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Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders
Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 57 – 65 www.elsevier.com/locate/pnpbp
Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders Enrique Bacaa, Margarida Garcia-Garciab, Alberto Porras-Chavarinoc,* a
Department of Psychiatry, Hospital Puerta de Hierro, Madrid, Spain b Project Management Unit, Biometrica S.L., Barcelona, Spain c Medical Unit, Pfizer S.A., Parque Empresarial La Moraleja, Avda. Europa 20B, 28108 Alcobendas, Madrid, Spain Accepted 11 July 2003
Abstract There is evidence of gender differences in depressive disorders in terms of epidemiology and clinical manifestations. However, few studies have addressed the gender differences in terms of antidepressant treatment response in clinical practice. The aim of this study was to examine gender differences in the acute antidepressant response to sertraline and imipramine in nonmelancholic depressive disorders. A total of 239 patients with nonmelancholic major depression or dysthymia (DSM-III-R) and a score of z 18 at baseline on the Hamilton Depression Rating Scale (HAM-D) were randomised in a 1:1 ratio treatment with flexible doses of sertraline (50 – 200 mg/day) or imipramine (75 – 225 mg/day) for 8 weeks in a multicenter, randomised, open-labeled, parallel group comparative trial. Depressive and anxiety symptoms were assessed using the HAM-D and the Hamilton Anxiety Rating Scale (HAM-A). Using HAM-D criteria, women were significantly more likely to respond to sertraline than to imipramine (72.2% vs. 52.1%, P=.008), whilst men respond similarly to sertraline and to imipramine (56.5% vs. 59.3%, P>.05). Response analysis based on HAM-A shows similar results (women: 68.9% vs. 43.6%, P=.001; men: 56.5% vs. 51.9%, P>.05). Women taking sertraline show statistically significant higher reductions in HAM-D, HAM-A, and in CGI-S than women taking imipramine. The proportion of women who dropped out due to adverse events was much lower in sertraline than in imipramine (10.9% vs. 27.8%, P=.006), with no differences between treatments in men (8.3% vs. 11.5%, P>.05). It was concluded that sertraline is more effective and better tolerated than imipramine in the acute treatment of nonmelancholic depressive disorders in women, whereas men responded similarly to sertraline and to imipramine. D 2003 Elsevier Inc. All rights reserved. Keywords: Depressive disorder; Dysthymic disorder; Gender differences; Imipramine; Sertraline
1. Introduction The study of gender differences in psychiatric disorders has received increasing attention in recent years. Epidemiological studies have consistently shown that depression is about twice as common in women as in men (Regier et al., 1988; Kessler et al., 1993; Weissman et al., 1993; Maier et al., 1999). There is also some evidence of gender differences in the clinical manifestations. It has been shown that depressed women appear to present a greater number of
Abbreviations: CGI-I, Clinical Global Impression Scale of Improvement; CGI-S, Clinical Global Impression Scale of Severity; HAM-A, Hamilton Anxiety Rating Scale; HAM-D21, 21-item Hamilton Depression Rating Scale. * Corresponding author. Tel.: +34-91-4909825; fax: +34-91-4909720. E-mail address: [email protected] (A. Porras-Chavarino). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0278-5846(03)00177-5
symptoms than men (Angst and Dobler-Mikola, 1984) and that they are more likely to present reverse vegetative or atypical symptoms, such as increased appetite and weight gain, as well as anxiety and somatic symptoms (Kornstein, 1997; Silverstein, 1999). Some authors have also reported that depression in women tends to be more severe (Thase et al., 1994; Kornstein et al., 1996) and is associated with increased functional impairment (Kornstein et al., 1996). Finally, it has also been consistently found that although women are more likely to attempt suicide, the rate of ‘‘successfully carried out’’ suicide is higher in men (Kessler et al., 1981; Isometsa et al., 1994; Canetto and Sakinofsky, 1998; Murphy, 1998). Although the underlying causality of this gender difference is not clear, it appears to depend on genetic, neuroanatomical, biochemical, and environmental factors (Gold, 1998; Neuger et al., 1999; Ensom, 2000). Several studies
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have suggested that these factors could also lead to gender differences in pharmacokinetics and pharmacodynamics of antidepressant medications, such as higher plasma levels of imipramine (Moody et al., 1967; Glassman et al., 1977; Hamilton et al., 1996) and amitriptyline (Preskorn and Mac, 1985) in women, as well as lower hydroxylation clearance of clomipramine (Gex-Fabry et al., 1990) and an increased volume of distribution of trazodone (Greenblatt et al., 1987). Specific gender effects on some peripheral markers of the serotonin transporter, such as the [3H]paroxetine binding to human platelets, have also been found (Marazziti et al., 1998). Moreover, some studies have suggested that these different pharmacokinetics and pharmacodynamics could also lead to gender differences in sexual dysfunction (Montejo et al., 1997; Kennedy et al., 2000) and in overall adverse event profiles (Frackiewicz et al., 2000). Remarkably few studies have addressed the epidemiological and pharmacological implications of gender-associated differences in terms of overall treatment response to antidepressants in clinical practice. Several decades ago, it was first noted that women respond more poorly to tricyclics compared with men (Raskin, 1974; Glassman et al., 1977), although poorer tolerability in women may skew these efficacy results. Recent evidence has arisen to suggest that women may respond better to selective serotonin reuptake inhibitors than men (Kornstein et al., 2000; Thase et al., 2000; Marte´nyi et al., 2001). However, the evidence for gender differences in treatment response to antidepressants is not definite (Quitkin et al., 2001; Kornstein et al., 2001). In fact, recently, additional available data also suggest that no gender differences may exist in response to serotonin uptake inhibitor sertraline in panic disorder (Clayton, 2001) or to nefazodone in chronic depression (Kornstein et al., 2002). The present study was undertaken to evaluate the comparative effectiveness and patient acceptance of sertraline versus imipramine in outpatients with nonmelancholic depressive disorders. In this article, we examine the gender differences in treatment response to both antidepressants.
2. Methods 2.1. Patient population Outpatients of both genders, aged 18 or over, not suffering from significant concomitant diseases, and with a DSM-III-R (American Psychiatric Association, 1987) diagnosis of nonmelancholic major depression or dysthymia were eligible for participation in the study. Patients were required to have a score of at least 18 at baseline on the 21item Hamilton Depression Rating scale (HAM-D21) (Hamilton, 1960, 1967). Patients were excluded (1) if they fulfilled the criteria for meeting DSM-III-R (American Psychiatric Associa-
tion, 1987) and ICD-10 (World Health Organization, 1992) diagnosis of depressive disorder of the melancholic type, bipolar, psychotic, eating, or substance abuse disorders, (2) if their HAM-D21 score had decreased by more than 50% between screening and baseline assessments, (3) if they had any other clinically significant organic disorder, (4) if they showed alterations in thyroid function, or (5) if they had previously failed to respond to antidepressant treatment on one or more occasions in the past. Women were excluded if pregnant or if not using a reliable method of contraception throughout the study. After a complete description of the study, all subjects gave written informed consent to participate. 2.2. Drug administration Patients were given open-label medication. Patients not receiving psychoactive treatment started study treatment without washout period. Patients currently taking psychoactive medication entered a washout period whose duration corresponded to five half-lives of their previous medication or 1 week, whichever was longer. Patients were then randomly assigned to start on an oral dose of 50 mg sertraline (hydrochloride) or 75 mg imipramine (hydrochloride), once daily. Depending on clinical response and tolerability, the dose of each drug could be titrated up to 100, 150, or 200 mg/day for sertraline and 125, 175, or 225 mg/day for imipramine. Doses were increased to the next level after a period of at least 2 weeks at the previous level. Once patients had reached a clinically effective dose, they were maintained on that dose throughout the study unless side effects required a reduction in dose. 2.3. Study design The study had a multicenter, randomised, open-label, parallel group design. Patients were randomised in a 1:1 ratio treatment with flexible doses of sertraline or imipramine for 8 weeks. The random allocation sequence was electronically generated being only restricted by blocking on blocks of four patients. The study protocol was approved by the relevant ethics committees and was conducted in accordance with the Declaration of Helsinki (World Medical Association, 1989). 2.4. Assessments Sociodemographic variables recorded were age, gender, educational level, job status, and marital status. Clinical variables recorded included psychiatric history of patient including diagnosis DSM-III-R (American Psychiatric Association, 1987), previous psychopharmacological treatment, and concomitant treatment. A nonstructured diagnostic interview including the assessment of a checklist of DSM-III-R symptoms of nonmelancholic major depression
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and dysthymia conducted by expert psychiatrists was used to determine DSM-III-R diagnosis. Patients were scheduled at biweekly intervals after starting medication. The following rating scales were administered at baseline and at 2, 4, 6, and 8 weeks: the HAM-D21 (Hamilton, 1960, 1967), the Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1967), and the Clinical Global Impression Severity and Improvement scales (CGI-S and CGI-I, respectively) (Guy, 1976). The endpoint for each subject was defined as the last study visit attended, with the last observation carried forward. Adverse events, either reported by the patient or the clinician, were also recorded at each visit. 2.5. Response and remission criteria Response to treatment from baseline to Week 8 was defined as a 50% decrease in the HAM-D21 scale for depressive symptoms and as a 50% decrease in the HAM-
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A scale for anxiety symptoms. Remission for depressive and anxiety symptoms was defined as reaching a HAM-D21 score V 8 and as reaching a HAM-A score V 8, respectively. 2.6. Statistical methods The sociodemographic and clinical characteristics of patients were compared according to gender and treatment in order to verify the similarity of groups at baseline by using chi-square tests for categorical variables and t tests for continuous variables. The dosage was described in terms of mean and standard deviation. From the variables of dose and weight, a new variable was created, dose – weight, dividing the dose administered by the weight of the patient in order to detect a possible differential adjustment in dosage for gender according to the weight. Effectiveness variables were analysed using an intent-totreat approach (including all randomised patients for whom
Table 1 Baseline characteristics of patients Men
Women
Sertraline (n = 23)
Imipramine (n = 27)
Sertraline (n = 90)
Imipramine (n = 94)
Age (mean, S.D.)
