Geriatric Depression: Does Gender Make a Difference?

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Our society is experiencing significant demographic changes that are altering the profile of late-life depression in the United States. Both men and women are living longer, but the gender gap in longevity is widening. This disparity introduces a puzzling paradox: In the United States, women report more illnesses and health care utilization on average than men, despite the consistently greater life expectancy of women (Riley, 1990). Given the greater prevalence of depression in women compared to men, we are likely to see a correspondingly greater prevalence of geriatric depression in years to come. Similarly, data from the Centers for Disease Control and Prevention (2002) show that men have higher rates of completed suicide, despite the fact that women suffer from depression more frequently. There are many proposed explanations for these paradoxes, including sociocultural, biological and genetic causes.

Diagnosing depression in the elderly may be difficult in late life due to the presence of medical comorbidity, cognitive impairment, multiple losses, heterogeneity and atypical features. Reported prevalence rates for clinical depression in individuals older than 65 years of age range from 11% to 25% among patients in primary care and nursing home settings and at about 3% among healthy elderly living in the community (Brown et al., 2002; Lebowitz et al., 1997).

Differences in Prevalence Among Men and Women

Large epidemiologic studies report higher rates of depression among women, with about 4% of women and 1.7% of men carrying the diagnosis of major depression. The Epidemiologic Catchment Area-reported prevalence of major depression is 0.1% to 0.8% for men and 0.6% to 1% for women after age 65 (Nolen-Hoeksema, 1995). The differences appear to be age-specific with little difference in childhood, a considerable difference in mid-life (due to a sharp rise of depression in females), and a decrease in this difference in older age (Jorm, 1987). Some data suggest that the incidence of depression for women in the postmenopausal period may decrease relative to its incidence in men, although earlier research suggested that the difference in rates of depression between men and women become progressively smaller and may disappear among members of older age groups (Blazer and Williams, 1980). The explanation for this reduction is not yet available.

Gender Differences in Risk Factors

The pattern of depressive symptoms does not appear to be different between men and women (Sonnenberg et al., 2000), although the course and outcomes may differ. While higher rates of chronicity and recurrence of depression in younger adult women has been reported in several longitudinal studies (Kornstein, 1997), the male gender is reportedly associated with poorer outcomes of late-life depression in patient sample-based longitudinal studies (Baldwin and Jolley, 1986).

Research on gender differences in risk factors for late-life depression is limited. Family history of depression remains the best-known genetic risk factor for depression in both genders, but even this factor has limited predictive value. In a community-based study of depression in Australian twins, only moderate familial aggregation of depression occurred in women, "with heritability estimates ranging from 36% to 44%. In men, depression was only modestly familial, and thus, individual environmental factors played a larger role in the development of depression" (Bierut et al., 1999).

Biological theories point to the hormonal changes that occur in women during the critical periods of puberty, childbirth and menopause in explaining gender differences in depression rates. Gender differences in affective disorders' prevalence have been ascribed to variations in the levels or activity of monoamine transmitters, which are themselves changed by gonadal hormones. Halbreich et al. (1984) wrote, "Several aspects connected with the monoamine biosynthesis, availability, uptake and metabolism were found to be more abnormal in normal women and depressed women, as compared to men." However, many studies failed to confirm increased rates of depression in postmenopausal women.

Differences in Patterns of Attachment and Loss

Behavioral theories try to explain differences in rates of depression according to gender differences in attachment patterns: women base their self-esteem on their relationships with others; they are less assertive and lack confidence in controlling their lives. Stressors of late life include multiple losses/negative changes in relationships, employment, financial status and health problems. Retirement has been considered a major stressor for men as widowhood has been for women. In a recent community study of widowhood and depression, however, widowhood was more "depressogenic" in men compared to women (van Grootheest et al., 1999). Maciejewski et al. (2001) examined gender differences in event-related risk for major depression and found a three times greater likelihood for women to develop depression in response to stressful events as compared to men. With the dramatic changes in the workforce, most of these theories may change.

Medical Comorbidity and Late-Life Depression

Geriatric depression often occurs concurrently with a variety of chronic medical illnesses. Depression associated with the presence of chronic medical illness also increases the incidence of premature mortality, primarily from increased rates of cardiovascular and cancer deaths. Okiishi and colleagues (2001) reviewed the literature on gender differences in depression associated with neurological illness. They found a female preponderance of depression in diffuse neurological disease but not in focal neurological disease.

Men are generally known to have higher gender-specific mortality rates caused by smoking, heart disease, atherosclerosis and cerebrovascular disease, which may contribute to a changing sex-ratio in rates of late-onset depression with onset after age 60 (Lavretsky, 1998).

