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        Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: A meta-analysis
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        Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: A meta-analysis
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        Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: A meta-analysis
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Abstract

Background

In individual studies and limited meta-analyses venlafaxine has been reported to be more effective than comparator antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs).

Aims

To perform a systematic review of all such studies.

Method

We conducted a systematic review of double-blind, randomised trials comparing venlafaxine with alternative antidepressants in the treatment of depression. The primary outcome was the difference in final depression rating scale value, expressed as a standardised effect size. Secondary outcomes were response rate, remission rate and tolerability.

Results

A total of 32 randomised trials were included. Venlafaxine was more effective than other antidepressants (standardised effect size was −0.14, 95% Cl −0.07 to −0.22). A similar significant advantage was found against SSRIs (20 studies) but nottricyclic antidepressants (7 studies).

Conclusions

Venlafaxine has greater efficacy than SSRIs although there is uncertainty in comparison with other antidepressants. Further studies are required to determine the clinical importance of this finding.

Footnotes

The Editor, Greg Wilkinson, is in receipt of a consultancy fee from Neurolink (sponsored by Wyeth) so took no part in, and was kept blind to, the assessment of this paper. After enquiries by Professor Wilkinson, neither the Editorial Board member who acted as Editor in respect of this paper, nor those assessors who took part in the peer-review process, declared any interest relevant to the publication of this paper.

Declaration of interest

The study was funded by Wyeth Laboratories. D. S. has received funding on another study from Wyeth Laboratories and N. F. and I. A. have received speaker's fees and honoraria in connection with this work.

Depressive disorders are the second most important cause of disability in developed countries (Reference Murray and LopezMurray & Lopez, 1997) but a substantial minority of depressed patients fail to respond to antidepressant treatment (Reference Anderson, Nutt and DeakinAnderson et al, 2000). Although newer antidepressants have tolerability and safety benefits over older tricyclic antidepressants (TCAs), similar efficacy generally is reported (Reference EdwardsEdwards, 1992; Reference Gross and HuberGross & Huber, 1999; Reference AndersonAnderson, 2000; Reference Geddes, Freemantle and MasonGeddes et al, 2001). It is potentially of great clinical importance if an antidepressant were to be more effective than comparators, and understanding why may shed light on how antidepressants work. It has been proposed (Reference Nelson, Mazure and BowersNelson et al, 1991; Reference Seth, Jennings and BindmanSeth et al, 1992; Reference Heninger, Delgado and CharneyHeninger et al, 1996) that antidepressants with a dual action of inhibiting the reuptake of both noradrenalin and serotonin (5-hydroxytryptamine, 5-HT) may be more effective than drugs acting on a single monoamine (e.g. selective serotonin reuptake inhibitors, SSRIs). Venlafaxine is the first drug to be marketed that inhibits both noradrenalin and 5-HT reuptake without actions at other receptors (Reference Holliday and BenfieldHolliday & Benfield, 1995). We present a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with other antidepressants.

METHOD

Relevant trials were identified from our existing database (Reference Eccles, Freemantle and MasonEccles et al, 2000) and from systematic searches of electronic databases. The search terms were VENLAFAXINE, EFEXOR or EFFEXOR. Databases searched included Medline, Embase, Biosis, PsychLit, National Research Register, Healthstar, SIGLE, Cochrane Database of Systematic Reviews, DARE, Cochrane Controlled Trials Register and Current Controlled Trials. A total of 2349 trials were identified from our electronic search strategy. We carried out a manual search of reference lists of included studies and requested unpublished data from authors and study sponsors.

Inclusion criteria

Trials were included if they were double-blind, randomised studies comparing venlafaxine with an alternative antidepressant for the treatment of depression. The definition of depression was intentionally broad and included explicit clinical or research criteria for major depression (such as DSM-IV; American Psychiatric Association, 1994) or if the clinician considered the patient to be depressed and eligible for antidepressant treatment. Two of the researchers (D. S. and C. D.) made an independent assessment of each potentially eligible study and disagreements were resolved through discussion within the team.