42.6
13.0
40.3
13.4
37.9
13.7
41.2
13.0
Educational level (n, %) University Tertiary Secondary Primary No studies
2 4 7 10 –
8.7 17.4 30.4 43.5 –
2 4 8 11 2
7.4 14.8 29.6 40.7 7.4
11 12 17 42 8
12.2 13.3 18.9 46.7 8.9
7 10 18 40 19
7.4 10.6 19.1 42.6 20.2
Employment status (n, %)a Employed Unemployed Homemaker Student Retired
10 7 – 1 5
43.5 30.4 – 4.3 21.7
17 7 – – 2
65.4 26.9 – – 7.7
34 13 35 6 2
37.8 14.4 38.9 6.7 2.2
38 9 41 4 2
40.4 9.6 43.6 4.3 2.1
Marital status (n, %)b Unmarried Married Separated Widowed
10 9 3 1
43.5 39.1 13.0 4.3
11 12 4 –
40.7 44.4 14.8 –
26 55 6 3
28.9 61.1 6.7 3.3
23 59 6 6
24.5 62.8 6.4 6.4
Weight (mean, S.D.)c,d
70.5
60.1
10.1
59.4
10.5
DSM-III-R diagnosis (n, %) Major depression Dysthymia Double depression
13 9 1
40 33 17
44.4 36.7 18.9
44 33 17
46.8 35.1 18.1
Rating scale scores HAM-D21 (mean, S.D.) HAM-A (mean, S.D.) CGI-S (mean, range)
24.5 20.4 4.4
a b c d
8.3
56.5 39.1 4.3
4.6 6.1 2–6
77.4
16 7 4
24.0 21.2 4.4
9.9
59.3 25.9 14.8
4.6 6.1 3–6
Significant difference between men and women (v2 = 42.44, df = 4, P=.000). Significant difference between men and women (v2 = 9.30, df = 3, P=.025). Significant difference between men and women (Student t = 8.91, df = 228, P=.000). Significant difference between men taking sertraline and men taking imipramine (Student t =
25.0 22.2 4.33
4.8 6.1 3–6
2.63, df = 47, P=.01).
24.5 22.1 4.52
4.5 7.0 3–6
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3. Results 3.1. Subjects characteristics A total of 239 patients (i.e., the safety population) from 12 centres in Spain entered the study, 116 in the sertraline group and 123 in the imipramine group. Of these 239 patients, 3/116 in sertraline (2.6%) and 2/123 in imipramine (1.6%) were excluded from the effectiveness analysis for not having at least one effectiveness data after treatment initiation, leaving a total of 234 patients included in the effectiveness analysis. Table 1 shows the sociodemographic and clinical characteristics of these 234 patients, 50 men and 184 women. No statistically significant differences were observed between the sertraline and imipramine groups on sociodemographic and clinical variables, except for weight in men (Student’s t; P=.01) where mean weight was higher in the imipramine group. Comparing between men and women, there were more married and employed men than women (v2, P < .001), and mean weight was also significantly higher in men than in women (Student’s t; P=.025). 3.2. Dosages Fig. 1. Response (a) and remission (b) rates to sertraline and imipramine at endpoint among men and women for depression symptoms. Response defined as reduction from baseline in HAM-D21 score = 50%. Remission defined as a score = 8 on the HAM-D21 scale. Endpoint was the subject’s last study visit with the last observation carried forward.
any effectiveness data were available after treatment had started) and performing a last observation carried forward analysis. The primary effectiveness parameters were the proportions of responder and remitter patients defined according to the criteria described above. Response and remission rates were compared at the end point by gender and treatment by using chi-square test with a Yates correction. Response and remission rates were examined by using a logistic regression model, evaluating for statistical significance the pairwise interactions among gender, treatment, and depression. Changes from baseline to each follow-up visit and to endpoint in the HAM-D21 and HAM-A scales were examined by using analysis of covariance (ANCOVA) with effect for baseline score, gender, treatment (imipramine, sertraline), and DSM-III-R diagnosis of depressive disorder (major depression, dysthymia, double depression). Proportions of patients who dropped out due to adverse events and who presented any adverse event were compared by treatment using a chi-square test. Proportion of patients who presented each of the most frequent adverse events ( z 10%) due to treatment leading, or not to withdrawal, were compared by treatment using a chi-square test with a Yates correction or Fisher’s Exact Test for small samples. For all the tests, the type I error was fixed at 5% and the probability values were considered two-tailed.
The mean sertraline dose at final visit was 107.9 mg/day (S.D. = 53.4) in men and 84.3 mg/day (S.D. = 41.1) in
Fig. 2. Response (a) and remission (b) rates to sertraline and imipramine at endpoint among men and women for anxiety symptoms. Response defined as reduction from baseline in HAM-A score = 50%. Remission defined as a score = 8 on the HAM-A scale. Endpoint was the subject’s last study visit with the last observation carried forward.
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women. The mean imipramine dose at final visit was 104.2 mg/day (S.D. = 39.5) in men and 100.8 mg/day (S.D. = 39.3) in women. No statistically significant differences were found between men and women for either sertraline or for imipramine.
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Table 3 Response and remission rates to sertraline and imipramine for depression and anxiety symptoms in women by age < 40 years
z 40 years
Sertraline
Imipramine
Sertraline
Imipramine
3.3. Discontinuations
HAM-A Response rate (%) Remission rate (%)
76.4a 60.0
52.2a 52.2b
57.1 51.4c
35.4 25.0b,c
In the safety population groups, 94/116 (81.0%) patients in the sertraline group completed 8 weeks of treatment compared with 78/123 (63.4%) in the imipramine group
HAM-D21 Response rate (%) Remission rate (%)
78.2 61.8
63.0 47.8
62.9 40.0
41.7 27.1
Table 2 Depression and anxiety severity scores at baseline, Weeks 2, 4, and 6, and endpointa of men and women receiving sertraline or imipramine Measure and Men time Sertraline Mean HAM-D21 scale Baseline Week 2 Week 4 Week 6 Endpoint Change from baseline Week 2 Week 4b Week 6c Endpointd
Women Imipramine
S.D. Mean
score 24.5 20.6 15.7 13.7 12.0
4.6 5.6 8.1 8.1 8.5
3.9 8.9 10.8 12.6
4.7 7.1 7.4 7.4
HAM-A scale score Baseline 20.4 6.1 Week 2 17.9 6.8 Week 4 14.0 8.1 Week 6 12.6 8.9 Endpoint 11.1 8.3 Change from baseline Week 2e 2.5 6.6 Week 4f 6.3 9.2 7.8 10.7 Week 6g Endpointh 9.3 9.8 CGI—severity scale score Baseline 4.4 1.0 Week 2 4.1 1.2 Week 4 3.3 1.3 Week 6 2.9 1.3 Endpoint 2.6 1.3 Change from baseline Week 2 0.3 0.6 Week 4i 1.1 1.1 Week 6j 1.6 1.1 Endpointk 1.9 1.1 CGI—improvement scale score Week 2 3.4 0.9 Week 4 2.9 1.2 Week 6 2.3 1.1 Endpoint 2.2 1.1
Sertraline
Imipramine
S.D. Mean
S.D. Mean
24.0 20.96 17.6 13.7 12.8
4.6 6.3 7.9 8.2 8.7
25.0 18.5 14.3 11.5 9.9
4.8 6.0 6.5 6.7 7.0
24.5 19.1 16.9 15.1 13.2
4.5 6.1 6.7 7.9 8.6
3.4 6.4 10.3 11.1
5.2 7.0 7.8 8.6
6.4 10.7 13.5 15.1
5.8 6.8 7.9 8.3
5.4 7.6 9.4 11.2
5.7 6.6 8.0 8.8
21.2 20.6 17.7 14.3 13.0
6.1 7.5 8.1 9.3 9.8
22.2 17.0 13.0 10.6 9.1
6.1 5.9 5.8 6.3 6.7
22.1 19.0 17.2 15.8 14.1
7.0 7.5 8.1 8.9 9.6
0.7 3.5 6.9 8.3
5.1 5.5 7.1 8.1
5.2 9.2 11.6 13.1
5.1 6.9 8.0 8.4
3.1 6.6 4.9 7.9 6.3 9.3 7.9 10.0
4.4 4.0 3.5 2.8 2.6
1.0 1.1 1.5 1.3 1.4
4.3 3.7 3.0 2.4 2.0
0.7 1.0 1.2 1.3 1.2
4.5 3.9 3.4 3.1 2.7
0.8 1.0 1.2 1.4 1.5
0.4 0.9 1.6 1.8
0.7 1.3 1.2 1.3
0.6 1.4 1.9 2.3
0.8 1.1 1.3 1.3
0.6 1.1 1.4 1.8
0.9 1.2 1.4 1.5
3.5 3.1 2.4 2.3
1.0 1.3 1.3 1.3
3.0 2.3 2.1 1.8
1.1 1.2 1.3 1.2
3.1 2.9 2.7 2.5
1.2 1.3 1.4 1.4
Response defined as reduction from baseline in HAM scores = 50%. Remission defined as a score = 8 on HAM scales. a Significant difference between imipramine and sertraline (v2 = 5.45, df = 1, P=.020, with Yates correction). b Significant difference between younger and older women taking imipramine (v2 = 6.24, df = 1, P=.013, with Yates correction). c Significant difference between imipramine and sertraline (v2 = 5.03, df = 1, P=.025, with Yates correction).
