutic Research, 53, 457-465.Google Scholar
Remick, R. A., Reesal, R., Oakander, M., et al (1994) Comparison of fluvoxamine and amitriptyline in depressed outpatients. Current Therapeutic Research, 55, 243-250.Google Scholar
Robertson, M. M., Abou-Saleh, M. T., Harrison, D. A., et al (1994) A double-blind controlled comparison of fluoxetine and lofepramine in major depressive illness. Journal of Psychopharmacology, 8, 98-103.Google Scholar
Ropert, R. (1989) Fluoxetine versus clomipramine in major depressive disorders. International Clinical Psychopharmacology, 4 (suppl. 1), 89-95.Google Scholar
Rosenberg, C., Damsbo, N., Fuglum, E., et al (1994) Citalopram and imipramine in the treatment of depressive patients in general practice. A Nordic multicentre clinical study. International Clinical Psychopharmacology, 9 (suppl. 1), 41-48.CrossRefGoogle ScholarPubMed
Roth, D., Mattes, J., Sheehan, K. H., et al (1990) A double-blind comparison of fluvoxamine, desipramine and placebo in outpatients with depression. Progress in Neuropsychopharmacology, Biology & Psychiatry, 14, 929-939.CrossRefGoogle ScholarPubMed
Rush, A. J., Armitage, R., Gillin, J. C., et al (1998) Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder. Biological Psychiatry, 44, 3-14.Google Scholar
Schnyder, U. & Koller-Leiser, A. (1996) A double-blind, multicentre study of paroxetine and maprotiline in major depression. Canadian Journal of Psychiatry, 41, 239-244.Google Scholar
Shaw, D. M., Thomas, D. R., Briscoe, M. H., et al (1986) A comparison of the antidepressant action of citalopram and amitriptyline. British Journal of Psychiatry, 149, 515-517.Google Scholar
South Wales Antidepressant Drug Trial Group (1988) A double-blind multi-centre trial of fluoxetine and dothiepin in major depressive illness. International Clinical Psychopharmacology, 3, 75-81.Google Scholar
Staner, L., Kerkhofs, M., Detroux, D., et al (1995) Acute, subchronic and withdrawal sleep EEG changes during treatment with paroxetine and amitriptyline: a double-blind randomized trial in major depression. Sleep, 18, 470-477.Google ScholarPubMed
Stark, P. & Hardison, C. D. (1985) A review of multicenter controlled studies of fluoxetine vs imipramine and placebo in out patients with major depressive disorder. Journal of Clinical Psychiatry, 46, 53-58.Google Scholar
Stott, P. C., Blagden, M. D. & Aitken, C. A. (1993) Depression and associated anxiety in primary care: a double-blind comparison of paroxetine and amitriptyline. European Neuropsychopharmacology, 3, 324-325.Google Scholar
Stratta, P., Bolino, F., Cupillari, M., et al (1991) A double-blind parallel study comparing fluoxetine with imipramine in the treatment of atypical depression. International Clinical Psychopharmacology, 6, 193-196.Google Scholar
Stuppaeck, C. H., Geretsegger, C., Whitworth, A. B., et al (1994) A multicenter double-blind trial of paroxetine versus amitriptyline in depressed inpatients. Journal of Clinical Psychopharmacology, 14, 241-246.Google Scholar
Szegedi, A., Wetzel, H., Angersbach, D., et al (1997) Response to treatment in minor and major depression: results of a double-blind comparative study with paroxetine and maprotiline. Journal of Affective Disorders, 45, 167-178.Google Scholar
Timmerman, L., de Beurs, P., Tan, B. K., et al (1987) A double-blind comparative clinical trial of citalopram vs maprotiline in hospitalized depressed patients. International Clinical Psychopharmacology, 2, 239-253.Google Scholar
Tollefson, G. D., Greist, J. H., Jefferson, J. W., et al (1994) Is baseline agitation a relative contraindication for a selective serotonin reuptake inhibitor: a comparative trial of fluoxetine versus imipramine. International Clinical Psychopharmacology, 14, 385-391.Google ScholarPubMed
Tylee, A., Beaumont, G., Bowden, M. W., et al on behalf of the General Practice Study Group (1997) A double-blind randomized, 12 week comparison study of the safety and efficacy of venlafaxine and fluoxetine in moderate to severe major depression in general practice. Primary Care Psychiatry, 3, 51-58.Google Scholar
Young, J. P. R., Coleman, A. & Lader, M. H. (1987) A controlled comparison of fluoxetine and amitriptyline in depressed out-patients. British Journal of Psychiatry, 151, 337-340.Google Scholar