Data abstraction

Design characteristics and quality assessment

We abstracted data on the inclusion and exclusion criteria for each study, the dose and regimen of venlafaxine and alternative antidepressants, the adequacy of randomisation and concealment of allocation (as reported in the paper), number of patients randomised, loss to follow-up, form of analysis (completer analysis or last observation carried forward), relevant clinical outcomes reported, age and gender of participants and length of follow-up. When specific variables were not reported within a given trial, the authors of the paper were contacted to obtain the missing data. If this was unsuccessful, we contacted the sponsors. Data were abstracted on all available patients randomised in the trials and patients were analysed on the basis of initial random allocation to treatment group (intention to treat) whenever possible.

Clinical outcomes

The primary outcome was the mean depression severity measure assessed by the final (end of trial) Hamilton Rating Scale for Depression (HRSD; Reference HamiltonHamilton, 1960), the Montgomery and Åsberg Depression Rating Scale (Reference Montgomery and ÅsbergMontgomery & Åsberg, 1979) or the Clinical Global Impression (Reference GuyGuy, 1976), with preference given in that order if more than one scale was reported. Secondary outcome variables were response rate (typically 50% or greater drop in depression rating scale from baseline) and remission rate (depression rating scale below a certain score, e.g. HRSD <8). Data on tolerability were abstracted by collecting ‘all cause’ withdrawals from each treatment group and also the attributed reason for withdrawal from therapy (lack of efficacy and adverse effects).

Statistical analysis

The primary efficacy outcome was the pooled standardised difference in mean treatment effect. For this measure, standardised effect sizes (difference in final rating scale means divided by the within-study standard deviation) were estimated from the efficacy data for each treatment group. Where an estimate of study variance was not available, this was imputed by taking the average for the studies using the same outcome measure. Secondary binary outcomes of response and remission, as well as tolerability data, were calculated as the odds ratio and absolute risk difference.

A simulation method was used to estimate pooled treatment effects using Gibbs sampling in BUGS software (Reference Smith, Spiegelhalter and ThomasSmithet al, 1995; Reference Freemantle, Cleland and YoungFreemantle et al, 1999). This method is analogous to standard methods but does not require large sample assumptions, making it superior in meta-analysis where these assumptions frequently are not met. It has the additional advantage that the predictive value of different factors, such as patient severity or dose, may be examined using meta-regression approaches (Reference Freemantle, Cleland and YoungFreemantle et al, 1999). Absolute risk differences were calculated using standard methods (Reference DerSimonian and LairdDerSimonian & Laird, 1986) and interpreted as ‘number needed to treat’ (NNT). Negative NNTs are often described as ‘number needed to harm’.

Fixed effects approaches to meta-analysis assume that each trial contributes an estimate of a constant population effect for a treatment, whereas random effects approaches assume that there is no single population effect but a distribution (range) of effects. Random effects models were used where venlafaxine was compared with a variety of agents (e.g. in comparison with SSRIs) but fixed effects models were used where venlafaxine was compared with individual agents.

Meta-regression was used to examine the predictive value of potentially important explanatory factors on the primary efficacy outcome measure (Reference Freemantle, Cleland and YoungFreemantle et al, 1999). This hierarchical approach to data modelling enables examination of the effect of trial characteristics while preserving the structure of individual trials. The factors that we identified a priori were: size of trial; in-patient v. out-patient status; design criteria (last observation carried forward v. completer analysis). The analysis on size of trial is a particularly helpful method of identifying potential publication bias and is analogous to using a funnel plot. Other factors also investigated were age and gender, comparator drug class, length of follow-up, rating scale used (e.g. HRSD or Montgomery and Å sberg Depression Rating Scale), dose of venlafaxine and if the variance was imputed.

