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.
Collectively, 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.
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.