S.D.
(v2 = 8.33, df = 1, P=.004, with Yates correction). The most frequent reason for discontinuation in both groups of treatment was due to adverse events, being higher on imipramine (n = 30/123, 24.4%) than on sertraline (n = 12/116, 10.3%) (v2 = 7.19, df = 1, P=.007, with Yates correction). There were less than half the number of discontinuations in women on sertraline (n = 17/92, 18.5%) than on imipramine (n = 37/97, 38.1%) (v2 = 8.01, df = 1, P=.005, with Yates correction). But no statistically significant differences were observed in men for discontinuations between sertraline (n = 5/24, 20.8%) and imipramine (n = 8/26, 30.8%). 3.4. Effectiveness Overall, statistically significant differences between men and women were not found. By sex, statistically significant Notes to Table 2: a Endpoint was the subject’s last study visit for each parameter, with the last observation carried forward. b Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 9.36, df = 1, P=.003). c Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 12.39, df = 1, P=.001). d Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 9.18, df = 1, P=.003). e Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 6.91, df = 1, P=.009). f Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 19.61, df = 1, P=.000). g Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 23.10, df = 1, P=.000). h Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 17.99, df = 1, P=.000). i Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 15.61, df = 1, P=.000). j Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 10.17, df = 1, P=.002). k Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 11.03, df = 1, P=.001).
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Fig. 3. Dropout rates due to adverse event among men and women receiving sertraline and imipramine.
differences between sertraline and imipramine were not found either for response or for remission rates on men, whilst women tended to respond and remit better to sertraline than to imipramine. Fig. 1 shows response and remission on HAM-D21 scores. Statistically significant differences were found between women taking sertraline and women taking imipramine in the percentage of responders (v2 = 7.05, df = 1, P=.008, with Yate’s correction) and in the percentage of remitters (v2 = 4.18, df = 1, P=.041, with Yates correction). Fig. 2 shows response and remission on HAMA scores. Statistically significant differences were found between women taking sertraline and women taking imipramine in the percentage of responders (v2 = 10.91, df = 1, P=.001, with Yates correction) and in the percentage of remitters (v2 = 5.51, df = 1, P=.019, with Yates correction). However, interaction of gender and treatment did not reach statistical significance in logistic regression analyses either
on the primary intent-to-treat analysis or in an additional per protocol analysis with only patients who remained in the study at least up to Week 4. Analysis directly based on mean and change scores showed similar results. Table 2 shows mean scores in HAM-D21, HAM-A, CGI-S, and CGI-I scales at baseline and at each visit, as well as mean changes in scores reflecting improvement in depression. Statistically significant differences were found between women taking sertraline and women taking imipramine in reductions in HAM-D21 (at Weeks 4, 6, and endpoint), in HAM-A (at Weeks 2, 4, 6, and endpoint), and in CGI-S (at Weeks 4, 6, and endpoint). In particular, higher reduction in these scores was found in women taking sertraline. Nevertheless, interaction of gender and treatment did not reach statistical significance in ANCOVA analyses in either case. Table 3 shows the results of additional response and remission rates analyses in women comparing between < 40 years and z 40 years patients in order to study differences in treatment response by menopausal status in women. 3.5. Tolerability In the safety population groups, Fig. 3 shows that the proportion of women who dropped out due to adverse events was much lower in sertraline (n = 10/92, 10.9%) than in imipramine (n = 27/97, 27.8%) (v2 with Yates correction; P=.006), whilst no differences were found between both treatments in men (n = 2/24, 8.3% in sertraline, vs. n = 3/26, 11.5% in imipramine). Furthermore, the proportion of women with adverse events was also lower in the sertraline group (n = 50/92, 54.3%) than in imipramine (n = 78/97, 80.4%) (v2 = 13.51, df = 1, P=.000, with Yates correction),
Table 4 Adverse events in men and women receiving sertraline or imipramine Adverse event
Men
a
Any adverse event Anxiety Constipationb Diarrhoeac,d Dizziness Dry mouthe Gastritis Insomnia Nauseaf Sweatingg Tremorh a b c d e f g h
Women
Sertraline (n = 24)
Imipramine (n = 26)
Sertraline (n = 92)
Imipramine (n = 97)
n
%
n
%
n
%
n
%
18 2 2 6 0 9 3 5 3 3 2
75.0 8.3 8.3 25.0 0 37.5 12.5 20.8 12.5 12.5 8.3
22 2 6 0 2 16 4 6 3 5 6
84.6 7.7 23.1 0 7.7 61.5 15.4 23.1 11.5 19.2 23.1
50 11 1 8 11 10 12 5 15 5 6
54.3 12.0 1.1 8.7 12.0 10.9 13.0 5.4 16.3 5.4 6.5
78 16 30 1 18 58 4 7 5 19 19
80.4 16.5 30.9 1.0 18.6 59.8 4.1 7.2 5.2 19.6 19.6
Significant difference between women taking sertraline and women taking imipramine (v2 = 13.51, df = 1, P=.000, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 28.52, df = 1, P=.000, with Yates correction). Significant difference between men taking sertraline and men taking imipramine (v2 = 7.39, df = 1, P=.008, v2 exact test). Significant difference between women taking sertraline and women taking imipramine (v2 = 6.12, df = 1, P=.016, v2 exact test). Significant difference between women taking sertraline and women taking imipramine (v2 = 46.96, df = 1, P=.000, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 5.08, df = 1, P=.024, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 7.30, df = 1, P=.007, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 5.93, df = 1, P=.015, with Yates correction).
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whilst no statistically significant differences were found between both treatments in men (n = 18/24, 75.0% in sertraline, vs. n = 22/26, 84.6% in imipramine). No significant differences were found between men and women either in the proportion of discontinuations due to adverse events or in the presence of frequent adverse events for sertraline or imipramine. Table 4 shows that there were statistically significant differences by treatment in the presence of several adverse effects with frequencies of occurrence of z 10% in men or women. In particular, among men, it was found that those patients taking sertraline were significantly more likely to report diarrhea. Among women, those patients taking sertraline were significantly more likely to report diarrhea and nausea, whilst those patients taking imipramine were more likely to report constipation, dry mouth, sweating, and tremor.
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4.1. Gender differences in anxiety response Analyses based on mean and change scores also showed an effect of gender on the specificity of response to antidepressant treatment, with women taking sertraline responding more highly for anxiety symptoms as assessed by means of the HAM-A scale than those taking imipramine from an early stage (Week 2). This finding is consistent with other published studies (Frank et al., 1988; Kornstein et al., 2000), though in such studies, response was studied with respect to general depressive symptoms without considering anxiety separately from merely depressive symptoms. Furthermore, it may lead to the conclusion that the assessment of specific subsets of symptoms should be explored in future studies in order to understand more precisely gender differences in the evolution of depression when responding to treatment. 4.2. Gender differences in tolerability
4. Discussion The aim of the study was to examine gender differences in the acute antidepressant response to sertraline and imipramine in nonmelancholic depression. The results show that men responded similarly whether assigned to sertraline or imipramine, whilst women assigned to sertraline were more likely to respond well—and to remit—to treatment. This result may be attributed to the differential tolerability profile of sertraline and imipramine in women. Whilst men showed similar dropout rates irrespective of which drug they were taking, in women assigned to imipramine, the likelihood of discontinuing due to adverse events was almost threefold. This study is one of the few that we are aware of to report gender differences in antidepressants response in nonmelancholic depressive disorders. These findings are consistent with other results previously reported showing more efficacy in women than in men being treated with antidepressants (Raskin, 1974). Moreover, recent results (Kornstein et al., 2000) suggest that women respond significantly better with sertraline than with imipramine in chronic depression, although in this study, a statistically significant interaction of gender and treatment for efficacy parameters was also found even though it has not reached statistical significance in our study. Underlying biological explanations for these gender differences in treatment response still remain unclear. It has been suggested that female sex hormones may influence treatment effect finding that, for example, estrogen enhances response to SSRIs or inhibits response to TCA (Halbreich and Kahn, 2001). In addition, several findings on gender differences such as differences in cerebral blood flow (Videbech et al., 2001) or state regulation during sleep (Armitage and Hoffman, 2001) also support that there may be gender differences in treatment response. However, further studies are needed to determine factors of differential antidepressant treatment response.