RESULTS

Included trials

A total of 32 studies met the inclusion criteria (Table 1), with comparisons of venlafaxine with TCAs (clomipramine, imipramine, dothiepin (dosulepin) and amitriptyline), SSRIs (fluoxetine, fluvoxamine, paroxetine and sertraline) and other drugs (trazodone and mirtazapine). There were 5562 patients in totalFootnote 1 : 3844 in the twenty trials comparing venlafaxine with SSRIs (SSRI n=1857); 1356 in the nine trials comparing venlafaxine with TCAs (TCA n=579); and 418 in the three trials comparing venlafaxine with other drugs (othern=212). The average trial size was 179 patients (range 28-382). The average length of follow-up was 10 weeks (range 4-48). Most trials used the last observation carried forward for the primary analysis (see Table 1). For three of the trials, we imputed the measure of variance because the data were not available and could not be obtained from the authors or sponsors. None of the trials indicated whether concealment of allocation was conducted appropriately.

Table 1 Description of included trials1

Drug class Comparator Trial Citation No. of studies No. of patients Venlafaxine dose Mean age Female (%) Method Setting
TCA 9 1508 1315 50 685
Amitriptyline Gentil et al, 2000 23 1 116 103 39 81 LOCF Out-patient
Clomipramine Smeraldi et al, 1998 24 2 113 83 72 73 LOCF Out-patient
Samuelian & Hackett, 1998 25 102 105 47 62 LOCF Out-patient
Dothiepin (dosulepin) Mahapatra & Hackett, 1997 26 2 92 100 74 70 LOCF Out-patient
Stanley et al, 1998 14 86 75 NA NA Completers Out-patient
Imipramine Shrivastava et al, 1994 27 4 381 165 43 54 LOCF Out-patient
Benkert et al, 1996 28 167 233 47 68 LOCF In-patient
Lecrubier et al, 1997 29 153 111 40 69 LOCF Out-patient
Schweizer et al, 1994 30 146 182 42 66 LOCF Out-patient
SSRI 20 3989 1505 47 675
Fluoxetine Costa & Silva, 1998 31 13 382 91 40 79 LOCF Out-patient
Tylee et al, 1997 15 341 75 45 71 Completers Out-patient
Dierick et al, 1996 32 314 111 44 65 LOCF Out-patient
Rudolph et al, 1998 33 308 300 Not clear Out-patient
Silverstone & Ravindran, 1999 34 249 141 42 60 Completers Out-patient
Schatzberg & Cantillon, 2000 35 204 150 71 50 LOCF Out-patient
Rudolph & Feiger, 1999 36 203 175 40 70 LOCF Out-patient
Unpublished data2 37 196 150 NA NA LOCF Out-patient
Unpublished data3 38 156 150 NA NA LOCF Out-patient
Geerts et al, 1999 39 146 102 43 68 LOCF Out-patient
Tzanakaki et al, 2000 40 109 225 48 79 LOCF In-patient
Alves et al, 1999 41 87 113 NA NA LOCF Out-patient
Clerc et al, 1994 42 68 200 51 68 LOCF In-patient
Fluvoxamine Unpublished data4 43 2 92 150 NA NA LOCF Out-patient
Zanardi et al, 2000 44 28 225 51 64 LOCF In-patient
Paroxetine McPartlin et al, 1998 45 4 361 75 45 68 LOCF Out-patient
Salinas, 1997 46 246 113 47 63 LOCF Out-patient
Poirier & Boyer, 1999 47 123 269 43 72 LOCF Out-patient
Ballus et al, 2000 48 84 113 NA NA LOCF Out-patient
Sertraline Mehtonen et al, 2000 49 1 147 114 43 66 LOCF Out-patient
Other 3 418 1665 53 645
Mirtazapine Guelfi, 1999 50 1 157 255 45 64 LOCF In-patient
Trazodone Cunningham et al, 1994 51 2 149 160 41 55 LOCF Out-patient
Trazodone Smeraldi et al, 1998 24 112 83 72 72 LOCF Out-patient
Total 32 5562 1475 48 675

Primary outcome

There were 29 comparisons in the effect size analysis of clinical efficacy (Table 2). The overall effect size estimate was −0.14 (95% CI −0.22 to −0.07) in favour of venlafaxine. The size of effect (given a pooled standard deviation of 8.3) is equivalent to the final HRSD score, being about 1.2 points lower on venlafaxine. For the SSRIs, the effect size estimate was −0.17 (95% CI −0.27 to −0.08). Effect sizes for the TCAs and the ‘other drug’ categories were similar but not significantly different from venlafaxine (Table 2, Fig. 1).

