University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA
Clinical Research and Development, Wyeth-Ayerst Research, Philadelphia, PA, USA
Correspondence: Michael E. Thase, Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213-2593, USA
Declaration of interest M.E.T. is a paid consultant to Wyeth-Ayerst Laboratories, the employer of A.R.E. and R.L.R.
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ABSTRACT |
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Aims To compare remission rates during treatment with SSRIs or venlafaxine.
Method Data from eight comparable randomised, double-blind studies
of major depressive disorder were pooled to compare remission rates (Hamilton
Rating Scale for Depression score 7) during treatment with venlafaxine
(n=851), SSRIs (fluoxetine, paroxetine, fluvoxamine; n=748)
or placebo (four studies; n=446).
Results Remission rates were: venlafaxine, 45% (382/851); SSRIs, 35% (260/748); placebo, 25% (110/446) (P < 0.001; odds ratio for remission is 1.50 (1.3-1.9), favouring venlafaxine v. SSRIs). The difference between venlafaxine and the SSRIs was significant at week 2, whereas the difference between SSRIs and placebo reached significance at week 4. Results were not dependent on any one study or the definition of remission.
Conclusions Remission rates were significantly higher with venlafaxine than with an SSRI.
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INTRODUCTION |
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METHOD |
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Patients
Patients could be enrolled if they were at least 18 years old and met the
criteria of the Diagnostic and Statistical Manual of Mental Disorders
(DSM; American Psychiatric Association,
1987,
1994) for major depression
(DSM-III-R) or major depressive disorder (DSM-IV) for at least 1 month. There
were 68 in-patients (one study, Clerc
et al, 1994) and 1977 out-patients; all patients had
minimum scores of either 20 on the HRSD21
(Hamilton, 1960) or 25 on the
Montgomery-sberg Depression Rating Scale
(MADRS; Montgomery &
sberg, 1979) at both pre-study and
baseline (study day -1), with no greater than a 20% decrease in severity
between pre-study and baseline evaluations.
Patients with clinically significant cardiovascular, renal or hepatic disease, seizure disorders, a recent history of alcohol or drug misuse or clinically significant abnormalities on baseline physical examination, electrocardiogram (ECG) or laboratory tests were excluded from participation. Patients who were hypersensitive to the study drugs or had used any investigational or antipsychotic drug within 30 days, a monoamine oxidase inhibitor within 14 days or other antidepressant, anxiolytic, sedative-hypnotic or non-psychopharmacological drugs with psychotropic effects within 7 days of double-blind treatment also were excluded. Chloral hydrate (maximum 2000 mg) or temazepam (20 mg; one study) were permitted as hypnotics. Table 2 summarises the socio-demographic and pre-treatment clinical characteristics of the pooled study groups.
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Study drugs
Patients were randomly assigned to treatment with venlafaxine
(n=865), an SSRI (fluoxetine, n=563; paroxetine,
n=160; or fluvoxamine, n=34) or placebo (four studies only,
n=450) during the double-blind treatment period at the daily dosages
shown in Table 1.
Efficacy and safety assessments
The HRSD, MADRS and Clinical Global Impression Severity of Illness
(CGI-S) (National Institute of Mental
Health, 1985) were performed at study day -1, prior to
double-blind therapy. These measures (along with the CGI improvement score)
were reassessed on study days 7, 14, 21, 28, 42 and, if available, 56.
Remission was defined as a total score of 7 on the first 17 items of the
HRSD (Frank et al,
1991).
Safety and tolerability were evaluated on the basis of adverse events that were recorded throughout the study evaluation period and changes that occurred in the physical examination, vital signs, 12-lead ECG recordings and clinical laboratory tests during treatment. For this report, only the proportions of patients withdrawn from double-blind therapy because of side-effects and lack of efficacy were compared.
