ANNUAL REVIEWS
Annu.
Rev. Med. 1991. 42:261-{j6 Copyr(qht © 1991 by Annual Reviews
Further
Quick links to online content Inc. All r(qhts reserved
ORGANIC BASES OF Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
DEPRESSION IN THE ELDERLY K. Ranga Rama Krishnan, M.D.
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710 KEY WORDS:
affective disorders,
leukoencephalopathy,
basal ganglia,
peri
ventricular white matter
ABSTRACT
Early studies suggested that cerebrovascular change may be an etiological factor in the development of late-life depression. With the advent of mag netic resonance imaging (MRI), it has become possible to examine this hypothesis. MRI studies have demonstrated that patients with late-onset depression have more severe and frequent patchy lesions in the frontal deep white matter and basal ganglia than do controls or patients with early onset depression. Patients with basal ganglia lesions, primarily caudate, are more likely to develop delirium with antidepressants and electroshock treatment (EST). The prognostic significance and the relationship of these lesions to cognitive impairment is unclear. INTRODUCTION
Affective disorders, especially depression, are quite common in the elderly. Approximately 1-2% of elderly subjects in the community fulfill criteria for DSM-III major depression, though more than 10% have symptoms of depression. Major depression is probably a syndrome and its etio pathogenesis is not well understood. In the young, genetic factors appear to be important. In the elderly patient presenting with depression for the first time, genetic predisposition is less likely and nongenetic factors may be more important. One such factor is focal cerebrovascular change. Mayer Gross, Slater & Roth (1) noted that sustained affective and other psy261 0066-4219/91/0401--0261$02.00
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
262
KRISHNAN
chiatric symptoms occurred frequently in patients with cerebral arterio sclerotic disease. Post (2) reported that 12% of patients over the age of 60 had focal cerebrovascular changes. He hypothesized that such changes may trigger the depressive reaction. With the advent of magnetic resonance imaging (MRI), it has become possible to examine the hypothesis that subtle cerebrovascular changes may play a role in the etiopathophysiology of depression in the elderly. Patchy foci of increased signal intensity are often identified on Tz-weighted magnetic resonance images of the brain, especially in the elderly. These lesions are often associated with cerebrovascular disease (3). Age, prior history of brain ischemia, and hypertension are the most significant pre dictors of the incidence and severity of such lesions (4). The lesions are seen in the deep white matter, periventricular, and basal ganglia region. Their pathology varies and includes perivascular dilatation, gliosis, areas of myelin pallor, and on rare occasions, frank infarction. Brainstem hyperintensities are also common (4) and are seen primarily in the pons. Anatomically, the sites correspond to the distal distributions of the penetrating arterioles. The pathogenesis of these lesions is not known, though deposition of lipids within arteriolar walls (lipohyalinosis) has been linked to hyperintensities. The penetrating arteries affected by this process include lenticulostriate, thalamoperforate, and medullary arteries arising from cortical branches to supply deep portions of the hemispheric white matter. At the brainstem level, penetrating branches from the basilar artery are also affected. These lesions on MRI have been variably referred to as leukoencephalopathy, subcortical hyperintensities, subarteriosclerotic encephalopathy, and leukoaraiosis. LEUKOENCEPHALOPATHY IN DEPRESSED
PATIENTS
As leukoencephalopathy might reflect subtle alterations in cerebrovascular function, we assessed the occurrence of patchy white matter lesions (leuko encephalopathy) in 35 patients who presented with depression in middle and late life (5). The striking finding of this study was a high prevalence (72%) of patchy white matter lesions in patients with late-onset depression. The absence of controls limited the conclusions drawn from this study. Coffey et al (6) confirmed these findings. They studied 67 depressed patients referred for electroconvulsive therapy (ECT). Of these, 36 patients were studied using MRI and 39 with computerized tomography. Leuko encephalopathy was seen in 66% of the patients and was present in 86% of the MRI scans and 50% of the computerized tomography scans (con tinning the higher sensitivity of MRI), and was noted primarily in the peri-
