Kaiser Center for Health Research, Portland, Oregon, USA
University of Dumfries and Galloway, Scotland
NHS Centre for Reviews and Dissemination, University of York
Department of Primary Care & General Practice, University of Birmingham
Neuroscience and Psychiatry Unit, University of Manchester, UK
Correspondence: Nick Freemantle, Department of Primary Care and General Practice, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Tel: +44 (0) 121 414 7943; fax: +44 (0) 121 414 6571; e-mail: N.Freemantle{at}bham.ac.uk
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.
* 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.
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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ABSTRACT |
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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 not tricyclic 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.
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INTRODUCTION |
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METHOD |
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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;
Hamilton, 1960), the
Montgomery and Åsberg Depression Rating Scale
(Montgomery & Åsberg,
1979) or the Clinical Global Impression
(Guy, 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 (Smith et al, 1995; Freemantle 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 (Freemantle et al, 1999). Absolute risk differences were calculated using standard methods (DerSimonian & 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 (Freemantle 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 Åsberg Depression Rating Scale), dose of venlafaxine and if the variance was imputed.
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RESULTS |
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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).
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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).
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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).
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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.
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DISCUSSION |
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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 (Ferrier, 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 (Cornwall & 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 (2001), 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
(Freemantle 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
(Holliday & 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
(Owens et al, 1997;
Tatsumi 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
(Abdelmawla et al,
1999). It is of interest that previous meta-analyses have
suggested superior efficacy for amitriptyline against other antidepressants,
particularly SSRIs (Anderson,
2000; Barbui & 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 doseresponse 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 doseresponse over the range used but cannot rule out a non-linear relationship. Two fixed-dose studies of venlafaxine against placebo have suggested a doseresponse over the range 60-225 mg (Kelsey, 1996; Rudolph 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
(Stewart & Parmar, 1996;
Freemantle 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.
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Clinical Implications and Limitations |
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LIMITATIONS
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APPENDIX: Studies included in the meta-analysis |
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Ballus, C., Quiros, G., de-Flores, T., et al (2000) The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder of dysthymia. International Clinical Psychopharmacology, 15, 43-48.[Medline]
Benkert, O., Gruender, G., Wetzel, H., et al (1996) A randomised, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. Journal of Psychiatric Research, 30, 441-451.[CrossRef][Medline]
Clerc, G. E., Ruimy, P. & Verdeau, P.J. (1994) A double-blind comparison of venlafaxine and fluoxetine in patients hospitalised for major depression and melancholia. International Clinical Psychopharmacology, 9, 139-143.[Medline]
Costa, E. & Silva, J. (1998) Randomised, double-blind comparison of venlafaxine and fluoxetine in outpatients with major depression. Journal of Clinical Psychiatry, 59, 352-357.[Medline]
Cunningham, L., Borison, R., Carman, J., et al (1994) A comparison of venlafaxine, trazodone and placebo in major depression. Journal of Clinical Psychopharmacology, 14, 99-106.[Medline]
Dierick, M., Ravizza, L., Realini, R., et al (1996) A double-blind comparison of venlafaxine and fluoxetine for treatment of major depression in outpatients. Progress in NeuroPsychopharmacology and Biological Psychiatry, 20, 57-71.[CrossRef][Medline]
Geerts, S., Lacante, P. & Migon, A. (1999) Venlafaxine versus fluoxetine in the treatment of depressed patients with concomitant anxiety. Journal of the European College of Neuropsychopharmacology, 9 (suppl. 5), S224.
Gentil, V., Kerr-Correa, F., Moreno, R., et al (2000) Double-blind comparison of venlafaxine and amitriptyline in outpatients with major depression with or without melancholia. Journal of Psychopharmacology, 14, 61-66.[Medline]
Guelfi, J. D. (1999) Efficacy and Tolerability of Mirtazapine versus Venlafaxine in Hospitalised, Severely Depressed Patients with Melancholia [Abstract]. London: Association of Clinical Neuropsychopharmacology.
Lecrubier, Y., Bourin, M., Moon, C-A.L., et al (1997) Efficacy of venlafaxine in depressive illness in general practice. Acta Psychiatrica Scandinavica, 95, 485-493.[Medline]
McPartlin, G. M., Reynolds, A., Anderson, C., et al (1998) A comparison of once-daily venlafaxine XR and paroxetine in depressed outpatients treated in general practice. Primary Care Psychiatry, 693, 127-132.
Mahapatra, S. N. & Hackett, D. (1997) A randomised, double-blind, parallel-group comparison of venlafaxine and dothiepin in geriatric patients with major depression. International Journal of Clinical Practice, 51, 209-213.[Medline]
Mehtonen, O., Sogaard, J., Roponen, P., et al (2000) Randomised, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. Journal of Clinical Psychiatry, 61, 95-100.[Medline]
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Rudolph R., Fabre, L., Feighner, J., et al (1998) A randomised, placebo-controlled, doseresponse trial of venlafaxine hydrochloride in the treatment of major depression. Clinical Psychiatry, 59, 116-122.
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Salinas, E. (1997) Once-daily venlafaxine XR versus paroxetine outpatients with major depression. Biological Psychiatry, 42 (suppl. 1), 297S.[CrossRef]
Samuelian, J. C. & Hackett, D. (1998) A randomised, double-blind, parallel-group comparison of venlafaxine and clomipramine in outpatients with major depression. Journal of Psychopharmacology, 12, 273-278.[Medline]
Schatzberg, A. & Cantillon, M. (2000) Antidepressant early response and remission with venlafaxine or fluoxetine in depressed geriatric patients. International Journal of Neuropsychopharmacology, 3 (suppl. 1), S191.
Schweizer, E., Feighner, J., Mandos, L. A., et al (1994) Comparison of venlafaxine and imipramine in the acute treatment of major depression in outpatients. Journal of Clinical Psychiatry, 55, 104-108.[Medline]
Shrivastava, R. K., Cohn, C., Crowder, J., et al (1994) Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression. Journal of Clinical Psychopharmacology, 14, 322-329.[Medline]
Silverstone, P. H. & Ravindran, A. (1999) Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. Venlafaxine XR 360 Study Group. Journal of Clinical Psychiatry, 60, 22-28.
Smeraldi, E., Rizzo, F. & Crespi, G. (1998) Double-blind, randomised study of venlafaxine, clomipramine and trazodone in geriatric patients with major depression. Primary Care Psychiatry, 4, 189-195.
Stanley, N., Kimber, S., Fairweather, D., et al (1998) Venlafaxine and dothiepin in depressed patients: a comparison of efficacy and effect on cognition and subjective sleep [Abstract P1044]. 11th European Congress of Neuropsychopharmacology. Paris, France.
Tylee, A., Beaumont, G., Bowden, M. W., et al (1997) A double-blind, randomised, 12-week comparison study of the safety and efficacy of venlafaxine and fluoxetine in moderate to severe depression in general practice. Primary Care Psychiatry, 3, 51-58.
Tzanakaki, M., Guazzelli, M., Nimatoudis, I., et al (2000) Increased remission rates with venlafaxine compared with fluoxetine in hospitalised patients with major depression and melancholia. International Clinical Psychopharmacology, 15, 29-34.[Medline]
Zanardi, R., Franchini, L., Serretti, A., et al (2000) Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. Journal of Clinical Psychiatry, 61, 26-29.
Received for publication July 8, 2001. Revision received January 18, 2002. Accepted for publication January 31, 2002.