Statistical analyses
The analyses were performed on data from a modified intent-to-treat sample,
which included all patients who received at least one dose of study medication
and had at least one HRSD evaluation during therapy. Remission rates were
calculated using the last-observation-carried-forward (LOCF) method, which
allowed the inclusion of patients who were withdrawn early. Pairwise
comparisons of remission rates were made with Fisher's exact test. All tests
of hypotheses were two-sided. Results of statistical analyses were considered
significant when P was 0.05. The 95% confidence intervals (CIs)
for differences in remission rates between groups were calculated for the
pooled data at each interval. The odds ratios for remission with a 95% CI
(Rothman, 1986) were also
calculated for venlafaxine or an SSRI v. placebo and for venlafaxine
v. the SSRIs. Homogeneity of the odds ratios across studies was
tested with the BreslowDay test
(Breslow & Day, 1980).
Analyses of various subgroups were performed to corroborate the overall
findings, including studies using the extended-release or immediate-release
formulations, active-controlled studies, placebo-controlled studies, the
single inpatient study, the seven out-patient studies and studies utilising
fluoxetine v. those using other SSRIs. Additional analyses compared
alternative definitions of remission to ensure the robustness of the findings.
The following additional definitions were examined: HRSD21 7,
HRSD21
8, HRSD21
10, HRSD17
10
plus CGI=1, MADRS <10, and
50% decrease from baseline HRSD21
scores. Finally, a sensitivity analysis was performed by removing each
individual study from the pooled analysis, one at a time
(Thase et al,
1997).
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RESULTS |
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Final remission rates were 45% for venlafaxine (382/851), 35% for the SSRIs (260/748) and 25% for placebo (110/446). The differences for venlafaxine v. SSRIs, venlafaxine v. placebo and SSRIs v. placebo were highly statistically significant (P <0.001 for all comparisons).
Week-by-week comparisons are illustrated in Fig. 1. Venlafaxine was statistically significantly more effective than the SSRIs from week 2 onwards and versus placebo from week 3 onwards. The SSRI group had a significantly higher remission rate than the placebo group from week 4 onwards.
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The results of the eight individual studies are summarised in
Table 3. Odds ratios for
remission ranged from 1.0 to 3.5, with an overall odds ratio of 1.5 (95% CI
1.3-1.9). Thus, there was a 50% greater chance of remission during venlafaxine
treatment than during SSRI treatment. Testing for homogeneity of the odds
ratios revealed no significant difference (2=8.63, d.f.=7,
P=0.28). The sensitivity analysis similarly found that the
significant difference between venlafaxine and the SSRIs was not dependent on
any one study.
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Figure 2 illustrates the results for various subgroup comparisons. The differences between venlafaxine and the SSRIs were statistically significant for all but one of the subgroup analyses. The comparison of venlafaxine and SSRI that included only the four studies that were not placebocontrolled was not statistically significant (P=0.055).
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Figure 3 summarises the results according to multiple alternative outcome criteria. Regardless of the definition used, venlafaxine was significantly more effective than the SSRIs, and the SSRIs were significantly more effective than placebo.
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In total, 83 (9%) patients were withdrawn from venlafaxine therapy because of side-effects, compared with 57 (7%) SSRI-treated patients and 10 (2%) patients given placebo (Fisher's exact test, P=0.001, venlafaxine v. placebo and SSRI v. placebo; the venlafaxine v. SSRI comparison was not significant, P=0.185). A total of 33/895 (4%) of the venlafaxine-treated patients were withdrawn because of lack of efficacy, compared with 46/769 (6%) of patients given an SSRI and 63/453 (14%) of patients given placebo (Fisher's exact test, P=0.037, venlafaxine v. SSRI; P=0.001, venlafaxine v. placebo; P=0.001, SSRI v. placebo).
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DISCUSSION |
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Meta-analysis provides useful alternative methods to compare active treatments. For example, meta-analyses comparing tricyclic antidepressants and SSRIs found differences in subgroup comparisons not apparent in qualitative reviews (Anderson & Tomenson, 1994; Edwards & Anderson, 1999). However, because the statistical power of a conventional meta-analysis is determined by the number of studies included, a large number of comparative trials must be available. For comparisons between newer antidepressants, meeting this requirement is often difficult. A second type of meta-analysis, using the data of individual patients participating in a series of related clinical trials, permits powerful comparisons to be made with a much smaller number of studies. Such pooled analyses have been used to document the efficacy of monoamine oxidase inhibitors in the treatment of atypical depression (Quitkin et al, 1993), to examine the association between fluoxetine and suicidality (Beasley et al, 1991), to examine the effects of venlafaxine treatment on blood pressure (Thase, 1998) and to compare psychotherapy and pharmacotherapy (Thase et al, 1997; DeRubeis et al, 1999).
