Are there gender differences in major depression and its response to antidepressants?

Abstract

Background: The prevalence of major depression for women is about twice that for men. This gender difference in prevalence rates has led to much research addressing gender differences in the presentation and features of major depression, and, to a lesser extent, research addressing gender differences in treatment response and personality. However, studies differ considerably in the population sampled, and findings vary significantly. In the current retrospective examination of data, we investigated all of these variables in one single sample of outpatients with major depression seen in a tertiary care centre. Methods: A sample of 139 men and 246 women with major depression receiving antidepressant treatment (SSRIs, TCAs, SNRIs, MAOIs, or RIMAs) in an outpatient setting were contrasted with regard to symptoms and severity of depression, course of illness, treatment response, and personality. Results: Women were found to experience more vegetative and atypical symptoms, anxiety, and anger than men, and to report higher severity of depression on self-report measures. Regarding personality, women scored higher on conscientiousness, the extraversion facet warmth, the openness facet feelings, and sociotropy. Effect sizes were small to moderate. No differences were found in the course of the illness and treatment response. Limitations: Findings are not generalizable to inpatient or community samples, and some of the gender differences may be accounted for by gender differences in treatment seeking behaviour. Conclusions: While men and women receiving antidepressant treatment show some gender differences in the psychopathology of major depression, these differences do not appear to translate into differences in response to antidepressants. Gender differences in personality appear less profound than in the average population, indicating the potential role of a certain personality type that predisposes individuals to develop clinical depression, independent of gender. Clinical relevance: The current examination underscores the role gender plays in the presentation and treatment of major depression.

Introduction

Women are at higher risk to develop depressive disorders than are men. Empirical investigations over a period of more than 20 years have demonstrated that women are typically twice as likely to develop depressive disorders than men are (Weissman and Klerman, 1977, Kessler et al., 1993, Weissman et al., 1993), although this ratio has been reported to vary across different types of depressive disorders (Perugi et al., 1990). For example, while women are two times more likely to develop a single episode unipolar depression, they are four times more likely to develop recurrent unipolar depression (Perugi et al., 1990). These ratios have been reported in a wide range of patient and non-patient populations, including clinical and community samples with major depression, and community samples with sub-threshold depressive symptoms (e.g., Weissman and Klerman, 1977, Oldehinkel et al., 1999).

While the preponderance of women suffering from depressive disorders is well-established and frequently replicated, considerably less attention has been given to gender differences in the presentation and features of depression. This related line of research has attempted to determine empirically whether, and in what specific aspects, depression in men differs from depression in women (Angst and Dobler-Mikola, 1984, Frank et al., 1988, Perugi et al., 1990, Thase et al., 1994, Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992, Derogatis, 1992, Rapaport et al., 1995, Zlotnik et al., 1996, Simpson et al., 1997, Bracke, 1998, Silverstein, 1999). Gender differences have been reported in severity and symptoms of depression, course of illness, and treatment response in some of these studies, while other studies reported negative results. Few studies have also examined the differences in the personality traits of depressed men and women. However, these studies differ considerably in terms of the population sampled, which may have contributed to inconsistent findings across these different studies. For example, while some studies have investigated community samples of individuals with sub-threshold clinical depression (e.g., Angst and Dobler-Mikola, 1984, Bracke, 1998), other studies have included depressed patients meeting full diagnostic criteria (e.g., Thase et al., 1994, Fava et al., 1996, Silverstein, 1999). Several clinical studies have included both unipolar and bipolar depressed patients (Frank et al., 1988, Perugi et al., 1990, Rapaport et al., 1995, Croughan et al., 1988; Simpson et al., 1997), which are likely to have contributed to inconsistent findings. Other studies have investigated quite narrowly defined populations, such as samples with chronic depression (i.e., longer than 2 years) (Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992, Derogatis, 1992), recurrent depression (i.e., at least two previous episodes) (Frank et al., 1988), or pure depression (i.e., exclusion of individuals with comorbid Axis I disorders) (Sotsky et al., 1991, Kornstein et al., 1995, Zlotnik et al., 1996).