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
ORGANIC DEPRESSION IN THE ELDERLY
263
ventricular, thalamic, and basal ganglia regions. Most patients with leuko encephalopathy had their first episode of depression after the age of 60. In a subsequent prospective study, Coffey et al (7) reported that 100% of 51 elderly (> 60 years old) depressed (80% late-onset) patients referred for electroshock therapy showed leukoencephalopathy on MRI. Fifty-one percent of the patients also had lesions in the basal ganglia and thalamus (8). Compared to age-matched control subjects, depressed subjects had more severe periventricular and subcortical hyperintensities (8). Lesions of the thalamus and basal ganglia were also significantly more common in depressed patients. A relationship between subcortical hyperintensities and the presence of risk factors for vascular disease was also noted. Figiel et al (9) compared elderly patients with late-onset depression (onset after the age of 60) and elderly depressed patients whose first episode of depression occurred before the age of 60. Caudate lesions were observed in 60% of the late-onset patients compared to 11% of the early-onset patients. Late-onset patients had a higher incidence of deep white matter lesions, primarily frontal lobe, larger than 1 cm (60%) compared to the early-onset group. Ninety percent of the late-onset patients had either a basal ganglia lesion or a large deep white matter lesion, whereas only 11% of patients with early-onset depression had such lesions. The exact pathological correlate of these lesions in depressed elderly remains unde termined. That they are ischemic in nature is suggested by a study by Tomlinson et al (10), who found cerebral ischemic degenerative change at autopsy in the elderly. Leukoencephalopathy is seen in elderly patients with other psychiatric disorders, though the location is different. Elderly patients with late-onset mania have lesions primarily in the frontal and parietal regions (11). Patients with late-onset psychosis almost invariably have large deep white matter lesions in the parietal and occipital regions (12). Lesions in the occipital region geniculocalcarine tract are associated with the presence of visual hallucinations in these patients. ETIOLOGICAL SIGNIFICANCE OF LEUKOENCEPHALOPATHY IN DEPRESSION
Indirect supportive evidence that lesions of the caudate and deep frontal white matter may be of etiological significance in depression comes from a number of studies in both animals and humans. Animal studies have demonstrated that the caudate nuclei are functionally and anatomically related to the prefrontal cortex and that destruction of the caudate leads to marked changes in complex behaviors. In humans, the knowledge of caudate function comes primarily from the study of Huntington's disease, whose major pathology involves the caudate nuclei. A number of studies
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
264
KRISHNAN
show that major depression is common in patients with Huntington's disease ( 13). Further, the cognitive impairment seen in Huntington's dis ease is similar to that seen in depressed patients, although Huntington's disease also involves other structures, such as the putamen and cortex. Thus, it is difficult to attribute conclusively the cognitive and behavioral changes to caudate atrophy. More definitive evidence comes from the work of Mendez et al ( 14), who showed that a group of patients with caudate lesions secondary to cerebrovascular disease had behavioral symptoms similar to those seen in depression. We recently compared caudate volumes in 39 depressed patients with 39 age-matched controls and demonstrated that caudate volume was markedly diminished in patients with major depression ( 15). This study coupled with that of Baxter et al (16), who showed a diminished metabolism in the caudate nuclei of depressed patients, provides direct evidence of a role for the caudate nuclei in the etiopathophysiology of depression. OTHER STRUCTURAL CHANGES IN LATE-ONSET DEPRESSION