The clinical significance of the magnitude of the differences between venlafaxine and the SSRIs warrants comment. In a conventional antidepressant clinical trial, the size of the study groups is such that statistically significant effects parallel relatively large differences in response rates (i.e. 20-25%) that are clearly clinically significant. An analysis of pooled data from an extremely large group of patients, by contrast, would have the statistical power to detect differences in remission rates so small that they would be considered trivial by most (i.e. 3-5%). The difference in remission rates observed in our pooled analysis is roughly halfway between these extremes. Given the high prevalence of depression and the staggering associated illness burden, a 10% advantage in remission rates could have substantial public health implications, particularly if costs and tolerability are comparable. From another perspective, we observed that venlafaxine-treated patients had a 50% greater chance of attaining remission than patients treated with an SSRI. In terms of the number of patients needed to treat to realise a difference, ten patients would need to be treated with venlafaxine in order to obtain one extra case of remission when compared with the SSRIs. When considered together, these various indicators point to a clinically meaningful difference.
Relationships to pharmacological mechanisms
It is proposed that the greater efficacy of venlafaxine is the result of
reuptake inhibition of both serotonin and noradrenaline. Of course, reuptake
inhibition is not essential to therapeutic action and it is possible that
medications that potently and selectively affect either serotonergic or
noradrenergic neurotransmission may initiate cascades of intracellular events
that ultimately modulate the same changes in gene activity
(Duman et al, 1997).
Nevertheless, several previous studies found clomipramine, another potent dual
reuptake inhibitor, to have a significant advantage relative to SSRIs (see
Anderson & Tomenson, 1994). It appears that relatively higher doses of venlafaxine may be necessary to
achieve significant noradrenergic effects, as inferred from in vitro
(Muth et al, 1986;
Owens et al, 2000), animal
(Redrobe et al, 1998)
and human (Thase, 1998;
Harvey et al, 2000)
studies. Consistent with this, there is a clear doseresponse
relationship for venlafaxine (Rudolph
et al, 1998b) and patients who fail to benefit
from 75 mg/day often respond to higher doses
(Dierick et al, 1996;
Costa e Silva, 1998;
Diaz-Martinez et al,
1998; Mehtonen et al,
2000). Therefore, it is likely that the difference in efficacy
between venlafaxine and SSRIs is dose dependent. Unfortunately, the flexible
dose schedules utilised in five of the studies included in our meta-analysis
precluded a valid examination of doseresponse relationships. Research
using modern molecular biological techniques would help to confirm that the
greater antidepressant efficacy of venlafaxine is directly linked to a dual
reuptakeinhibitory mechanism of action.
Review of other comparative studies
The most important limitation of a pooled analysis is that the results can
be biased by selection of a non-representative group of studies. Our data set
included all eight comparative studies conducted by the WyethAyerst
Clinical Research and Development department; no studies were excluded.
However, there are at least 12 other studies comparing venlafaxine and SSRIs
for treatment of non-psychotic depression. Among these, three recently
completed studies (double-blind, placebo- and fluoxetine-controlled trials in
out-patients with melancholia, in-patients with melancholia or elderly
patients) could not be included because data analyses were not complete. The
remaining nine published studies were not included because we did not have
access to the original data sets (see Table
4).
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It is possible that the inclusion of these additional trials would have affected the findings of the current pooled analysis. We therefore conducted a qualitative review of the nine published studies. Two studies found no evidence of differences in response or remission rates (Tylee et al, 1997; McPartlin et al, 1998). These studies were conducted in primary care clinics and compared the minimum therapeutic dosages of venlafaxine (75 mg/day) and fluoxetine (20 mg/day) (Tylee et al, 1997) or paroxetine (20 mg/day) (McPartlin et al, 1998).