Fig. 1 Plot of pooled efficacy of venlafaxine compared with other antidepressants. The bars show the effect size (difference in final rating scale score divided by pooled final standard deviation) and the 95% CI. Results falling to the left of the line of no effect (zero) indicate an advantage to venlafaxine.

Table 2 Effect size analysis

Class Comparator Effect size 95% CI Study
TCA Amitriptyline 0.26 -0.10 to 0.63 Gentil et al, 2000
Pooled amitriptyline 0.26 -0.10 to 0.63
Clomipramine 0.05 -0.32 to 0.42 Smeraldi et al, 1998
Clomipramine -0.11 -0.51 to 0.28 Samuelian & Hackett, 1998
Pooled clomipramine -0.03 -0.29 to 0.24
Dothiepin -0.02 -0.44 to 0.4 Mahapatra & Hackett, 1997
Dothiepin -0.18 -0.71 to 0.36 Stanley et al, 1998
Pooled dothiepin -0.08 -0.40 to 0.24
Imipramine -0.4 -0.64 to −0.16 Shrivastava et al, 1994
Imipramine -0.32 -0.65 to 0.02 Schweizer et al, 1994
Pooled imipramine -0.38 -0.57 to −0.19
Pooled TCA -0.13 -0.33 to 0.09
SSRI Fluoxetine -0.02 -0.22 to 0.19 Costa & Silva, 1998
Fluoxetine 0.18 -0.07 to 0.43 Tylee et al, 1997
Fluoxetine -0.18 -0.40 to 0.04 Dierick et al, 1996
Fluoxetine -0.14 -0.37 to 0.09 Rudolph et al, 1998
Fluoxetine -0.12 -0.37 to 0.14 Silverstone & Ravindran, 1999
Fluoxetine -0.48 -0.76 to −0.2 Schatzberg & Cantillon, 2000
Fluoxetine -0.21 -0.49 to 0.07 Rudolph & Feiger, 1999
Fluoxetine -0.22 -0.50 to 0.06 Unpublished data1
Fluoxetine 0.02 -0.30 to 0.35 Unpublished data2
Fluoxetine -0.5 -0.85 to −0.15 Geerts et al, 1999
Fluoxetine -0.08 -0.46 to 0.3 Tzanakaki et al, 2000
Fluoxetine -0.34 -0.77 to 0.1 Alves et al, 1999
Fluoxetine -0.58 -1.06 to −0.09 Clerc et al, 1994
Pooled fluoxetine -0.14 -0.22 to −0.06
Fluvoxamine 0.56 -0.23 to 1.34 Zanardi et al, 2000
Pooled fluvoxamine 0.56 -0.23 to 1.34
Paroxetine -0.1 -0.31 to 0.12 McPartlin et al, 1998
Paroxetine -0.46 -0.73 to −0.19 Salinas, 1997
Paroxetine -0.07 -0.42 to 0.29 Poirier & Boyer, 1999
Paroxetine -0.07 -0.50 to 0.37 Ballus et al, 2000
Pooled paroxetine -0.19 -0.34 to −0.05
Sertraline -0.31 -0.67 to 0.06 Mehtonen et al, 2000
Pooled sertraline -0.31 -0.67 to 0.06
Pooled SSRI -0.17 -0.27 to −0.08
Other Mirtazapine 0.23 0.55 to −0.09 Guelfi, 1999
Pooled mirtazapine 0.23 0.55 to −0.09
Trazodone -0.11 -0.44 to 0.23 Cunningham et al, 1994
Trazodone -0.37 -0.74 to 0.01 Smeraldi et al, 1998
Pooled trazodone -0.23 -0.47 to 0.02
Pooled ‘other drug’ -0.09 -0.42 to 0.23
Overall pooled -0.14 -0.22 to −0.07

The results appeared consistent across the SSRIs but there were differences between the TCA studies, notably imipramine: the effect size was −0.38 (95% CI −0.57 to −0.19), favouring venlafaxine, whereas there was no benefit in studies against other TCAs (Table 2, Fig. 1).