Besides leukoencephalopathy, enlargement of the lateral ventricles has been reported in depressed patients ( 17). In another study, enlargement of the ventricles was related to leukoencephalopathy (18). Recent studies demonstrated that other structures in the brain such as the hippocampus and the putamen may also be involved. Putamen volume is markedly diminished in depressed patients compared to controls ( 19). Changes in the hippocampus were assessed by measuring Tj relaxation times on MRI (which is an indirect measure of water balance and might reflect atrophy). The Tj relaxation times were decreased in older depressed patients com pared to controls (20). The finding that changes in the putamen may be common in depressed patients is not surprising given the close relationship between the putamen and the caudate nuclei. The link between hippo campal and basal ganglia changes is currently being explored. Both the basal ganglia circuit and the limbic circuit are involved in the regulation of mood. The lesions in the caudate nuclei and deep frontal white matter affect these circuits (primarily the basal ganglia circuit) and may thus be involved in rendering an individual more prone to depression. LEUKOENCEPHALOPATHY AND BIOLOGICAL MARKERS OF DEPRESSION
Nonsuppression of cortisol after the administration of dexamethasone is the best-studied biological marker of depression. A tentative relationship
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
ORGANIC DEPRESSION IN THE ELDERLY
265
between leukoencephalopathy and nonsuppression on the dexamethasone suppression test (DST) was observed (18). Another marker, platelet-imi pramine binding, has also been investigated. In a recent study, we demon strated that diminished platelet-imipramine binding is inversely related to the severity of leukoencephalopathy in depressed patients (21). Although it has been suggested that patients with leukoencephalopathy may be less responsive to antidepressant drugs than to electroconvulsive therapy, the evidence for this remains preliminary. There appears to be a relationship between the presence of caudate lesions and the extent of clinical recovery from depression, in that such patients do not completely recover (unpublished observation). The relationship between leuko encephalopathy and cognitive impainnent in patients with depression is unclear at present. Rao et al (22) found no relationship between cognitive function and leukoencephalopathy in healthy subjects, though Junque et al (23) found that severity of leukoencephalopathy correlated with a mea sure of speed of information processing and with tests involving complex
cognitive processes. Whether the significant cognitive impainnent seen in elderly depressed patients is related to leukoencephalopathy is not known. The prognostic implications of these lesions is also not known. One clinically important aspect of leukoencephalopathy is the relation ship between basal ganglia lesions and delirium. Since delirium is a fairly common problem when treating elderly patients with antidepressants or EST, identifying individuals at high risk becomes very important. Figiel et al (24) reported that patients with severe basal ganglia lesions were more prone to develop prolonged but reversible interictal delirium after EST. Another study demonstrated that individuals with basal ganglia lesions are also more prone to developing delirium following antidepressant ther apy (25). These findings are important since individuals prone to develop delirium, once identified, could be managed more conservatively, and this may significantly reduce the morbidity in the treatment of depression. ACKNOWLEDGMENTS
Supported by MH 44716. The author thanks Martha Payne for the prep aration of this manuscript. Literature Cited
I. Mayer Gross, W., Slater, E., Roth, M. 1960. Clinical Psychiatry, pp. 505-42. Baltimore: William & Wilkins 2. Post, F. 1962. The significance of affec tive symptoms in old age. Inst. Psychiatry, Maudsley Monogr. London: Oxford Univ. Press
3. Awad, I. A., Spetzler, R. F., Hodak, J.
A., Awad, C. A., Carey, R. 1986. Inci dental subcortical lesions identified on magnetic resonance imaging in the elderly. Correlation with age and cere brovascular risk factors. Stroke 17: 1084-89
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
266
KRISHNAN
4. Salomon, A., Yeates, A. E., Burger, P. C., Heinz, R. 1987. Subcortical arterio sclerotic encephalopathy: Brainstem findings with MR imaging. Radiology 165:625-29 5. Krishnan, K. R. R., Goli,V., Ellinwood, E. H., France, R. P., Blazer, D. G., et al. 1988. Leukoencephalopathy in patients diagnosed as major depressive. Bioi. Psychiatry 23 : 519-22 6. Coffey, C. E., Figiel, G. S., Djang, W. T., Cress, M., Saunders, W. B., et al. 1988. Leukoencephalopathy in elderly depressed patients referred for ECT. BioI. Psychiatry 24: 143-61 7. Coffey, C. E., Figiel, G. S., Djang, W. T., Saunders, W. B., Weiner, R. D. 1989. White matter hyperintensity on mag netic resonance imaging: Clinical and neuroanatomic correlates in the depressed elderly. J. Neuropsychiatry I:
16.
