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Brief Report   |    
Response to Tricyclic Antidepressants: Independent of Gender?
Tamar Wohlfarth, Ph.D.; Jitschak G. Storosum, M.D., Ph.D.; André J.A. Elferink, M.D., Ph.D.; Barbara J. van Zwieten, Ph.D.; Annemarie Fouwels, M.D.; Wim van den Brink, M.D., Ph.D.
Am J Psychiatry 2004;161:370-372. doi:10.1176/appi.ajp.161.2.370
Abstract

OBJECTIVE: The authors examined gender differences in response to tricyclic antidepressants. METHOD: A total of 30 randomized, placebo-controlled trials that included 3,886 patients (1,555 men and 2,331 women), submitted between 1979 and 1991 in order to obtain marketing authorization, were reviewed. Gender differences in response to treatment were tested in various multiple regression models using a variety of response definitions. RESULTS: Different response definitions all pointed to no gender difference in the efficacy of tricyclic antidepressants. The estimated effect size was similar for women younger and older than age 50 and for men. CONCLUSIONS: Tricyclic antidepressant response is independent of gender.

Abstract Teaser
Figures in this Article

Major depression occurs twice as often in women than in men (1). This may suggest other gender differences in etiology and pathogenesis of depression and thereby possible differences in efficacy of antidepressant treatment across gender lines.

Recent investigations of this issue have revealed conflicting results (24). One study that compared a tricyclic antidepressant to a selective serotonin reuptake inhibitor (SSRI) indicated that depressed women were more likely to show a favorable response to the SSRI (sertraline) than to the tricyclic antidepressant (imipramine), whereas for men the opposite was true (2). In contrast, the results of a data synthesis of nine studies (4) suggested no gender difference in response to tricyclics or to fluoxetine. However, the data for this latter study were collected in one clinic with overrepresentation of patients with atypical depression. In addition, response to antidepressants was measured in terms of Clinical Global Impression ratings rather than in terms of a depression-specific measure, which was different from the outcome measure used in the study where differences were observed (2).

The purpose of this study was to investigate gender differences in response to tricyclic antidepressants in terms of the Hamilton Depression Rating Scale, a depression-specific measure, in a data set that included 32 published and unpublished randomized placebo-controlled studies (5).

The database incorporated 32 studies submitted between 1979 and 1991 to the Medicines Evaluation Board as part of a registration dossier for different drugs under development. The Medicines Evaluation Board is the regulatory authority in the Netherlands that is responsible for granting marketing authorizations to medical compounds.

The studies consisted of three treatment arms: an experimental compound, an active control (tricyclic antidepressant), and placebo. The data for the placebo and the tricyclic antidepressant arms was made available to the Medicines Evaluation Board by the pharmaceutical companies.

All patients had received a DSM-III-R diagnosis of major depression. The Hamilton Depression Rating Scale was used as the outcome measure for efficacy.

Statistical analyses were based on the intent-to-treat population. This population included all patients who were randomly assigned to receive double-blind treatment, had taken at least one dose of study medication, and had at least one efficacy evaluation. The last observation was carried forward for patients who had dropped out before the planned end of the study.

Several outcome variables were examined: change in Hamilton depression scale scores from baseline to end of study, response rate (response defined as a 50% reduction from baseline in Hamilton depression scale score), remission rate (remission defined as a Hamilton depression scale score ≤7 [6]), and patient dropout rate. Gender differences in response to treatment on each of these outcomes were examined in each study by testing the interaction term between gender and treatment in a regression model (linear regression in the case of the Hamilton depression scale change score and logistic regression for response, remission, and dropout rates).

In addition, efficacy of tricyclic antidepressant compared with placebo in terms of Hamilton depression scale change scores was estimated separately among men and among women older and younger than 50 in order to evaluate the effect of hormonal status on response. This was done over all studies by using a random effect model meta-analysis.

Of the 32 submitted studies, two had no information about gender of responders and hence had to be excluded from further analysis. The remaining 30 studies included a total of 3,886 patients, of whom 2,331 (60%) were women, and 1,555 (40%) were men. The majority of women (1,809 [78%]) were younger than 50 years. Imipramine was the active comparator in 27 (90%) of the 30 studies; amitriptyline was the active comparator in the remaining three (10%).

Two studies (out of the 30 that were examined) showed a significant interaction (at the 0.05 level) between gender and treatment when change in Hamilton depression scale score was the dependent variable. With response as the dependent variable, two different studies showed a significant interaction; with remission as the defining variable, two yet different studies showed a significant interaction. With dropouts as the dependent variable, none of the studies showed a significant interaction. In some of the studies with significant interaction, women showed a more favorable response, whereas in others men responded better.

The random effect estimates (from the meta-analyses) of the difference in Hamilton depression scale score improvement between tricyclic antidepressants and placebo were essentially similar for men (–2.38, 95% confidence interval [CI]=–3.21 to –1.55), women older than 50 (–3.04, 95% CI=–5.08 to –1.01), and women younger than 50 (–2.44, 95% CI=–3.30 to –1.58). The heterogeneity test came out as nonsignificant for men (χ2=31.43, df=29, p<0.35) and for women younger than 50 (χ2=34.03, df=28, p=0.20). For women older than 50, heterogeneity was significant (χ2=39.27, df=23, p<0.02), but this is probably due to the small sample sizes in this stratum (more than half of the studies included less than 15 women older than 50 years).