The proportion of women who dropped out due to adverse events was much lower in the sertraline group (10.9%) than in imipramine (27.8%), whilst no differences were found between both treatments in men (8.3% in sertraline vs. 11.5% in imipramine). These results are also similar to those found in previous studies (Kornstein et al., 2000), although in our study, differences between both treatments in women were greater. Several significant gender differences in types of adverse events were also noted in our study as similar to previous studies, with women taking imipramine being more likely to report constipation, dry mouth, sweating, and tremor and thus reinforcing that women have more tolerability problems with imipramine than with sertraline. However, it has been suggested elsewhere that some specific adverse events, such as sexual dysfunction, require specific consideration and specific measures in order to ensure their right assessment (Montejo et al., 1997; Kornstein and McEnany, 2000). Consequently, it should be taken into consideration that some adverse events may be underreported in our study, which may limit our findings relative to gender differences in tolerability. 4.3. Age comparisons In previous studies, it has been shown that the gender differences in treatment response to selective serotonin reuptake inhibitors is predominantly determined by a higher responsiveness in premenopausal women (Kornstein et al., 2000; Marte´nyi et al., 2001). The menopausal status was not specifically determined in this study. However, in order to examine the potential effect of this, additional analyses were carried out stratifying women by age ( < 40 years, z 40 years). Results from these analyses suggest that younger women show higher responsiveness for depression and anxiety symptoms than older women, al-
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though statistically significant superiority was only found on imipramine for anxiety symptoms. Differences in women between both treatments were only found in older women ( z 40 years) with lower remission rate for anxiety symptoms and poorer tolerability in imipramine. These results are not completely consistent with previous studies (Kornstein et al., 2000; Marte´nyi et al., 2001), although the effects of oral contraceptives and hormone replacement therapy and their potential interaction with serotoninergic antidepressants should have been addressed to properly examine the effect of the menopausal status. 4.4. Limitations of the study Some limitations must be noted in our study, first of which is the relatively small size of the men group, which may impede seeing the statistical significance for the interaction of gender and treatment. The other most important limitations are the consequence of conducting a clinical effectiveness study rather than a classic doubleblind, placebo-controlled efficacy study. These include lack of a placebo control to provide assay sensitivity for the trial (Temple and Ellenberg, 2000) and lack of blinding methodology. The latter may be of less importance than it seems at first since both study treatments are known to be effective antidepressants. Still, it is clearly a study limitation whose full effect is uncertain. Another limitation is that the mean dose of imipramine (104 mg in men, 101 mg in women) was lower than may have been necessary to optimise efficacy. Investigators could increase the dose of imipramine to 225 mg/day depending on clinical response and tolerability, but the optimal dosing for imipramine may have appeared to be lower than necessary to optimise efficacy. This means that no inferences concerning the comparative pharmacological efficacy of sertraline versus imipramine can be made. All that can be said is that from a practical clinical standpoint, sertraline was a significantly more effective and welltolerated treatment, and that optimal dosing of imipramine appeared to be limited by lack of patient acceptance of its higher side effect burden.
5. Conclusions The study results point out that there are gender differences in the effectiveness and tolerability of antidepressants in the treatment of nonmelancholic depression. Specifically, sertraline is more effective and better tolerated than imipramine in the acute treatment of nonmelancholic depression in women with an earlier and higher response for anxiety symptoms, whereas men responded similarly whether assigned to sertraline or imipramine. However, further studies are needed in order to have more precise evidence for gender differences in treatment response in depression.
Acknowledgements The authors wish to thank additional investigators and collaborating sites: M.Gonza´lez de Cha´vez (Hospital Gregorio Maran˜o´n, Madrid); S. Oliveros (Hospital Puerta de Hierro, Madrid); B. Franco (C.S.M. Colmenar Viejo, Madrid); A. Rivera, B. Penasa, and I. Lo´pez (C.S.M. Salamanca, Madrid); E. Capdevila (Centro de Psiquiatrı´a y Psicoterapia, Madrid); F. Pe´rez Arnau and F. Teba (C.S.M. Prat de Llobregat, Barcelona); C. Gasto´, J. Blanch, and L. Pintor (Hospital Clinic, Barcelona); J. Pe´rez de los Cobos, J. Fa´bregas, and L. Del Angel (Centro de Psicoterapia, Barcelona); R. Noguera and L. Jorda´ (Hospital Psiquia´trico, Gerona); and M. Garcı´a Toro and A. Gonza´lez (H. Psiquia´trico, Palma de Mallorca). Authors thank Inmaculada Expo´sito (Pfizer, Madrid) for her technical help. This study was supported by a research grant from Pfizer, Madrid, Spain. References American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. American Psychiatric Association, Washington. Revised. Angst, J., Dobler-Mikola, A., 1984. Do the diagnostic criteria determine the sex ratio in depression? J. Affect. Disord. 7, 189 – 198. Armitage, R., Hoffmann, R.F., 2001. Sleep EEG, depression and gender. Sleep Med. Rev. 5 (3), 237 – 246. Canetto, S.S., Sakinofsky, I., 1998. The gender paradox in suicide. Suicide Life-Threat. Behav. 28, 1 – 23. Clayton, A., 2001. Panic in women across the life cycle: clinical presentation and response to sertraline. Annual Meeting of 154rd American Psychiatric Association. New Orleans, LA, NR 597. Ensom, M.H., 2000. Gender-based differences and menstrual cycle-related changes in specific diseases: implications for pharmacotherapy. Pharmacotherapy 20, 523 – 539. Frackiewicz, E.J., Sramek, J.J., Cutler, N.R., 2000. Gender differences in depression and antidepressant pharmacokinetics and adverse events. Ann. Pharmacother. 34, 80 – 88. Frank, E., Carpenter, L.L., Kupfer, D.J., 1988. Sex differences in recurrent depression: are there any that are significant? Am. J. Psychiatry 145, 41 – 45. Gex-Fabry, M., Balant-Gorgia, A.E., Balant, L.P., Garrone, G., 1990. Clomipramine metabolism: model-based analysis of variability factors from drug monitoring data. Clin. Pharmacokinet. 19, 241 – 255. Glassman, A.H., Perel, J.M., Shostak, M., Kantor, S.J., Fleiss, J.L., 1977. Clinical implications of imipramine plasma levels for depressive illness. Arch. Gen. Psychiatry 34, 197 – 204. Gold, J.H., 1998. Gender differences in psychiatric illness and treatments: a critical review. J. of Nerv. Ment. Dis. 186, 769 – 775. Greenblatt, D.J., Friedman, H., Burstein, E.S., Scavone, J.M., Blyden, G.T., Ochs, H.R., Miller, L.G., Harmatz, J.S., Shader, R.I., 1987. Trazodone kinetics: effect of age, gender, and obesity. Clin. Pharmacol. Ther. 42, 193 – 200. Guy, W., 1976. Clinical global impressions. In: Guy, W. (Ed.), Early Clinical Drug Evaluation (ECDEU). Assessment Manual for Psychopharmacology. NIMH, Rockville, pp. 217 – 222. Halbreich, U., Kahn, L.S., 2001. Role of estrogen in the aetiology and treatment of mood disorders. CNS Drugs 15 (10), 797 – 817. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56 – 62.
E. Baca et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 57–65 Hamilton, M., 1967. Development of a rating scale for primary depressive illness. Br. J. Soc. Clin. Psychol. 6, 278 – 296. Hamilton, J.A., Grant, M., Jensvold, M.F., 1996. Sex and treatment of depressions: when does it matter? In: Jensvold, M.F., Halbreich, U., Hamilton, J.A. (Eds.), Psychopharmacology and Women: Sex, Gender, and Hormones. American Psychiatric Press, Washington, pp. 241 – 257. Isometsa, E.T., Henriksson, M.M., Aro, H.M., Heikkinen, M.E., Kuoppasalmi, K.I., Lonnqvist, J.K., 1994. Suicide in major depression. Am. J. Psychiatry 151, 530 – 536. Kennedy, S.H., Eisfeld, B.S., Dickens, S.E., Bacchiochi, J.R., Bagby, R.M., 2000. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and velafaxine. J. Clin. Psychiatry 61, 276 – 281. Kessler, R.C., Brown, R.L., Broman, C.L., 1981. Sex differences in psychiatric help-seeking: evidence from four large-scale surveys. J. Health Soc. Behav. 22, 49 – 64. Kessler, R.C., McGonagle, K.A., Swartz, M., Blazer, D.G., Nelson, C.B., 1993. Sex and depression in the National Comorbidity Survey: I. Lifetime, prevalence, chronicity, and recurrance. J. Affect. Disord. 29, 85 – 96. Kornstein, S.G., 1997. Gender differences in depression: implications for treatment. J. Clin. Psychiatry 58 (Suppl. 15), 12 – 18. Kornstein, S.G., McEnany, G., 2000. Enhancing pharmacologic effects in the treatment of depression in women. J. Clin. Psychiatry 61 (Suppl. 11), 18 – 27. Kornstein, S.G., Schatzberg, A.F., Yonkers, K.A., Thase, M.E., Keitner, G.I., Ryan, C.E., Schlager, D., 1996. Gender differences in presentation of chronic major depression. Psychopharmacol. Bull. 31, 711 – 718. Kornstein, S.G., Shatzberg, A.F., Thase, M.E., Yonkers, K.A., McCullough, J.P., Keitner, G.I., Gelenberg, A.J., Davis, S.M., Harrison, W.M., Keller, M.B., 2000. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am. J. Psychiatry 157, 1445 – 1452. Kornstein, S.G., Shatzberg, A.F., Thase, M.E., Yonkers, K.A., McCullough, J.P., Keitner, G.I., Gelenberg, A.J., Davis, S.M., Harrison, W.M., Keller, M.B., 2001. Dr Kornstein and collegues reply (letter). Am. J. Psychiatry 158, 1532 – 1533. Kornstein, S.G., Schatzberg, A.F., Thase, M.E., Svikis, D., Gelenberg, A.J., Keitner, G.I., Borian, F.E., 2002. Gender differences in response to combination treatment for chronic depression. Annual Meeting of 155rd American Psychiatric Association. Philadelphia, NR 249. Maier, W., Ga¨nsicke, M., Rezaki, M., Tiemens, B., Urzu´a, R.F., 1999. Gender differences in the prevalence of depression: a survey in primary care. J. Affect. Disord. 53, 241 – 252. Marazziti, D., Rossi, A., Palengo, L., Barsanti, A., Carrai, M., Giannaccini, G., Serra, P., Lucacchini, A., Cassano, G.B., 1998. Effect of aging and sex on the [3H]-paroxetine binding to human platelets. J. Affect. Disord. 50, 11 – 15. Marte´nyi, F., Dossenbach, M., Mraz, K., Metcalfe, S., 2001. Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotoninergic or norepi-