17. 18.
-
19.
135-43
8. Coffey, C. E., Figiel, G. S., Djang, W. T., Weiner, R. D. 1990. Subcortical hyperintensity on magnetic resonance imaging: A comparison of normal and depressed elderly subjects. Am. J. Psy
20.
chiatry 147: 187-89
9. Figiel, G. S., Krishnan, K. R. R., Dorai swamy, P. M., Boyko, O. B., Nemeroff, C. B. 1990. Brain MRI subcortical struc tural changes in late onset depression. Bioi. Psychiatry 27(Suppl. 9A): 46 10. Tomlinson, B. E., Blessed, C., Roth, M. 1968. Observations of the brains of non demented old people. J. Neural. Sci. 7: 331-56 11. McDonald. W. M., Krishnan, K. R. R., Doraiswamy, P. M., Blazer, D. G. 1990. Subcortical hyperintensities in elderly subjects with mania. Bioi. Psychiatry 27(Suppl. 9A): 273 12. Breitner, J., Husain, M. M., Krishnan, K. R. R., Figiel, G. S., Boyko, O. B. 1990. Leukoencephalopathy on MR imaging in late onset schizophrenia. Bioi. Psychiatry 27(Suppl. 9A): 136 13. Caine, E. D., Shoulson, I. 1983. Psy chiatric syndrome in Huntington's dis ease. Am. J. Psychiatry 140: 728-33 14. Mendez, M. F., Adams, N. L., Lewan dowski, K. S. 1989. Neurobehavioral changes associated with caudate lesions. Neurology 39: 349-54 15. McDonald, W. M., Husain, M. M., Doraiswamy, P. M., Figie1, G. S.,
Boyko, O. B., et al. 1990. Diminished caudate volumes in major depression. Am. Psychiatr. Assoc. 143rd Ann. Mtg. New Res. Program Abstrs., Abstr. 62, p. 70. Washington, DC: Am. Psychiatr. Assoc. Baxter, L. R., Phelps, M. E., Mazziotta, J. c., Schwartz, J. M., Gerner, R. H., et al. 1978. Cerebral metabolic rates for glucose in mood disorder. Arch. Gen. Psychiatry 42: 441-47 Pearlson, G. D., Veroff, A. E. 1981. Computerized tomographic changes in manic depressive illness. Lancet I: 470 Rao, V. P., Krishnan, K. R. R., Goli, V., Saunders, W. B., Ellinwood, E. H., et al. 1989. Neuroanatomical changes and hypothalamopituitary adrenal axis ab normalities. Bioi. Psychiatry 26: 729 32 Husain, M. M., McDonald, W., Dorai swamy, P. M., Figiel, G. S., Boyko, O. B., et al. 1990. In vivo assessment of putamen volume in depression. See Ref. IS, Abstr. 121, p. 92 Doraiswamy, P. M., Shah, S. A., Figiel, G. S., Husain, M. M., McDonald, W. M., et al. 1990. Hippocampal pathology in major depression. See Ref. 15, Abstr. 75,p. 74 Husain, M. M., Doraiswamy, P. M., Figiel, G. S., Knight, D. L., Boyko, O. B., et al. 1990. Platelet [H)3 imipramine binding and leukoencephalopathy in geriatric depression. BioI. Psychiatry 27(Suppl. 9A): 187 Rao, S. M., Mittenberg, W., Bemandin, L., Haughton, V., Leo, G. J. 1989. Neuropsychological test findings in sub jects with leukoaraiosis. A rch . Neurol.
21.
22.