Response rates

Table 3 shows the estimated response rates. The overall odds ratio for response was 1.27 (95% CI 1.07-1.52). The risk difference was 0.05 (95% CI 0.02-0.09), with an NNT of 19 (95% CI 11-63). The pooled results for different drug classes were similar to this overall effect (Fig. 2).

Fig. 2 Plot of pooled response rate to venlafaxine compared with other antidepressants. The bars show the odds ratio and the 95% CI. Results falling to the right of the line of no effect (I) indicate an advantage to venlafaxine.

Table 3 Response analysis

Class Comparator Odds ratio 95% Cl Study
TCA Amitriptyline 1.02 0.4-2.62 Gentil et al, 2000
Pooled amitriptyline 1.02 0.4-2.62
Clomipramine 0.54 0.21-1.36 Smeraldi et al, 1998
Clomipramine 1.92 0.8-4.64 Samuelian & Hackett, 1998
Pooled clomipramine 1.02 0.57-1.83
Dothiepin 1.04 0.41-2.63 Mahapatra & Hackett, 1997
Pooled dothiepin 1.04 0.41-2.63
Imipramine 1.72 1.04-2.87 Shrivastava et al, 1994
Imipramine 0.76 0.39-1.47 Benkert et al, 1996
Imipramine 2.55 1.1-6.14 Lecrubier et al, 1997
Imipramine 2.18 0.79-6.14 Schweizer et al, 1994
Pooled imipramine 1.51 1.10-2.07
Pooled TCA 1.29 0.89-1.85
SSRI Fluoxetine 0.99 0.55-1.78 Costa & Silva, 1998
Fluoxetine 0.82 0.47-1.43 Tylee et al, 1997
Fluoxetine 0.54 0.33-0.87 Dierick et al, 1996
Fluoxetine 1.59 0.96-2.61 Rudolph et al, 1998
Fluoxetine 1.29 0.74-2.27 Silverstone & Ravindran, 1999
Fluoxetine 1.42 0.79-2.56 Schatzberg & Cantillon, 2000
Fluoxetine 1.32 0.73-2.39 Rudolph & Feiger, 1999
Fluoxetine 0.97 0.47-1.97 Unpublished data1
Fluoxetine 2.63 1.2-5.82 Geerts et al, 1999
Fluoxetine 1.44 0.6-3.5 Tzanakaki et al, 2000
Fluoxetine 2.26 0.64-9.05 Alves et al, 1999
Fluoxetine 2.67 0.86-8.45 Clerc et al, 1994
Pooled fluoxetine 1.17 0.99-1.38
Fluvoxamine 1.41 0.51-3.82 Unpublished data2
Pooled fluvoxamine 1.41 0.51-3.82
Paroxetine 1.01 0.58-1.75 McPartlin et al, 1998
Paroxetine 1.49 0.68-3.29 Poirier & Boyer, 1999
Paroxetine 1.15 0.43-3.07 Ballus et al, 2000
Pooled paroxetine 1.14 0.78-1.67
Sertraline 2.27 0.88-6.08 Mehtonen et al, 2000
Pooled sertraline 2.27 0.88-6.08
Pooled SSRI 1.26 1.02-1.58
Other Mirtazapine 0.65 0.33-1.31 Guelfi, 1999
Pooled mirtazapine 0.65 0.33-1.31
Trazodone 1.7 0.78-3.75 Cunningham et al, 1994
Trazodone 2.06 0.89-4.78 Smeraldi et al, 1998
Pooled trazodone 1.88 1.11-3.17
Pooled ‘other drug’ 1.28 0.43-4.31
Overall pooled 1.27 1.07-1.52

Remission rates

Table 4 and Fig. 3 display the pooled remission results. The overall odds ratio for remission rate was 1.36 (95% CI 1.14-1.61), favouring venlafaxine. The overall risk difference was 0.07 (95% CI 0.03-0.11), giving an NNT of 14 (95% CI 9-29).