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nephrinergic reuptake inhibition profile. Eur. Neuropsychopharmacol. 11, 227 – 232. Montejo, A.L., Llorca, G., Izquierdo, J.A., Ledesma, A., Bouson˜o, M., Calcedo, A., Carrasco, J.L., Ciudad, J., Daniel, E., De la Ga´ndara, J., Derecho, J., Franco, M., Go´mez, M.J., Macı´as, J.A., Martı´n, T., Pe´rez, V., Sa´nchez, J.M., Vicens, E., 1997. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J. Sex Marital Ther. 23, 176 – 194. Moody, J.P., Tait, A.C., Todrick, A., 1967. Plasma levels of imipramine and desmethy limipramine during therapy. Br. J. Psychiatry 113, 183 – 193. Murphy, G.E., 1998. Why women are less likely than men to commit suicide. Compr. Psychiatry 39, 165 – 175. Neuger, J., El Khoury, A., Kjellman, B.F., Wahlund, B., Aberg-Wistedt, A., Stain-Malmgren, R., 1999. Platelet serotonin functions in untreated major depression. Psychiatry Res. 85, 189 – 198. Preskorn, S.H., Mac, D.S., 1985. Plasma levels of amitriptyline: effects of age and sex. J. Clin. Psychiatry 46, 276 – 277. Quitkin, F.M., Stewart, J.W., McGrath, P.J., 2001. Gender differences in treatment response (letter). Am. J. Psychiatry 158, 1531 – 1532. Raskin, A., 1974. Age – sex differences in response to antidepressant drugs. J. of Nerv. Ment. Dis. 159, 120 – 130. Regier, D.A., Boyd, J.H., Burke Jr., J.D., Rae, D.S., Myers, J.K., Kramer, M., Robins, L.N., George, L.K., Karno, M., Locke, B.Z., 1988. Onemonth prevalence of mental disorders in the United States: based on five epidemiologic catchment area sites. Arch. Gen. Psychiatry 45, 977 – 986. Silverstein, B., 1999. Gender difference in the prevalence of clinical depression: the role played by depression associated with somatic symptoms. Am. J. Psychiatry 156, 480 – 482. Temple, R., Ellenberg, S.S., 2000. Placebo-controlled trials and active-control trials in the evaluation of new treatments: Part 1. Ethical and scientific issues. Ann. Intern. Med. 133, 455 – 463. Thase, M.E., Reynolds, C.F., Frank, E., Simons, A.D., McGeary, J., Fasiczka, A.L., Garamoni, G.G., Jennings, J.R., Kupfer, D.J., 1994. Do depressed men and women respond similarly to cognitive behavior therapy? Am. J. Psychiatry 151, 500 – 505. Thase, M.A., Frank, E., Korsntein, S., Yonkers, K.A., 2000. Gender differences in response to treatments of depression. In: Frank, E. (Ed.), Gender and Its Effects on Psychopathology. American Psychiatric Press, Washington, pp. 103 – 125. Videbech, P., Ravnkilde, B., Pedersen, A.R., Egander, A., Landbo, B., Rasmussen, N.A., Andersen, F., Stodkilde-Jorgensen, H., Gjedde, A., Rosenberg, R., 2001. The Danish PET/depression project: PET findings in patients with major depression. Psychol. Med. 31 (7), 1147 – 1158. Weissman, M.M., Band, R., Joyce, P.R., Newman, S., Wells, J.E., Witchen, H.U., 1993. Sex differences in rates of depression: cross-national perspectives. J. Affect. Disord. 29, 77 – 84. World Health Organization, 1992. Classification of Mental and Behavioural Disorders, 10th ed. World Health Organization, Geneva. World Medical Association, 1989. Declaration of Helsinki, 41st World Medical Assembly, Hong Kong.
Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders Enrique Bacaa, Margarida Garcia-Garciab, Alberto Porras-Chavarinoc,* a
Department of Psychiatry, Hospital Puerta de Hierro, Madrid, Spain b Project Management Unit, Biometrica S.L., Barcelona, Spain c Medical Unit, Pfizer S.A., Parque Empresarial La Moraleja, Avda. Europa 20B, 28108 Alcobendas, Madrid, Spain Accepted 11 July 2003
Abstract There is evidence of gender differences in depressive disorders in terms of epidemiology and clinical manifestations. However, few studies have addressed the gender differences in terms of antidepressant treatment response in clinical practice. The aim of this study was to examine gender differences in the acute antidepressant response to sertraline and imipramine in nonmelancholic depressive disorders. A total of 239 patients with nonmelancholic major depression or dysthymia (DSM-III-R) and a score of z 18 at baseline on the Hamilton Depression Rating Scale (HAM-D) were randomised in a 1:1 ratio treatment with flexible doses of sertraline (50 – 200 mg/day) or imipramine (75 – 225 mg/day) for 8 weeks in a multicenter, randomised, open-labeled, parallel group comparative trial. Depressive and anxiety symptoms were assessed using the HAM-D and the Hamilton Anxiety Rating Scale (HAM-A). Using HAM-D criteria, women were significantly more likely to respond to sertraline than to imipramine (72.2% vs. 52.1%, P=.008), whilst men respond similarly to sertraline and to imipramine (56.5% vs. 59.3%, P>.05). Response analysis based on HAM-A shows similar results (women: 68.9% vs. 43.6%, P=.001; men: 56.5% vs. 51.9%, P>.05). Women taking sertraline show statistically significant higher reductions in HAM-D, HAM-A, and in CGI-S than women taking imipramine. The proportion of women who dropped out due to adverse events was much lower in sertraline than in imipramine (10.9% vs. 27.8%, P=.006), with no differences between treatments in men (8.3% vs. 11.5%, P>.05). It was concluded that sertraline is more effective and better tolerated than imipramine in the acute treatment of nonmelancholic depressive disorders in women, whereas men responded similarly to sertraline and to imipramine. D 2003 Elsevier Inc. All rights reserved. Keywords: Depressive disorder; Dysthymic disorder; Gender differences; Imipramine; Sertraline
1. Introduction The study of gender differences in psychiatric disorders has received increasing attention in recent years. Epidemiological studies have consistently shown that depression is about twice as common in women as in men (Regier et al., 1988; Kessler et al., 1993; Weissman et al., 1993; Maier et al., 1999). There is also some evidence of gender differences in the clinical manifestations. It has been shown that depressed women appear to present a greater number of
Abbreviations: CGI-I, Clinical Global Impression Scale of Improvement; CGI-S, Clinical Global Impression Scale of Severity; HAM-A, Hamilton Anxiety Rating Scale; HAM-D21, 21-item Hamilton Depression Rating Scale. * Corresponding author. Tel.: +34-91-4909825; fax: +34-91-4909720. E-mail address: [email protected] (A. Porras-Chavarino). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0278-5846(03)00177-5
symptoms than men (Angst and Dobler-Mikola, 1984) and that they are more likely to present reverse vegetative or atypical symptoms, such as increased appetite and weight gain, as well as anxiety and somatic symptoms (Kornstein, 1997; Silverstein, 1999). Some authors have also reported that depression in women tends to be more severe (Thase et al., 1994; Kornstein et al., 1996) and is associated with increased functional impairment (Kornstein et al., 1996). Finally, it has also been consistently found that although women are more likely to attempt suicide, the rate of ‘‘successfully carried out’’ suicide is higher in men (Kessler et al., 1981; Isometsa et al., 1994; Canetto and Sakinofsky, 1998; Murphy, 1998). Although the underlying causality of this gender difference is not clear, it appears to depend on genetic, neuroanatomical, biochemical, and environmental factors (Gold, 1998; Neuger et al., 1999; Ensom, 2000). Several studies
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have suggested that these factors could also lead to gender differences in pharmacokinetics and pharmacodynamics of antidepressant medications, such as higher plasma levels of imipramine (Moody et al., 1967; Glassman et al., 1977; Hamilton et al., 1996) and amitriptyline (Preskorn and Mac, 1985) in women, as well as lower hydroxylation clearance of clomipramine (Gex-Fabry et al., 1990) and an increased volume of distribution of trazodone (Greenblatt et al., 1987). Specific gender effects on some peripheral markers of the serotonin transporter, such as the [3H]paroxetine binding to human platelets, have also been found (Marazziti et al., 1998). Moreover, some studies have suggested that these different pharmacokinetics and pharmacodynamics could also lead to gender differences in sexual dysfunction (Montejo et al., 1997; Kennedy et al., 2000) and in overall adverse event profiles (Frackiewicz et al., 2000). Remarkably few studies have addressed the epidemiological and pharmacological implications of gender-associated differences in terms of overall treatment response to antidepressants in clinical practice. Several decades ago, it was first noted that women respond more poorly to tricyclics compared with men (Raskin, 1974; Glassman et al., 1977), although poorer tolerability in women may skew these efficacy results. Recent evidence has arisen to suggest that women may respond better to selective serotonin reuptake inhibitors than men (Kornstein et al., 2000; Thase et al., 2000; Marte´nyi et al., 2001). However, the evidence for gender differences in treatment response to antidepressants is not definite (Quitkin et al., 2001; Kornstein et al., 2001). In fact, recently, additional available data also suggest that no gender differences may exist in response to serotonin uptake inhibitor sertraline in panic disorder (Clayton, 2001) or to nefazodone in chronic depression (Kornstein et al., 2002). The present study was undertaken to evaluate the comparative effectiveness and patient acceptance of sertraline versus imipramine in outpatients with nonmelancholic depressive disorders. In this article, we examine the gender differences in treatment response to both antidepressants.