One goal of this paper was to review systematically the literature on gender differences and depression with respect to symptoms, severity, course of illness, personality, and treatment response, with particular attention to the different populations sampled. As none of the reviewed studies examined all of these variables in a single sample, resulting, perhaps, in inconsistent findings, a second goal was to investigate all of these potential factors related to gender differences in depression in one sample of unipolar depressed patients receiving antidepressant treatment. We believe that such an analysis provides a more cohesive and meaningful depiction of gender and depression, at least for those depressed persons receiving treatment.

In a community sample of individuals with dysphoric mood, Angst and Dobler-Mikola (1984) found that women reported more appetite and sleep disturbances, while men reported more psychomotor changes, feelings of worthlessness, and decreased concentration. Silverstein (1999) reported that clinically depressed women in the general population exhibited a higher number of somatic symptoms including fatigue, sleep and appetite disturbance. Accordingly, in clinical in- and outpatient populations, women were reported to be more likely to have vegetative and/or atypical symptoms such as increased appetite, weight gain, and sleep disturbance (Frank et al., 1988, Perugi et al., 1990, Young et al., 1990). Clinically depressed women were also reported to show higher levels of anxiety and somatization (Frank et al., 1988, Perugi et al., 1990, Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992), as well as anger (Frank et al., 1988) and psychomotor retardation (Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992). One study of clinically depressed individuals reported that men are more likely to endorse weight loss (Frank et al., 1988). A study of recurrently depressed individuals that weighed patients during and between episodes only found a trend toward men losing more weight than women (Stunkard et al., 1990).

Women with clinical depression may tend to experience a greater severity of depressive symptoms (Frank et al., 1988, Perugi et al., 1990, Thase et al., 1994, Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992). Women with sub-threshold depression have also been reported to endorse a greater overall number of depressive symptoms (Angst and Dobler-Mikola, 1984, Bracke, 1998). Other clinical studies failed to find a gender difference in depression severity (Croughan et al., 1988, Young et al., 1990, Fava et al., 1996, Bothwell and Scott, 1997). Perugi et al. (1990) pointed out that gender differences are especially prominent in the self-reported severity of depressive symptoms as compared to interview-based measures of depression severity. Accordingly, Frank et al. (1988) and Kornstein et al. (2000a) reported that women presented as more severely depressed than men on the Beck Depression Inventory (BDI; Beck, 1978), while this difference was absent on the clinician-rated Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967).

Some studies reported that women have an earlier age of onset of the first depressive episode (Ernst and Angst, 1992, Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992, Fava et al., 1996), whereas other studies found no difference (Amenson and Lewinsohn, 1981, Frank et al., 1988, Perugi et al., 1990, Thase et al., 1994, Rapaport et al., 1995, Simpson et al., 1997). In community samples, it was found that depression in women is more likely to develop into a recurrent course (Amenson and Lewinsohn, 1981, Ernst and Angst, 1992, Bracke, 1998). However, most studies using clinical samples do not find a gender difference in the number of previous depressive episodes (Frank et al., 1988, Winokur et al., 1993, Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992, Bothwell and Scott, 1997). In addition, depression in women has been reported to be more chronic in community samples (Sargeant et al., 1990, Bracke, 1998) and in patients with pure depression (i.e., without comorbid Axis I disorders) (Keitner et al., 1991). However, again this gender effect in chronicity of depression was absent in other clinical studies (e.g., Amenson and Lewinsohn, 1981, Perugi et al., 1990, Winokur et al., 1993, Kornstein et al., 1995Derogatis, 1992, Derogatis, 1992, Rush et al., 1995). Moreover, in a prospective study following patients with a first episode of major depression for 15 years, Simpson et al. (1997) found no evidence of a more chronic or recurrent course in women.