46:40-44
23. Junque, C., Pujol, J., Vendrell, P., Bruna, 0., Jodar, M., et al. 1990. Leuko araiosis on magnetic resonance imaging and speed of mental processing. Arch. Neural. 47: 151-56 24. Figiel, G. S., Coffey, C. E., Djang, W. T., Hoffmann, G., Doraiswamy, M. 1990. Brain magnetic resonance imaging find ings in ECT induced delirium. J. Neuro psychiatry 2: 53-58 25. Figiel, G. S., Krishnan, K. R. R., Breitner, J. c., Nemeroff, C. B. 1989. Radiologic correlates of antidepressant induced delirium: The possible sig nificance of basal ganglia lesion. J. Neuropsychiatry I: 188-90
Annu.
Rev. Med. 1991. 42:261-{j6 Copyr(qht © 1991 by Annual Reviews
Further
Quick links to online content Inc. All r(qhts reserved
ORGANIC BASES OF Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
DEPRESSION IN THE ELDERLY K. Ranga Rama Krishnan, M.D.
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710 KEY WORDS:
affective disorders,
leukoencephalopathy,
basal ganglia,
peri
ventricular white matter
ABSTRACT
Early studies suggested that cerebrovascular change may be an etiological factor in the development of late-life depression. With the advent of mag netic resonance imaging (MRI), it has become possible to examine this hypothesis. MRI studies have demonstrated that patients with late-onset depression have more severe and frequent patchy lesions in the frontal deep white matter and basal ganglia than do controls or patients with early onset depression. Patients with basal ganglia lesions, primarily caudate, are more likely to develop delirium with antidepressants and electroshock treatment (EST). The prognostic significance and the relationship of these lesions to cognitive impairment is unclear. INTRODUCTION
Affective disorders, especially depression, are quite common in the elderly. Approximately 1-2% of elderly subjects in the community fulfill criteria for DSM-III major depression, though more than 10% have symptoms of depression. Major depression is probably a syndrome and its etio pathogenesis is not well understood. In the young, genetic factors appear to be important. In the elderly patient presenting with depression for the first time, genetic predisposition is less likely and nongenetic factors may be more important. One such factor is focal cerebrovascular change. Mayer Gross, Slater & Roth (1) noted that sustained affective and other psy261 0066-4219/91/0401--0261$02.00
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
262
KRISHNAN
chiatric symptoms occurred frequently in patients with cerebral arterio sclerotic disease. Post (2) reported that 12% of patients over the age of 60 had focal cerebrovascular changes. He hypothesized that such changes may trigger the depressive reaction. With the advent of magnetic resonance imaging (MRI), it has become possible to examine the hypothesis that subtle cerebrovascular changes may play a role in the etiopathophysiology of depression in the elderly. Patchy foci of increased signal intensity are often identified on Tz-weighted magnetic resonance images of the brain, especially in the elderly. These lesions are often associated with cerebrovascular disease (3). Age, prior history of brain ischemia, and hypertension are the most significant pre dictors of the incidence and severity of such lesions (4). The lesions are seen in the deep white matter, periventricular, and basal ganglia region. Their pathology varies and includes perivascular dilatation, gliosis, areas of myelin pallor, and on rare occasions, frank infarction. Brainstem hyperintensities are also common (4) and are seen primarily in the pons. Anatomically, the sites correspond to the distal distributions of the penetrating arterioles. The pathogenesis of these lesions is not known, though deposition of lipids within arteriolar walls (lipohyalinosis) has been linked to hyperintensities. The penetrating arteries affected by this process include lenticulostriate, thalamoperforate, and medullary arteries arising from cortical branches to supply deep portions of the hemispheric white matter. At the brainstem level, penetrating branches from the basilar artery are also affected. These lesions on MRI have been variably referred to as leukoencephalopathy, subcortical hyperintensities, subarteriosclerotic encephalopathy, and leukoaraiosis. LEUKOENCEPHALOPATHY IN DEPRESSED
PATIENTS