2. Methods 2.1. Patient population Outpatients of both genders, aged 18 or over, not suffering from significant concomitant diseases, and with a DSM-III-R (American Psychiatric Association, 1987) diagnosis of nonmelancholic major depression or dysthymia were eligible for participation in the study. Patients were required to have a score of at least 18 at baseline on the 21item Hamilton Depression Rating scale (HAM-D21) (Hamilton, 1960, 1967). Patients were excluded (1) if they fulfilled the criteria for meeting DSM-III-R (American Psychiatric Associa-
tion, 1987) and ICD-10 (World Health Organization, 1992) diagnosis of depressive disorder of the melancholic type, bipolar, psychotic, eating, or substance abuse disorders, (2) if their HAM-D21 score had decreased by more than 50% between screening and baseline assessments, (3) if they had any other clinically significant organic disorder, (4) if they showed alterations in thyroid function, or (5) if they had previously failed to respond to antidepressant treatment on one or more occasions in the past. Women were excluded if pregnant or if not using a reliable method of contraception throughout the study. After a complete description of the study, all subjects gave written informed consent to participate. 2.2. Drug administration Patients were given open-label medication. Patients not receiving psychoactive treatment started study treatment without washout period. Patients currently taking psychoactive medication entered a washout period whose duration corresponded to five half-lives of their previous medication or 1 week, whichever was longer. Patients were then randomly assigned to start on an oral dose of 50 mg sertraline (hydrochloride) or 75 mg imipramine (hydrochloride), once daily. Depending on clinical response and tolerability, the dose of each drug could be titrated up to 100, 150, or 200 mg/day for sertraline and 125, 175, or 225 mg/day for imipramine. Doses were increased to the next level after a period of at least 2 weeks at the previous level. Once patients had reached a clinically effective dose, they were maintained on that dose throughout the study unless side effects required a reduction in dose. 2.3. Study design The study had a multicenter, randomised, open-label, parallel group design. Patients were randomised in a 1:1 ratio treatment with flexible doses of sertraline or imipramine for 8 weeks. The random allocation sequence was electronically generated being only restricted by blocking on blocks of four patients. The study protocol was approved by the relevant ethics committees and was conducted in accordance with the Declaration of Helsinki (World Medical Association, 1989). 2.4. Assessments Sociodemographic variables recorded were age, gender, educational level, job status, and marital status. Clinical variables recorded included psychiatric history of patient including diagnosis DSM-III-R (American Psychiatric Association, 1987), previous psychopharmacological treatment, and concomitant treatment. A nonstructured diagnostic interview including the assessment of a checklist of DSM-III-R symptoms of nonmelancholic major depression
E. Baca et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 57–65
and dysthymia conducted by expert psychiatrists was used to determine DSM-III-R diagnosis. Patients were scheduled at biweekly intervals after starting medication. The following rating scales were administered at baseline and at 2, 4, 6, and 8 weeks: the HAM-D21 (Hamilton, 1960, 1967), the Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1967), and the Clinical Global Impression Severity and Improvement scales (CGI-S and CGI-I, respectively) (Guy, 1976). The endpoint for each subject was defined as the last study visit attended, with the last observation carried forward. Adverse events, either reported by the patient or the clinician, were also recorded at each visit. 2.5. Response and remission criteria Response to treatment from baseline to Week 8 was defined as a 50% decrease in the HAM-D21 scale for depressive symptoms and as a 50% decrease in the HAM-
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A scale for anxiety symptoms. Remission for depressive and anxiety symptoms was defined as reaching a HAM-D21 score V 8 and as reaching a HAM-A score V 8, respectively. 2.6. Statistical methods The sociodemographic and clinical characteristics of patients were compared according to gender and treatment in order to verify the similarity of groups at baseline by using chi-square tests for categorical variables and t tests for continuous variables. The dosage was described in terms of mean and standard deviation. From the variables of dose and weight, a new variable was created, dose – weight, dividing the dose administered by the weight of the patient in order to detect a possible differential adjustment in dosage for gender according to the weight. Effectiveness variables were analysed using an intent-totreat approach (including all randomised patients for whom
Table 1 Baseline characteristics of patients Men
Women
Sertraline (n = 23)
Imipramine (n = 27)
Sertraline (n = 90)
Imipramine (n = 94)
Age (mean, S.D.)
42.6
13.0
40.3
13.4
37.9
13.7
41.2
13.0
Educational level (n, %) University Tertiary Secondary Primary No studies
2 4 7 10 –
8.7 17.4 30.4 43.5 –
2 4 8 11 2
7.4 14.8 29.6 40.7 7.4
11 12 17 42 8
12.2 13.3 18.9 46.7 8.9
7 10 18 40 19
7.4 10.6 19.1 42.6 20.2
Employment status (n, %)a Employed Unemployed Homemaker Student Retired
10 7 – 1 5
43.5 30.4 – 4.3 21.7
17 7 – – 2
65.4 26.9 – – 7.7
34 13 35 6 2
37.8 14.4 38.9 6.7 2.2
38 9 41 4 2
40.4 9.6 43.6 4.3 2.1
Marital status (n, %)b Unmarried Married Separated Widowed
10 9 3 1
43.5 39.1 13.0 4.3
11 12 4 –
40.7 44.4 14.8 –
26 55 6 3
28.9 61.1 6.7 3.3
23 59 6 6
24.5 62.8 6.4 6.4
Weight (mean, S.D.)c,d
70.5
60.1
10.1
59.4
10.5
DSM-III-R diagnosis (n, %) Major depression Dysthymia Double depression
13 9 1
40 33 17
44.4 36.7 18.9
44 33 17
46.8 35.1 18.1
Rating scale scores HAM-D21 (mean, S.D.) HAM-A (mean, S.D.) CGI-S (mean, range)
24.5 20.4 4.4
a b c d
8.3
56.5 39.1 4.3
4.6 6.1 2–6
77.4
16 7 4
24.0 21.2 4.4
9.9
59.3 25.9 14.8
4.6 6.1 3–6
Significant difference between men and women (v2 = 42.44, df = 4, P=.000). Significant difference between men and women (v2 = 9.30, df = 3, P=.025). Significant difference between men and women (Student t = 8.91, df = 228, P=.000). Significant difference between men taking sertraline and men taking imipramine (Student t =
25.0 22.2 4.33
4.8 6.1 3–6
2.63, df = 47, P=.01).
24.5 22.1 4.52
4.5 7.0 3–6
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3. Results 3.1. Subjects characteristics A total of 239 patients (i.e., the safety population) from 12 centres in Spain entered the study, 116 in the sertraline group and 123 in the imipramine group. Of these 239 patients, 3/116 in sertraline (2.6%) and 2/123 in imipramine (1.6%) were excluded from the effectiveness analysis for not having at least one effectiveness data after treatment initiation, leaving a total of 234 patients included in the effectiveness analysis. Table 1 shows the sociodemographic and clinical characteristics of these 234 patients, 50 men and 184 women. No statistically significant differences were observed between the sertraline and imipramine groups on sociodemographic and clinical variables, except for weight in men (Student’s t; P=.01) where mean weight was higher in the imipramine group. Comparing between men and women, there were more married and employed men than women (v2, P < .001), and mean weight was also significantly higher in men than in women (Student’s t; P=.025). 3.2. Dosages Fig. 1. Response (a) and remission (b) rates to sertraline and imipramine at endpoint among men and women for depression symptoms. Response defined as reduction from baseline in HAM-D21 score = 50%. Remission defined as a score = 8 on the HAM-D21 scale. Endpoint was the subject’s last study visit with the last observation carried forward.
any effectiveness data were available after treatment had started) and performing a last observation carried forward analysis. The primary effectiveness parameters were the proportions of responder and remitter patients defined according to the criteria described above. Response and remission rates were compared at the end point by gender and treatment by using chi-square test with a Yates correction. Response and remission rates were examined by using a logistic regression model, evaluating for statistical significance the pairwise interactions among gender, treatment, and depression. Changes from baseline to each follow-up visit and to endpoint in the HAM-D21 and HAM-A scales were examined by using analysis of covariance (ANCOVA) with effect for baseline score, gender, treatment (imipramine, sertraline), and DSM-III-R diagnosis of depressive disorder (major depression, dysthymia, double depression). Proportions of patients who dropped out due to adverse events and who presented any adverse event were compared by treatment using a chi-square test. Proportion of patients who presented each of the most frequent adverse events ( z 10%) due to treatment leading, or not to withdrawal, were compared by treatment using a chi-square test with a Yates correction or Fisher’s Exact Test for small samples. For all the tests, the type I error was fixed at 5% and the probability values were considered two-tailed.
The mean sertraline dose at final visit was 107.9 mg/day (S.D. = 53.4) in men and 84.3 mg/day (S.D. = 41.1) in
Fig. 2. Response (a) and remission (b) rates to sertraline and imipramine at endpoint among men and women for anxiety symptoms. Response defined as reduction from baseline in HAM-A score = 50%. Remission defined as a score = 8 on the HAM-A scale. Endpoint was the subject’s last study visit with the last observation carried forward.
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women. The mean imipramine dose at final visit was 104.2 mg/day (S.D. = 39.5) in men and 100.8 mg/day (S.D. = 39.3) in women. No statistically significant differences were found between men and women for either sertraline or for imipramine.