Fig. 3 Plot of pooled remission rate on venlafaxine compared with other antidepressants. The bars show the odds ratio and the 95% CI. Results falling to the right of the line of no effect (I) indicate an advantage to venlafaxine.

Table 4 Remission analysis

Class Comparator Odds ratio 95% Cl Study
TCA Amitriptyline 1.03 0.46-2.32 Gentil et al, 2000
Pooled amitriptyline 1.03 0.46-2.32
Pooled TCA 1.03 0.46-2.32
SSRI Fluoxetine 1.15 0.52-2.57 Costa & Silva, 1998
Fluoxetine 1.06 0.61-1.85 Tylee et al, 1997
Fluoxetine 1.49 0.9-2.47 Rudolph et al, 1998
Fluoxetine 1.02 0.6-1.75 Silverstone & Ravindran, 1999
Fluoxetine 1.8 0.97-3.35 Schatzberg & Cantillon, 2000
Fluoxetine 2.03 1.04-3.99 Rudolph & Feiger, 1999
Fluoxetine 1.43 0.59-3.51 Unpublished data1
Fluoxetine 2.17 1.02-4.62 Geerts et al, 1999
Fluoxetine 1.23 0.52-2.89 Tzanakaki et al, 2000
Fluoxetine 1.5 0.57-3.92 Alves et al, 1999
Pooled fluoxetine 1.42 1.17-1.73
Fluvoxamine 0.36 0.05-2.44 Zanardi et al,
Pooled fluvoxamine 0.36 0.05-2.44
Paroxetine 1.09 0.69-1.71 McPartlin et al, 1998
Paroxetine 1.59 0.89-2.82 Salinas, 1997
Paroxetine 2.68 1.08-6.87 Poirier & Boyer, 1999
Paroxetine 1.47 0.57-3.85 Ballus et al, 2000
Pooled paroxetine 1.4 1.05-1.88
Sertraline 2.57 1.15-5.82 Mehtonen et al, 2000
Pooled sertraline 2.57 1.15-5.82
Pooled SSRI 1.43 1.21-1.71
Other Mirtazapine 0.69 0.33-1.43 Guelfi, 1999
Pooled mirtazapine 0.69 0.33-1.43
Pooled ‘other drug’ 0.69 0.33-1.43
Overall pooled 1.36 1.14-1.61

Remission rates were measured in only 18 of the trials and, of these, 16 used an SSRI agent as the comparator. The result for the pooled SSRI comparison was similar to the overall effect.

None of the factors that were hypothesised to influence the estimate of primary outcome were significantly predictive of greater efficacy in meta-regression analyses (analysis not shown).

Meta-regression analysis and visual inspection of funnel plots provided no evidence of publication bias, although did not exclude the possibility of the existence of such bias.

Treatment discontinuation

Table 5 shows an analysis of drop-outs by reason and comparator drug class. The overall risk difference of −0.004 (95% CI −0.029 to 0.020) indicates that there are 0.4% fewer drop-outs overall in the venlafaxine group, and the difference is not statistically or clinically significant. The only statistically significant drop-out comparison exists for drop-outs due to side-effects compared with the ‘other drug’ category, where there is a risk difference of 0.221 (95% CI 0.065-0.376), giving an NNT of 5 (95% CI 3-15) in favour of other drugs. However, because the overall difference in drop-out is equivalent, this result is countered by drop-out for all other causes.