'Vascular Depression' Hypothesis

Elderly people who develop depression demonstrate changes in cerebral brain structures (Simpson et al., 2001). There is a growing consensus that vascular factors contribute to depression in a subgroup of patients with late-life major depression. This thesis is supported by these observations:

• Data from computerized tomography and magnetic resonance neuroimaging studies, which identify hyperintensities (HI) in such patients;
• The association of HI with age and cerebrovascular risk factors;
• The pathophysiological evidence indicating that HI are associated with widespread reduction in cerebral perfusion (Sackeim, 2001).

The neuropathological correlates of HI are diverse and represent ischemic changes together with demyelination, edema and gliosis (Kumar et al., 2000; Sackeim, 2001); but, the putative link between HI and vascular disease forms the basis of the vascular theory of depression. In a study of patients meeting the DSM criteria for depression, silent cerebral infarctions were reported in 65% of patients (Fujikawa et al., 1996). These abnormalities, observed in MRI evaluations of elderly patients with major depressive disorder, can be classified into three types:

• Periventricular HI: halos or rims adjacent to ventricles;
• Single, patchy or confluent foci: may be observed in subcortical white matter or deep white matter HI;
• Hyperintensities in deep gray structures, particularly the basal ganglia, thalamus and pons.

bCollectively, these three types of abnormalities have been referred to as leukoareosis or encephalomalacia (Lavretsky and Kumar, 2002).

Because men are known to have higher rates of vascular risk factors (Khaw, 1996), it is possible that they could be more prone to developing late-onset vascular depression, as compared to women (Alexopoulos et al., 1997; Krishnan et al., 1997). Patients with clinically defined vascular depression tend to have a late onset of depression after age 60 and experience greater cognitive dysfunction, disability and retardation, although they do experience less agitation and fewer feelings of guilt than do patients with nonvascular depression. Currently, data on gender differences in vascular depression prevalence are lacking. In fact, Alexopoulos et al. (1997) did not find gender differences in their sample of patients classified as having vascular depression versus those who did not have this type of depression. In our study, gender differences were found only in a group with large white matter hyperintensity areas >10 cm². This group included a greater proportion of men (Lauretsky et al., 1998).

Frontal Lobe Volume Differences

The frontal lobes play an important role in the pathophysiology of depression. In another study (n=37), we found gender differences in the adjusted brain volumes among depressed elderly and age-matched controls. Depressed men had smaller total frontal and left frontal volumes compared to women. This difference was due to a decrease in frontal white matter volumes (Table) (Lavretsky et al., 2002). The frontal lobe has been implicated before in the pathophysiology of depression in younger and older adults (Kumar et al., 2000). It is possible that older men with ischemic changes in the brain may have greater atrophy of the frontal lobes. According to a recent report based on healthy younger adults, age was strongly associated with reduced dorsolateral prefrontal cortex volume, with reduced amounts of gray matter and increased levels of cerebrospinal fluid in men (Gur et al., 2002). These findings indicate that older men may be more vulnerable to developing depression due to structural brain changes.

Depression and the Hippocampus

In addition to brain atrophy and microvascular changes, the hippocampus is another brain structure that has attracted considerable interest, due to the hypothesis that stress hormones cause hippocampal atrophy. Several groups have examined volumetric changes in the hippocampus in major depression, but the results are inconsistent. Some reported no difference between the hippocampal volume in patients with major depression compared to normal controls (Coffey et al., 1993). Sheline et al. (1996) reported smaller left and right hippocampal volumes in elderly women with major depression. In another report, younger male and female control subjects were compared to patients with major depression (Vakili et al., 2000). The researchers found, "A significant correlation was observed between the left hippocampal volume of men and the Hamilton Depression Rating Scale (HAM-D)" scores used to measure the severity of their depression. The Danish PET/depression project found gender differences in cerebral blood flow and changes in the comparative distribution of blood with increasing age (Videbech et al., 2001). The hippocampal and cerebellar activity of patients was increased compared to healthy controls, after correcting for medication exposure, age and gender.

Conclusion

Gender differences in geriatric depression have been studied inconsistently. Future studies should address the possibility that men have higher rates of vascular depression associated with an onset in late life. These studies should investigate how brain structural changes are related to greater severity of depression and associated disability, and how vascular depression may place men at a higher risk for suicide. A better understanding of gender differences in the course of depression and treatment response may lead to improved treatment strategies and suicide prevention.

Acknowledgements

Supported in part by the K23-MH01948 Career Development Award from National Institute of Mental Health and National Alliance for Research in Schizophrenia and Depression Young Investigator Award.

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