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Table 3 Response and remission rates to sertraline and imipramine for depression and anxiety symptoms in women by age < 40 years
z 40 years
Sertraline
Imipramine
Sertraline
Imipramine
3.3. Discontinuations
HAM-A Response rate (%) Remission rate (%)
76.4a 60.0
52.2a 52.2b
57.1 51.4c
35.4 25.0b,c
In the safety population groups, 94/116 (81.0%) patients in the sertraline group completed 8 weeks of treatment compared with 78/123 (63.4%) in the imipramine group
HAM-D21 Response rate (%) Remission rate (%)
78.2 61.8
63.0 47.8
62.9 40.0
41.7 27.1
Table 2 Depression and anxiety severity scores at baseline, Weeks 2, 4, and 6, and endpointa of men and women receiving sertraline or imipramine Measure and Men time Sertraline Mean HAM-D21 scale Baseline Week 2 Week 4 Week 6 Endpoint Change from baseline Week 2 Week 4b Week 6c Endpointd
Women Imipramine
S.D. Mean
score 24.5 20.6 15.7 13.7 12.0
4.6 5.6 8.1 8.1 8.5
3.9 8.9 10.8 12.6
4.7 7.1 7.4 7.4
HAM-A scale score Baseline 20.4 6.1 Week 2 17.9 6.8 Week 4 14.0 8.1 Week 6 12.6 8.9 Endpoint 11.1 8.3 Change from baseline Week 2e 2.5 6.6 Week 4f 6.3 9.2 7.8 10.7 Week 6g Endpointh 9.3 9.8 CGI—severity scale score Baseline 4.4 1.0 Week 2 4.1 1.2 Week 4 3.3 1.3 Week 6 2.9 1.3 Endpoint 2.6 1.3 Change from baseline Week 2 0.3 0.6 Week 4i 1.1 1.1 Week 6j 1.6 1.1 Endpointk 1.9 1.1 CGI—improvement scale score Week 2 3.4 0.9 Week 4 2.9 1.2 Week 6 2.3 1.1 Endpoint 2.2 1.1
Sertraline
Imipramine
S.D. Mean
S.D. Mean
24.0 20.96 17.6 13.7 12.8
4.6 6.3 7.9 8.2 8.7
25.0 18.5 14.3 11.5 9.9
4.8 6.0 6.5 6.7 7.0
24.5 19.1 16.9 15.1 13.2
4.5 6.1 6.7 7.9 8.6
3.4 6.4 10.3 11.1
5.2 7.0 7.8 8.6
6.4 10.7 13.5 15.1
5.8 6.8 7.9 8.3
5.4 7.6 9.4 11.2
5.7 6.6 8.0 8.8
21.2 20.6 17.7 14.3 13.0
6.1 7.5 8.1 9.3 9.8
22.2 17.0 13.0 10.6 9.1
6.1 5.9 5.8 6.3 6.7
22.1 19.0 17.2 15.8 14.1
7.0 7.5 8.1 8.9 9.6
0.7 3.5 6.9 8.3
5.1 5.5 7.1 8.1
5.2 9.2 11.6 13.1
5.1 6.9 8.0 8.4
3.1 6.6 4.9 7.9 6.3 9.3 7.9 10.0
4.4 4.0 3.5 2.8 2.6
1.0 1.1 1.5 1.3 1.4
4.3 3.7 3.0 2.4 2.0
0.7 1.0 1.2 1.3 1.2
4.5 3.9 3.4 3.1 2.7
0.8 1.0 1.2 1.4 1.5
0.4 0.9 1.6 1.8
0.7 1.3 1.2 1.3
0.6 1.4 1.9 2.3
0.8 1.1 1.3 1.3
0.6 1.1 1.4 1.8
0.9 1.2 1.4 1.5
3.5 3.1 2.4 2.3
1.0 1.3 1.3 1.3
3.0 2.3 2.1 1.8
1.1 1.2 1.3 1.2
3.1 2.9 2.7 2.5
1.2 1.3 1.4 1.4
Response defined as reduction from baseline in HAM scores = 50%. Remission defined as a score = 8 on HAM scales. a Significant difference between imipramine and sertraline (v2 = 5.45, df = 1, P=.020, with Yates correction). b Significant difference between younger and older women taking imipramine (v2 = 6.24, df = 1, P=.013, with Yates correction). c Significant difference between imipramine and sertraline (v2 = 5.03, df = 1, P=.025, with Yates correction).
S.D.
(v2 = 8.33, df = 1, P=.004, with Yates correction). The most frequent reason for discontinuation in both groups of treatment was due to adverse events, being higher on imipramine (n = 30/123, 24.4%) than on sertraline (n = 12/116, 10.3%) (v2 = 7.19, df = 1, P=.007, with Yates correction). There were less than half the number of discontinuations in women on sertraline (n = 17/92, 18.5%) than on imipramine (n = 37/97, 38.1%) (v2 = 8.01, df = 1, P=.005, with Yates correction). But no statistically significant differences were observed in men for discontinuations between sertraline (n = 5/24, 20.8%) and imipramine (n = 8/26, 30.8%). 3.4. Effectiveness Overall, statistically significant differences between men and women were not found. By sex, statistically significant Notes to Table 2: a Endpoint was the subject’s last study visit for each parameter, with the last observation carried forward. b Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 9.36, df = 1, P=.003). c Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 12.39, df = 1, P=.001). d Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 9.18, df = 1, P=.003). e Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 6.91, df = 1, P=.009). f Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 19.61, df = 1, P=.000). g Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 23.10, df = 1, P=.000). h Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 17.99, df = 1, P=.000). i Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 15.61, df = 1, P=.000). j Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 10.17, df = 1, P=.002). k Significant difference between women taking sertraline and women taking imipramine (ANCOVA F = 11.03, df = 1, P=.001).
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Fig. 3. Dropout rates due to adverse event among men and women receiving sertraline and imipramine.
differences between sertraline and imipramine were not found either for response or for remission rates on men, whilst women tended to respond and remit better to sertraline than to imipramine. Fig. 1 shows response and remission on HAM-D21 scores. Statistically significant differences were found between women taking sertraline and women taking imipramine in the percentage of responders (v2 = 7.05, df = 1, P=.008, with Yate’s correction) and in the percentage of remitters (v2 = 4.18, df = 1, P=.041, with Yates correction). Fig. 2 shows response and remission on HAMA scores. Statistically significant differences were found between women taking sertraline and women taking imipramine in the percentage of responders (v2 = 10.91, df = 1, P=.001, with Yates correction) and in the percentage of remitters (v2 = 5.51, df = 1, P=.019, with Yates correction). However, interaction of gender and treatment did not reach statistical significance in logistic regression analyses either
on the primary intent-to-treat analysis or in an additional per protocol analysis with only patients who remained in the study at least up to Week 4. Analysis directly based on mean and change scores showed similar results. Table 2 shows mean scores in HAM-D21, HAM-A, CGI-S, and CGI-I scales at baseline and at each visit, as well as mean changes in scores reflecting improvement in depression. Statistically significant differences were found between women taking sertraline and women taking imipramine in reductions in HAM-D21 (at Weeks 4, 6, and endpoint), in HAM-A (at Weeks 2, 4, 6, and endpoint), and in CGI-S (at Weeks 4, 6, and endpoint). In particular, higher reduction in these scores was found in women taking sertraline. Nevertheless, interaction of gender and treatment did not reach statistical significance in ANCOVA analyses in either case. Table 3 shows the results of additional response and remission rates analyses in women comparing between < 40 years and z 40 years patients in order to study differences in treatment response by menopausal status in women. 3.5. Tolerability In the safety population groups, Fig. 3 shows that the proportion of women who dropped out due to adverse events was much lower in sertraline (n = 10/92, 10.9%) than in imipramine (n = 27/97, 27.8%) (v2 with Yates correction; P=.006), whilst no differences were found between both treatments in men (n = 2/24, 8.3% in sertraline, vs. n = 3/26, 11.5% in imipramine). Furthermore, the proportion of women with adverse events was also lower in the sertraline group (n = 50/92, 54.3%) than in imipramine (n = 78/97, 80.4%) (v2 = 13.51, df = 1, P=.000, with Yates correction),
Table 4 Adverse events in men and women receiving sertraline or imipramine Adverse event
Men
a
Any adverse event Anxiety Constipationb Diarrhoeac,d Dizziness Dry mouthe Gastritis Insomnia Nauseaf Sweatingg Tremorh a b c d e f g h
Women
Sertraline (n = 24)
Imipramine (n = 26)
Sertraline (n = 92)
Imipramine (n = 97)
n
%
n
%
n
%
n
%
18 2 2 6 0 9 3 5 3 3 2
75.0 8.3 8.3 25.0 0 37.5 12.5 20.8 12.5 12.5 8.3
22 2 6 0 2 16 4 6 3 5 6
84.6 7.7 23.1 0 7.7 61.5 15.4 23.1 11.5 19.2 23.1
50 11 1 8 11 10 12 5 15 5 6
54.3 12.0 1.1 8.7 12.0 10.9 13.0 5.4 16.3 5.4 6.5
78 16 30 1 18 58 4 7 5 19 19
80.4 16.5 30.9 1.0 18.6 59.8 4.1 7.2 5.2 19.6 19.6
Significant difference between women taking sertraline and women taking imipramine (v2 = 13.51, df = 1, P=.000, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 28.52, df = 1, P=.000, with Yates correction). Significant difference between men taking sertraline and men taking imipramine (v2 = 7.39, df = 1, P=.008, v2 exact test). Significant difference between women taking sertraline and women taking imipramine (v2 = 6.12, df = 1, P=.016, v2 exact test). Significant difference between women taking sertraline and women taking imipramine (v2 = 46.96, df = 1, P=.000, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 5.08, df = 1, P=.024, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 7.30, df = 1, P=.007, with Yates correction). Significant difference between women taking sertraline and women taking imipramine (v2 = 5.93, df = 1, P=.015, with Yates correction).