Table 5 Drop-out analysis by cause and drug class

Risk difference (venlafaxine minus comparator) Lower CL Upper CL NNT1 Lower CL Upper CL
All causes
All drugs -0.004 -0.029 0.020 -224 -34 49
SSRI 0.002 -0.025 0.029 494 -40 34
TCA -0.028 -0.089 0.033 -36 -11 30
Other drug -0.080 -0.196 0.035 -12 -5 28
Unsatisfactory response
All drugs -0.006 -0.016 0.004 -159 -62 275
SSRI -0.008 -0.019 0.003 -123 -52 350
TCA 0.003 -0.020 0.026 341 -50 39
Other drug -0.032 -0.123 0.059 -31 -8 17
Side-effects
All drugs 0.010 -0.007 0.026 105 -141 38
SSRI 0.017 -0.006 0.040 60 -161 25
TCA -0.025 -0.070 0.020 -40 -14 51
Other drug 0.221 0.065 0.376 5 15 3

DISCUSSION

Efficacy

This meta-analysis provides evidence that in the treatment of depressive disorders all antidepressants are not equal. Pooling data from all currently available studies reveals that venlafaxine carries an advantage of about 1.2 HRSD points over other antidepressants. The majority of comparisons were with SSRIs, where the effect appeared consistent across the different drugs. In contrast, it is less clear that the advantage is consistent across other antidepressants such as TCAs, where imipramine is the only individual drug that clearly demonstrates lesser efficacy. This does not, however, reduce the importance of the findings for the primary outcome measure — venlafaxinev. any other antidepressent in reducing symptoms of depression — in which a clear advantage was identified.

The results are of probable clinical significance, with an NNT of 19 (95% CI 11-63) for response and 14 (95% CI 9-29) for remission. The two data-sets do not include all of the same studies and are not as comprehensive as the data used in primary analysis of effect sizes, so the absolute figures must be viewed as approximate. However, this magnitude of advantage for venlafaxine over other antidepressants is potentially of considerable importance, given the often prolonged or even chronic nature of depressive episodes. It is increasingly recognised that improvement of depression on antidepressants is often incomplete or partial so that remission rates are relatively low (Reference FerrierFerrier, 1999) and only 42% of patients in the studies that we included achieved remission by the end of the study. Patients who fail to reach remission have significantly greater continuing morbidity and higher relapse rates than those who do experience remission (Reference Cornwall and ScottCornwall & Scott, 1997). If only one extra person reaches remission when treated with venlafaxine instead of an SSRI for every 14 patients treated, then this is a potentially important health benefit. It suggests that even if not used first line, venlafaxine should be considered for patients having an inadequate response to other antidepressants.

Our study confirms the more limited meta-analysis recently reported by Thase et al (Reference Thase, Entsuah and Rudolph2001), which only included a small subset (eight) of studies against SSRIs and therefore cannot be considered systematic. It only assessed efficacy using remission rates with an odds ratio of 1.5 (95% CI 1.3-1.9) in favour of venlafaxine. The NNT was not calculated formally but appears to be about 10 from the difference in remission rates (45% v. 35%); this is a greater advantage to venlafaxine than we found with a larger data-set.

Our analysis of the tolerability of venlafaxine as measured by total treatment drop-outs and those due to side-effects did not suggest that greater efficacy was offset by poorer tolerability overall or against SSRIs or TCAs. More patients dropped out of treatment owing to side-effects on venlafaxine than trazodone or mirtazapine, suggesting poorer tolerability than these drugs, but the small number of studies makes it difficult to draw conclusions.