Two studies reported non-significant differences (Diaz-Martinez et al, 1998; Alves et al, 1999). Diaz-Martinez et al (1998) reported that 41% of 70 patients treated with venlafaxine (75-150 mg/day) remitted during an open-label but randomised 8-week trial, as compared with 36% of 75 patients treated with fluoxetine (20-40 mg/day). The difference was 30% (i.e. 50% v. 20%) among those who received either 150 mg/day of venlafaxine (n=18) or 40 mg/day of fluoxetine (n=15). However, this numerically large difference was not statistically significant (P=0.07) in such a small subsample. Alves et al (1999) found a 19% difference (30% v. 11%) in remission rates favouring venlafaxine (75-150 mg/day) over fluoxetine (20-40 mg/day), which again was not statistically significant in a relatively small study (n=87).
Two studies reported inconsistent findings, with significant results
favouring venlafaxine over fluoxetine using a global definition of remission
but not according to the final HRSD score (see
Table 4). Costa e Silva
(1998) observed remission
rates of 58% for venlafaxine (75-150 mg/day) and 35% for fluoxetine (20-40
mg/day) using a CGI numeric score of 1 to define remission, although 60% of
the patients in each group remitted when an HRSD score of 7 was the
criterion. Tzanakaki et al
(2000) similarly found that
the groups were comparable using an HRSD criterion (<7) but significantly
different according to the CGI definition (see
Table 4).
The three remaining studies found significant differences favouring
venlafaxine; these studies all utilised maximum doses of 150 mg/day.
Ballús et al
(2000) observed remission rates
of 59% for venlafaxine (75-150 mg/day) and 31% for paroxetine (20-40 mg/day).
Mehtonen et al
(2000), defining remission as
a score of <10 on the 21-item version of the HRSD, reported rates of 68%
for venlafaxine (75-150 mg/day) and 45% for sertraline (50-100 mg/day) among
completers at week 8. Poirier & Boyer
(1999) enrolled only patients
who had failed to respond to at least two previous trials of antidepressants.
About 75% had not responded to a prior course of SSRI therapy. They found a
19% advantage (37% v. 18%) in remission rates in favour of
venlafaxine (200-300 mg/day) relative to paroxetine (20-40 mg/day).
Although these studies used various durations of treatment and definitions
of remission, two conclusions are evident. First, there is no evidence that
venlafaxine is more effective than the SSRIs at minimum therapeutic doses.
Second, among the studies that permitted a venlafaxine dosage of 150
mg/day, there was a 14.4% average difference (range 5-23%) in remission rates
favouring venlafaxine. It appears that the results of our pooled analysis
would not have changed if we could have included these studies.
Other limitations
The generalisability of the results of a group of controlled clinical
trials, like those of the individual studies, is limited by the exclusion of
patients with more complex conditions, such as significant psychiatric and
medical comorbidities. Although this lessens the relevance of these results to
clinical practice, there is no reason to suspect that this exclusivity favours
venlafaxine over the SSRIs. Other potential shortcomings of pooled analyses
include problems with the reliability of dependent measures and the
possibility that the results may be influenced by the data from one or two
particularly large studies. We found significant differences between SSRIs and
placebo, however, which indicates that the assay sensitivity
(Leber, 1991) of the pooled
analysis was, at the least, sufficient to overcome measurement error. We also
confirmed that the differences were not attributable to any particular study
and extended across multiple definitions of remission.
Three more specific limitations can be considered. First, the SSRIs were lumped together as a class. Although there is no evidence that any SSRI is more effective than another, they are not truly interchangeable and some patients respond poorly to one SSRI but well to another (Edwards & Anderson, 1999). In this respect, our pooled analysis included a disproportionate number of patients treated with fluoxetine. The studies listed in Table 4 provide a broader range of comparisons and, in aggregate, yielded similar results. Nevertheless, among the 17 comparative studies included in the pooled analysis or summarised in Table 4, there is only one study each utilising fluvoxamine or sertraline and, to date, there are no studies of citalopram.
Second, all of the studies were short term. It is possible that a longer treatment period could have resulted in comparable remission rates.
Third, none of the studies used in the pooled analysis excluded patients who had failed to respond to other SSRIs. Because several SSRIs were already widely available when these studies were conducted, it is possible that the advantage observed for venlafaxine was delimited to a subgroup of patients who had previously failed trials of other SSRIs (see, for example, Poirier & Boyer, 1999).
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication January 31, 2000. Revision received August 10, 2000. Accepted for publication August 14, 2000.