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whilst no statistically significant differences were found between both treatments in men (n = 18/24, 75.0% in sertraline, vs. n = 22/26, 84.6% in imipramine). No significant differences were found between men and women either in the proportion of discontinuations due to adverse events or in the presence of frequent adverse events for sertraline or imipramine. Table 4 shows that there were statistically significant differences by treatment in the presence of several adverse effects with frequencies of occurrence of z 10% in men or women. In particular, among men, it was found that those patients taking sertraline were significantly more likely to report diarrhea. Among women, those patients taking sertraline were significantly more likely to report diarrhea and nausea, whilst those patients taking imipramine were more likely to report constipation, dry mouth, sweating, and tremor.
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4.1. Gender differences in anxiety response Analyses based on mean and change scores also showed an effect of gender on the specificity of response to antidepressant treatment, with women taking sertraline responding more highly for anxiety symptoms as assessed by means of the HAM-A scale than those taking imipramine from an early stage (Week 2). This finding is consistent with other published studies (Frank et al., 1988; Kornstein et al., 2000), though in such studies, response was studied with respect to general depressive symptoms without considering anxiety separately from merely depressive symptoms. Furthermore, it may lead to the conclusion that the assessment of specific subsets of symptoms should be explored in future studies in order to understand more precisely gender differences in the evolution of depression when responding to treatment. 4.2. Gender differences in tolerability
4. Discussion The aim of the study was to examine gender differences in the acute antidepressant response to sertraline and imipramine in nonmelancholic depression. The results show that men responded similarly whether assigned to sertraline or imipramine, whilst women assigned to sertraline were more likely to respond well—and to remit—to treatment. This result may be attributed to the differential tolerability profile of sertraline and imipramine in women. Whilst men showed similar dropout rates irrespective of which drug they were taking, in women assigned to imipramine, the likelihood of discontinuing due to adverse events was almost threefold. This study is one of the few that we are aware of to report gender differences in antidepressants response in nonmelancholic depressive disorders. These findings are consistent with other results previously reported showing more efficacy in women than in men being treated with antidepressants (Raskin, 1974). Moreover, recent results (Kornstein et al., 2000) suggest that women respond significantly better with sertraline than with imipramine in chronic depression, although in this study, a statistically significant interaction of gender and treatment for efficacy parameters was also found even though it has not reached statistical significance in our study. Underlying biological explanations for these gender differences in treatment response still remain unclear. It has been suggested that female sex hormones may influence treatment effect finding that, for example, estrogen enhances response to SSRIs or inhibits response to TCA (Halbreich and Kahn, 2001). In addition, several findings on gender differences such as differences in cerebral blood flow (Videbech et al., 2001) or state regulation during sleep (Armitage and Hoffman, 2001) also support that there may be gender differences in treatment response. However, further studies are needed to determine factors of differential antidepressant treatment response.
The proportion of women who dropped out due to adverse events was much lower in the sertraline group (10.9%) than in imipramine (27.8%), whilst no differences were found between both treatments in men (8.3% in sertraline vs. 11.5% in imipramine). These results are also similar to those found in previous studies (Kornstein et al., 2000), although in our study, differences between both treatments in women were greater. Several significant gender differences in types of adverse events were also noted in our study as similar to previous studies, with women taking imipramine being more likely to report constipation, dry mouth, sweating, and tremor and thus reinforcing that women have more tolerability problems with imipramine than with sertraline. However, it has been suggested elsewhere that some specific adverse events, such as sexual dysfunction, require specific consideration and specific measures in order to ensure their right assessment (Montejo et al., 1997; Kornstein and McEnany, 2000). Consequently, it should be taken into consideration that some adverse events may be underreported in our study, which may limit our findings relative to gender differences in tolerability. 4.3. Age comparisons In previous studies, it has been shown that the gender differences in treatment response to selective serotonin reuptake inhibitors is predominantly determined by a higher responsiveness in premenopausal women (Kornstein et al., 2000; Marte´nyi et al., 2001). The menopausal status was not specifically determined in this study. However, in order to examine the potential effect of this, additional analyses were carried out stratifying women by age ( < 40 years, z 40 years). Results from these analyses suggest that younger women show higher responsiveness for depression and anxiety symptoms than older women, al-
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though statistically significant superiority was only found on imipramine for anxiety symptoms. Differences in women between both treatments were only found in older women ( z 40 years) with lower remission rate for anxiety symptoms and poorer tolerability in imipramine. These results are not completely consistent with previous studies (Kornstein et al., 2000; Marte´nyi et al., 2001), although the effects of oral contraceptives and hormone replacement therapy and their potential interaction with serotoninergic antidepressants should have been addressed to properly examine the effect of the menopausal status. 4.4. Limitations of the study Some limitations must be noted in our study, first of which is the relatively small size of the men group, which may impede seeing the statistical significance for the interaction of gender and treatment. The other most important limitations are the consequence of conducting a clinical effectiveness study rather than a classic doubleblind, placebo-controlled efficacy study. These include lack of a placebo control to provide assay sensitivity for the trial (Temple and Ellenberg, 2000) and lack of blinding methodology. The latter may be of less importance than it seems at first since both study treatments are known to be effective antidepressants. Still, it is clearly a study limitation whose full effect is uncertain. Another limitation is that the mean dose of imipramine (104 mg in men, 101 mg in women) was lower than may have been necessary to optimise efficacy. Investigators could increase the dose of imipramine to 225 mg/day depending on clinical response and tolerability, but the optimal dosing for imipramine may have appeared to be lower than necessary to optimise efficacy. This means that no inferences concerning the comparative pharmacological efficacy of sertraline versus imipramine can be made. All that can be said is that from a practical clinical standpoint, sertraline was a significantly more effective and welltolerated treatment, and that optimal dosing of imipramine appeared to be limited by lack of patient acceptance of its higher side effect burden.
5. Conclusions The study results point out that there are gender differences in the effectiveness and tolerability of antidepressants in the treatment of nonmelancholic depression. Specifically, sertraline is more effective and better tolerated than imipramine in the acute treatment of nonmelancholic depression in women with an earlier and higher response for anxiety symptoms, whereas men responded similarly whether assigned to sertraline or imipramine. However, further studies are needed in order to have more precise evidence for gender differences in treatment response in depression.
Acknowledgements The authors wish to thank additional investigators and collaborating sites: M.Gonza´lez de Cha´vez (Hospital Gregorio Maran˜o´n, Madrid); S. Oliveros (Hospital Puerta de Hierro, Madrid); B. Franco (C.S.M. Colmenar Viejo, Madrid); A. Rivera, B. Penasa, and I. Lo´pez (C.S.M. Salamanca, Madrid); E. Capdevila (Centro de Psiquiatrı´a y Psicoterapia, Madrid); F. Pe´rez Arnau and F. Teba (C.S.M. Prat de Llobregat, Barcelona); C. Gasto´, J. Blanch, and L. Pintor (Hospital Clinic, Barcelona); J. Pe´rez de los Cobos, J. Fa´bregas, and L. Del Angel (Centro de Psicoterapia, Barcelona); R. Noguera and L. Jorda´ (Hospital Psiquia´trico, Gerona); and M. Garcı´a Toro and A. Gonza´lez (H. Psiquia´trico, Palma de Mallorca). Authors thank Inmaculada Expo´sito (Pfizer, Madrid) for her technical help. This study was supported by a research grant from Pfizer, Madrid, Spain. References American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. American Psychiatric Association, Washington. Revised. Angst, J., Dobler-Mikola, A., 1984. Do the diagnostic criteria determine the sex ratio in depression? J. Affect. Disord. 7, 189 – 198. Armitage, R., Hoffmann, R.F., 2001. Sleep EEG, depression and gender. Sleep Med. Rev. 5 (3), 237 – 246. Canetto, S.S., Sakinofsky, I., 1998. The gender paradox in suicide. Suicide Life-Threat. Behav. 28, 1 – 23. Clayton, A., 2001. Panic in women across the life cycle: clinical presentation and response to sertraline. Annual Meeting of 154rd American Psychiatric Association. New Orleans, LA, NR 597. Ensom, M.H., 2000. Gender-based differences and menstrual cycle-related changes in specific diseases: implications for pharmacotherapy. Pharmacotherapy 20, 523 – 539. Frackiewicz, E.J., Sramek, J.J., Cutler, N.R., 2000. Gender differences in depression and antidepressant pharmacokinetics and adverse events. Ann. Pharmacother. 34, 80 – 88. Frank, E., Carpenter, L.L., Kupfer, D.J., 1988. Sex differences in recurrent depression: are there any that are significant? Am. J. Psychiatry 145, 41 – 45. Gex-Fabry, M., Balant-Gorgia, A.E., Balant, L.P., Garrone, G., 1990. Clomipramine metabolism: model-based analysis of variability factors from drug monitoring data. Clin. Pharmacokinet. 19, 241 – 255. Glassman, A.H., Perel, J.M., Shostak, M., Kantor, S.J., Fleiss, J.L., 1977. Clinical implications of imipramine plasma levels for depressive illness. Arch. Gen. Psychiatry 34, 197 – 204. Gold, J.H., 1998. Gender differences in psychiatric illness and treatments: a critical review. J. of Nerv. Ment. Dis. 186, 769 – 775. Greenblatt, D.J., Friedman, H., Burstein, E.S., Scavone, J.M., Blyden, G.T., Ochs, H.R., Miller, L.G., Harmatz, J.S., Shader, R.I., 1987. Trazodone kinetics: effect of age, gender, and obesity. Clin. Pharmacol. Ther. 42, 193 – 200. Guy, W., 1976. Clinical global impressions. In: Guy, W. (Ed.), Early Clinical Drug Evaluation (ECDEU). Assessment Manual for Psychopharmacology. NIMH, Rockville, pp. 217 – 222. Halbreich, U., Kahn, L.S., 2001. Role of estrogen in the aetiology and treatment of mood disorders. CNS Drugs 15 (10), 797 – 817. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56 – 62.
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