As leukoencephalopathy might reflect subtle alterations in cerebrovascular function, we assessed the occurrence of patchy white matter lesions (leuko encephalopathy) in 35 patients who presented with depression in middle and late life (5). The striking finding of this study was a high prevalence (72%) of patchy white matter lesions in patients with late-onset depression. The absence of controls limited the conclusions drawn from this study. Coffey et al (6) confirmed these findings. They studied 67 depressed patients referred for electroconvulsive therapy (ECT). Of these, 36 patients were studied using MRI and 39 with computerized tomography. Leuko encephalopathy was seen in 66% of the patients and was present in 86% of the MRI scans and 50% of the computerized tomography scans (con tinning the higher sensitivity of MRI), and was noted primarily in the peri-
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
ORGANIC DEPRESSION IN THE ELDERLY
263
ventricular, thalamic, and basal ganglia regions. Most patients with leuko encephalopathy had their first episode of depression after the age of 60. In a subsequent prospective study, Coffey et al (7) reported that 100% of 51 elderly (> 60 years old) depressed (80% late-onset) patients referred for electroshock therapy showed leukoencephalopathy on MRI. Fifty-one percent of the patients also had lesions in the basal ganglia and thalamus (8). Compared to age-matched control subjects, depressed subjects had more severe periventricular and subcortical hyperintensities (8). Lesions of the thalamus and basal ganglia were also significantly more common in depressed patients. A relationship between subcortical hyperintensities and the presence of risk factors for vascular disease was also noted. Figiel et al (9) compared elderly patients with late-onset depression (onset after the age of 60) and elderly depressed patients whose first episode of depression occurred before the age of 60. Caudate lesions were observed in 60% of the late-onset patients compared to 11% of the early-onset patients. Late-onset patients had a higher incidence of deep white matter lesions, primarily frontal lobe, larger than 1 cm (60%) compared to the early-onset group. Ninety percent of the late-onset patients had either a basal ganglia lesion or a large deep white matter lesion, whereas only 11% of patients with early-onset depression had such lesions. The exact pathological correlate of these lesions in depressed elderly remains unde termined. That they are ischemic in nature is suggested by a study by Tomlinson et al (10), who found cerebral ischemic degenerative change at autopsy in the elderly. Leukoencephalopathy is seen in elderly patients with other psychiatric disorders, though the location is different. Elderly patients with late-onset mania have lesions primarily in the frontal and parietal regions (11). Patients with late-onset psychosis almost invariably have large deep white matter lesions in the parietal and occipital regions (12). Lesions in the occipital region geniculocalcarine tract are associated with the presence of visual hallucinations in these patients. ETIOLOGICAL SIGNIFICANCE OF LEUKOENCEPHALOPATHY IN DEPRESSION
Indirect supportive evidence that lesions of the caudate and deep frontal white matter may be of etiological significance in depression comes from a number of studies in both animals and humans. Animal studies have demonstrated that the caudate nuclei are functionally and anatomically related to the prefrontal cortex and that destruction of the caudate leads to marked changes in complex behaviors. In humans, the knowledge of caudate function comes primarily from the study of Huntington's disease, whose major pathology involves the caudate nuclei. A number of studies
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
264
KRISHNAN
show that major depression is common in patients with Huntington's disease ( 13). Further, the cognitive impairment seen in Huntington's dis ease is similar to that seen in depressed patients, although Huntington's disease also involves other structures, such as the putamen and cortex. Thus, it is difficult to attribute conclusively the cognitive and behavioral changes to caudate atrophy. More definitive evidence comes from the work of Mendez et al ( 14), who showed that a group of patients with caudate lesions secondary to cerebrovascular disease had behavioral symptoms similar to those seen in depression. We recently compared caudate volumes in 39 depressed patients with 39 age-matched controls and demonstrated that caudate volume was markedly diminished in patients with major depression ( 15). This study coupled with that of Baxter et al (16), who showed a diminished metabolism in the caudate nuclei of depressed patients, provides direct evidence of a role for the caudate nuclei in the etiopathophysiology of depression. OTHER STRUCTURAL CHANGES IN LATE-ONSET DEPRESSION