The results presented in this study show no gender differences in response to tricyclic antidepressants in this large database consisting of 3,886 patients from 30 randomized clinical trials. Only few significant differences were found, and these are most likely the result of chance, given the number of comparisons that were performed. The fact that, depending on the measure of efficacy (i.e., change in Hamilton depression scale scores or rates of remission, response, or dropout), different sets of two studies showed significant treatment-by-gender interactions supports the contention that these interactions are chance results. With a type I error level of 5%, having two studies with significant results is only slightly higher than what could be expected by chance in a series of 30 studies. Furthermore, examination of the significant studies could not reveal any special characteristic that could distinguish these studies from the others. Finally, efficacy estimates based on a meta-analysis of these studies indicate that efficacy estimates were essentially similar among men and women older and younger than age 50.

These results corroborate those of Quitkin et al. (4), this time in a larger and more representative data set of depressed patients and using a variety of possible definitions of treatment efficacy, thereby providing more certainty regarding the generalizability of these results. The results suggest that previously found gender differences in response to tricyclics could have appeared by chance the same way as some of the studies presented in this study resulted in significant gender differences for some of the possible treatment outcome measures.

A limitation of this study is that only tricyclic antidepressants were examined. The issue of gender differences in response to SSRIs, which are much more widely used, remains unaddressed. It should also be noted that although no differential response of pre- and postmenopausal women was found, the power to detect a difference in this dataset was relatively small because of the few women older than 50. Other factors that may differentially influence efficacy were not examined in this paper. These include age, concomitant medication, and smoking status.

Received April 12, 2003; revision received July 3, 2003; accepted July 5, 2003. From the Medicines Evaluation Board of the Netherlands, Den Haag; and the Psychiatric Department of the Academic Medical Center, Amsterdam. Address reprint requests to Dr. Wohlfarth, Medicines Evaluation Board of the Netherlands, Kalvermarkt 53, P.O. Box 16229, 2500 BE Den Haag, the Netherlands; t.wohlfarth@CBG-MEB.nl (e-mail). The authors thank the following pharmaceutical companies for providing the data used in this study: Bristol-Meyers Squibb Company; Eli Lilly and Company; GlaxoSmithKline; H. Lundbeck A/S; Organon Inc.; Pfizer Inc.; Solvay Pharmaceuticals, Inc.; and Wyeth BV. The authors also thank Nefarma for making this study possible.

Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB: Sex and depression in the National Comorbidity Survey, I: lifetime prevalence, chronicity and recurrence. J Affect Disord  1993; 29:85–96
[PubMed]
[CrossRef]
 
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Harrison W, Keller MB: Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry  2000; 157:1445–1452
[PubMed]
[CrossRef]
 
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Keller MB: Reply to FM Quitkin: Gender differences in treatment response (letter). Am J Psychiatry  2001; 158:1532–1533
[CrossRef]
 
Quitkin FM, Stewart JW, McGrath PJ, Taylor BP, Tisminetzky MS, Petkova E, Ma YG, Klein DF: Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry  2002; 159:1848–1854
[PubMed]
[CrossRef]
 
Storosum JG, Elferink AJA, van Zwieten BJ, van den Brink W, Gersons BPR, Broekmans AW: Short-term efficacy of tricyclic antidepressants revisited: a meta-analytic study. Eur Neuropsychopharmacol  2001; 11:173–179
[PubMed]
[CrossRef]
 
Rios LP, Thase ME, Howland RH, Friedman ES, Simons AD, Tu XM: A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy. J Affect Disord  1997; 43:131–142
[PubMed]
[CrossRef]
 
+

References

Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB: Sex and depression in the National Comorbidity Survey, I: lifetime prevalence, chronicity and recurrence. J Affect Disord  1993; 29:85–96
[PubMed]
[CrossRef]
 
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Harrison W, Keller MB: Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry  2000; 157:1445–1452
[PubMed]
[CrossRef]
 
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Keller MB: Reply to FM Quitkin: Gender differences in treatment response (letter). Am J Psychiatry  2001; 158:1532–1533
[CrossRef]
 
Quitkin FM, Stewart JW, McGrath PJ, Taylor BP, Tisminetzky MS, Petkova E, Ma YG, Klein DF: Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry  2002; 159:1848–1854
[PubMed]
[CrossRef]
 
Storosum JG, Elferink AJA, van Zwieten BJ, van den Brink W, Gersons BPR, Broekmans AW: Short-term efficacy of tricyclic antidepressants revisited: a meta-analytic study. Eur Neuropsychopharmacol  2001; 11:173–179
[PubMed]
[CrossRef]
 
Rios LP, Thase ME, Howland RH, Friedman ES, Simons AD, Tu XM: A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy. J Affect Disord  1997; 43:131–142
[PubMed]
[CrossRef]
 
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