Gender may be an important variable in understanding variability of response to antidepressant treatment. There is some evidence that women respond more poorly than men to tricyclic antidepressants (TCAs), with imipramine studied the most. For example, Frank et al. (1988) reported that men with recurrent major depression have a more rapid and sustained response to imipramine than women. In a recent study, Kornstein et al. (2000b) found that chronically depressed men responded more favourably to imipramine than women, while women showed a more favourable response to sertraline [a selective serotonin re-uptake inhibitor (SSRI)] than men. Haykal and Akiskal (1999) further found that females diagnosed with dysthymia and treated with fluoxetine (another SSRI) had higher response rates compared to men. Davidson and Pelton (1986) investigated a sample of depressed individuals with comorbid panic attacks, and found that monoamine oxidase inhibitors (MAOIs) were superior to TCAs in women, while TCAs were superior to MAOIs in men. These differential findings have been related to gender differences in drug absorption, bioavailability, drug distribution, metabolism, and elimination. However, a number of other studies indicate that men and women are equally likely to respond to TCAs, including imipramine (Croughan et al., 1988, Sotsky et al., 1991, Zlotnik et al., 1996) and amitriptyline (Croughan et al., 1988, Paykel et al., 1988). There is a shortage of clinical trials comparing the response of men and women with major depression to antidepressants other than TCAs.

A number of personality features have been proposed as vulnerability factors for the development and maintenance of depression. These include neuroticism, introversion, interpersonal dependency, self-criticism, and perfectionism. All of these features have been reported to be more prominent in depressed individuals than in controls (Hirschfeld et al., 1984, Klein et al., 1988, Franche and Dobson, 1992, Bagby et al., 1994, Bagby et al., 1995, Enns and Cox, 1997). In addition, from a cognitive perspective, Beck (1983) proposed that the cognitive styles of autonomy and sociotropy predispose individuals to develop depression. Autonomy, which is related to the constructs of self-criticism and perfectionism, refers to excessive achievement expectations and a strong need for independence. Sociotropy, which is related to interpersonal dependency, refers to a strong need for affiliation and support from others. According to Beck (1983), as a result of socialization, women are more likely to develop sociotropic structures, while men are more likely to develop autonomous structures. This hypothesis was empirically confirmed in a university student sample (Robins et al., 1994). Only very few studies addressed the issue of gender differences in these personality variables in clinically depressed samples. In recovered depressed patients, Hirschfeld et al. (1984) failed to find an effect of gender on interpersonal dependency, and Zlotnick et al. (1996) failed to find gender differences in need for approval and perfectionism as measured by the Dysfunctional Attitude Scale (DAS; Weissman and Beck, 1978). Bothwell and Scott (1997) found acutely depressed men and women to have comparable scores in neuroticism. Perugi et al. (1990) reported that clinically depressed women were significantly more likely to have a ‘depressive temperament’, which includes features of self-criticism and preoccupation with inadequacy and failure. One problem of all studies investigating personality and acute depression, and a usual criticism of such investigations, is the potential influence of depressed mood on personality scores. However, while the finding of absolute change (i.e., the extent to which mean personality scores change or increase/decrease in the context of a depressive episode) of certain personality measures as a function of change in depression is well-established, relative stability (i.e., the extent to which the relative differences on personality scores among a group of individuals remain constant in the context of a depressive episode) has been demonstrated for a number of traits including neuroticism and extraversion (Santor et al., 1997), as well as sociotropy and autonomy (Bagby et al., 2001). Thus, there is mounting evidence that personality measures do have stability in the context of changing mood and, therefore do confer vulnerability to depression independent of the state effects of depressed mood (Bagby and Ryder, 2000).

In summary, it appears quite possible that the contradictory findings in the presentation of major depression are a result of variation in sampling procedures. Research is needed to elucidate which gender differences can be generalized to a wide range of depressive populations. In the present analyses, we tried to address this issue by investigating gender differences in a sample of outpatients with major depression of varying levels of chronicity and recurrency who are receiving antidepressant treatment. While it may be more difficult to detect gender differences in such a heterogenous population, we believe that potential findings are more powerful as they are not limited to specific depressive subtypes, such as chronic, recurrent, or pure depression.