Mechanism underlying venlafaxine's greater efficacy

We have reported previously being unable to identify a relationship between pharmacology and efficacy using a meta-regression analysis of a variety of antidepressants compared with SSRIs (Reference Freemantle, Anderson and YoungFreemantle et al, 2000). There were, however, considerable problems in that analysis, relating to being able to identify accurately the acute pharmacology of many antidepressants in vivo. In this study some of these problems are overcome through using a single agent and it appears that the most plausible mechanism by which venlafaxine may exert increased efficacy in comparison with SSRIs is its ability to inhibit not only 5-HT reuptake but also the reuptake of noradrenalin (Reference Holliday and BenfieldHolliday & Benfield, 1995). Whether this is the mechanism in the case of venlafaxine has yet to be confirmed, however. The profile of its binding to human monoamine transporters suggests a weak affinity for the noradrenalin transporter compared with the 5-HT transporter (Reference Owens, Morgan and PlottOwens et al, 1997; Reference Tatsumi, Groshan and BlakelyTatsumi et al, 1997). At lower doses, venlafaxine appears to act as an SSRI and it is unclear at what dose significant noradrenalin effects occur. Preliminary evidence suggests that, at least outside the brain, this is somewhere between 75 and 225 mg, with one study suggesting that it may occur by 150 mg (Reference Abdelmawla, Langley and SzabadiAbdelmawla et al, 1999). It is of interest that previous meta-analyses have suggested superior efficacy for amitriptyline against other antidepressants, particularly SSRIs (Reference AndersonAnderson, 2000; Reference Barbui and HotopfBarbui & Hotopf, 2001), which adds some support to dual action conferring greater efficacy than occurs when blocking the reuptake of a single transmitter.

We did not find an effect of dose on the size of the advantage to venlafaxine over SSRIs, raising some question as to the mechanism underlying its greater efficacy. However, the studies in this meta-analysis were not designed to detect dose—response effects, most employing flexible dosing. The lack of an association between efficacy and a venlafaxine dose below or above 150 mg is probably against a strong linear dose—response over the range used but cannot rule out a non-linear relationship. Two fixed-dose studies of venlafaxine against placebo have suggested a dose—response over the range 60-225 mg (Reference KelseyKelsey, 1996; Reference Rudolph, Fabre and FeighnerRudolph et al, 1998), but the differentiation between doses has not been statistically significant and the dose at which any possible greater efficacy may arise is not clear.

Methodological considerations

The major methodological challenge to all systematic overviews is publication bias — the selective availability of trials with positive results. The comprehensive search strategies used to identify trials, the systematic attempts to identify unpublished trials and unpublished data and examination of the distribution of the results from included trials all mediate against the importance of this threat to the validity of the results of this overview. However, it has to be acknowledged that the majority of studies were sponsored by the company that markets venlafaxine and sponsorship has been suggested as a potential factor influencing the outcome of the trials (Reference Stewart and ParmarStewart & Parmar, 1996; Reference Freemantle, Anderson and YoungFreemantle et al, 2000).

Although over 5000 patients were included in the trials identified for this meta-analysis, this number is small against other clinical areas where this number of patients commonly may be included in a single trial. Further randomised trials, including those of a naturalistic design, involving larger numbers of patients in different clinical settings (particularly primary care, where the majority of treatment for major depressive disorder is conducted) are required to find out how generalisable this result is to different settings and whether venlafaxine has increased effectiveness in usual clinical practice.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

  1. The findings from this systematic review and meta-analysis provide some confidence that venlafaxine is more effective than selective serotonin reuptake inhibitors (SSRIs) with comparable tolerability.

  2. The size of this advantage is of probable clinical importance when the prolonged or chronic nature of depression is taken into account.

  3. Venlafaxine should be considered for patients in whom efficacy needs to be maximised and in those failing to respond to an SSRI.

LIMITATIONS

  1. Apart from the comparison with fluoxetine, there are insufficient comparisons between venlafaxine and individual SSRIs and other antidepressants to draw strong conclusions with regard to specific comparisons.

  2. Meta-analysis is dependent on the quality of individual studies included in the analysis.

  3. Drop-outs are a relatively crude proxy for tolerability.

1 Multiple comparisons were made in a number of trials. As a quality criterion, and a rule of thumb, we cite the total number of patients in the trials, rather than the comparisons included, because there is good empirical evidence that the quality of studies is affected directly by the overall size.

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