References

Abdelmawla, A. H., Langley, R. W., Szabadi, E., et al (1999) Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline- and methoxamine-evoked constriction of the dorsal hand vein. British Journal of Clinical Pharmacology, 48, 345354.Google Scholar
Anderson, I. M. (1998) SSRIs versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depression and Anxiety, 7, 1117.Google Scholar
Anderson, I. M. (2000) Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. Journal of Affective Disorders, 58, 1936.CrossRefGoogle ScholarPubMed
Austin, M-P. V., Souza, F. G. M. & Goodwin, G. M. (1991) Lithium augmentation in antidepressant-resistant patients: a quantitative analysis. British Journal of Psychiatry, 159, 510514.Google Scholar
Barker, E. L. & Blakely, R. D. (1995) Norepinephrine and serotonin transporters. Molecular targets of antidepressant drugs. In: Psychopharmacology: The Fourth Generation of Progress (eds Bloom, F. E. & Kupfer, D. J.), pp. 321333. New York: Raven Press.Google Scholar
Blashki, T. G., Mowbray, R. & Davies, B. (1971) Controlled trial of amitriptyline in general practice. British Medical Journal, i, 133138.CrossRefGoogle Scholar
Bolden-Watson, C. & Richelson, E. (1993) Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sciences, 52, 10231029.Google Scholar
British Medical Association & Royal Pharmaceutical Society of Great Britain (1997) British National Formulary. London & Wallingford: BMJ Books & Pharmaceutical Press.Google Scholar
Clerc G. E., Rujmy, P., Verdeau-Paillès, J. on behalf of the Venlafaxine French Inpatient Study Group (1994) A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. International Clinical Psychopharmacology, 9, 139143.CrossRefGoogle Scholar
Cusack, B., Nelson, A. & Richelson, E. (1994) Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology, 114, 559565.Google Scholar
Davis, D., Thomson O'Brien, M. A., Freemantle, N., et al (1999) Impact of formal continuing medical education: Do conferences, workshops, rounds and other traditional continuing education activities change physician behavior or health care outcomes? Journal of the American Medical Association, 282, 867874.Google Scholar
Donaghue, J. M. & Tylee, A. (1996) The treatment of depression: prescribing patterns of antidepressants in primary care in the UK. British Journal of Psychiatry, 168, 164168.Google Scholar
Freemantle, N., Cleland, J. G. F., Young, P., et al (1999) What is the current place of blockade in secondary prevention after myocardial infarction? A systematic overview and meta regression analysis. British Medical Journal, 318, 17301737.Google Scholar
Geddes, J. R., Freemantle, N., Mason, J., et al (2000) SSRIs versus alternative antidepressants in depressive disorder. Cochrane Library, issue 3. Oxford: Update Software.Google Scholar
Gilks, W. R., Richardson, S. & Spiegelhalter, D. J. (1996) Markov Chain Monte Carlo in Practice. London: Chapman & Hall.Google Scholar
Guy, W. (1976) FCDFU Assessment Manual for Psychopharmacology (Revised). Rockville, MD: National Institute for Mental Health.Google Scholar
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology Neurosurgery and Psychiatry, 23, 5662.CrossRefGoogle ScholarPubMed
Healy, D. (1997) The Antidepressant Fra. London: Harvard University Press.Google Scholar
Hedges, L. V. & Olkin, I. (1985) Statistical Methods for Meta Analysis. London: Academic Press.Google Scholar
Lingjaerde, O. (1985) From clomipramine to mianserin: therapeutic relevance of interactions with serotonin uptake and storage, as studied in the blood platelet model. Acta Psychiatrica Scandinavica Supplementum, 320, 1019.Google Scholar
Montgomery, S. A. & Åsberg, M. (1979) A new depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382389.CrossRefGoogle ScholarPubMed
Nelson, J. C., Mazure, C. M., Bowers, M. B., et al (1991) A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Archives of General Psychiatry, 48, 303307.Google Scholar
Ohsuka, N., Mashiko, H., Kaneko, M., et al (1995) Effects of antidepressants and antipsychotics on the 5-HT2 receptor-mediated signal transducing system in human platelets. Psychopharmacology, 121, 428432.Google Scholar
Pälvimäki, E. P., Roth, B. L., Majasuo, H., et al (1996) Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2C receptor. Psychopharmacology, 126, 234240.Google Scholar
Richelson, E. & Pfenning, M. (1984) Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. European Journal of Pharmacology, 104, 277288.Google Scholar
Rudolph, R. L., Entsuah, R. & Chitra, R. (1998) A meta-analysis of the effects of venlafaxine on anxiety associated with depression. Journal of Clinical Psychopharmacology, 18, 136144.CrossRefGoogle ScholarPubMed
Smith, T. C., Spiegelhalter, D. J. & Thomas, A. (1995) Bayesian approaches to random-effects meta analysis: a comparative study. Statistics in Medicine, 14, 26852699.CrossRefGoogle ScholarPubMed
Tatsumi, M., Groshan, K., Blakely, R. D., et al (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. European Journal of Pharmacology, 340, 249258.CrossRefGoogle ScholarPubMed
Thompson, C. & Thompson, C. M. (1989) The prescribing of antidepressants in general practice. II A Placebo-controlled trial of low-dose dothiepin. Human Psychopharmacology, 4, 191204.Google Scholar
Wander, T. J., Nelson, A., Okazaki, H., et al (1986) Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro. European Journal of Pharmacology, 132, 115121.Google Scholar
Figure 0

Table 1 Selected pharmacological action of antidepressants in humans

Figure 1

Table 2 Major characteristics of included trials (references are listed in the Appendix)

Figure 2

Fig. 1 Coefficient values for predictive value of receptor site activity.For each coefficient described, the vertical line describes the point estimate of effect, and the diamond describes the limits of the 95% confidence intervals. The approach to estimation does not force assumptions of symmetry for confidence intervals. For pharmacological activity, a coefficient value less than zero implies an advantage for the presence of the factor described.For the structural factors examined:Setting: a positive value would suggest an increased efficacy for selective serotonin reuptake inhibitors (SSRIs) in in-patientsAge: a positive value would imply an increased efficacy for SSRIs where only those over 65 years are includedMethod: a positive value would imply an increased efficacy for SSRIs in studies that used last observation carried forward instead of end-point analysisScale: a positive value would imply an advantage for SSRIs where the Hamilton Depression Rating Scale was usedDose: a positive result would imply an advantage for SSRIs when a higher dose comparator was usedFunding: a positive result would imply an advantage for the sponsor's drug.

Figure 3

Table 3 Predictive effects of pharmacological action and other study factors

Submit a response

eLetters

No eLetters have been published for this article.