Besides leukoencephalopathy, enlargement of the lateral ventricles has been reported in depressed patients ( 17). In another study, enlargement of the ventricles was related to leukoencephalopathy (18). Recent studies demonstrated that other structures in the brain such as the hippocampus and the putamen may also be involved. Putamen volume is markedly diminished in depressed patients compared to controls ( 19). Changes in the hippocampus were assessed by measuring Tj relaxation times on MRI (which is an indirect measure of water balance and might reflect atrophy). The Tj relaxation times were decreased in older depressed patients com pared to controls (20). The finding that changes in the putamen may be common in depressed patients is not surprising given the close relationship between the putamen and the caudate nuclei. The link between hippo campal and basal ganglia changes is currently being explored. Both the basal ganglia circuit and the limbic circuit are involved in the regulation of mood. The lesions in the caudate nuclei and deep frontal white matter affect these circuits (primarily the basal ganglia circuit) and may thus be involved in rendering an individual more prone to depression. LEUKOENCEPHALOPATHY AND BIOLOGICAL MARKERS OF DEPRESSION
Nonsuppression of cortisol after the administration of dexamethasone is the best-studied biological marker of depression. A tentative relationship
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
ORGANIC DEPRESSION IN THE ELDERLY
265
between leukoencephalopathy and nonsuppression on the dexamethasone suppression test (DST) was observed (18). Another marker, platelet-imi pramine binding, has also been investigated. In a recent study, we demon strated that diminished platelet-imipramine binding is inversely related to the severity of leukoencephalopathy in depressed patients (21). Although it has been suggested that patients with leukoencephalopathy may be less responsive to antidepressant drugs than to electroconvulsive therapy, the evidence for this remains preliminary. There appears to be a relationship between the presence of caudate lesions and the extent of clinical recovery from depression, in that such patients do not completely recover (unpublished observation). The relationship between leuko encephalopathy and cognitive impainnent in patients with depression is unclear at present. Rao et al (22) found no relationship between cognitive function and leukoencephalopathy in healthy subjects, though Junque et al (23) found that severity of leukoencephalopathy correlated with a mea sure of speed of information processing and with tests involving complex
cognitive processes. Whether the significant cognitive impainnent seen in elderly depressed patients is related to leukoencephalopathy is not known. The prognostic implications of these lesions is also not known. One clinically important aspect of leukoencephalopathy is the relation ship between basal ganglia lesions and delirium. Since delirium is a fairly common problem when treating elderly patients with antidepressants or EST, identifying individuals at high risk becomes very important. Figiel et al (24) reported that patients with severe basal ganglia lesions were more prone to develop prolonged but reversible interictal delirium after EST. Another study demonstrated that individuals with basal ganglia lesions are also more prone to developing delirium following antidepressant ther apy (25). These findings are important since individuals prone to develop delirium, once identified, could be managed more conservatively, and this may significantly reduce the morbidity in the treatment of depression. ACKNOWLEDGMENTS
Supported by MH 44716. The author thanks Martha Payne for the prep aration of this manuscript. Literature Cited
I. Mayer Gross, W., Slater, E., Roth, M. 1960. Clinical Psychiatry, pp. 505-42. Baltimore: William & Wilkins 2. Post, F. 1962. The significance of affec tive symptoms in old age. Inst. Psychiatry, Maudsley Monogr. London: Oxford Univ. Press
3. Awad, I. A., Spetzler, R. F., Hodak, J.
A., Awad, C. A., Carey, R. 1986. Inci dental subcortical lesions identified on magnetic resonance imaging in the elderly. Correlation with age and cere brovascular risk factors. Stroke 17: 1084-89
Annu. Rev. Med. 1991.42:261-266. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 01/22/15. For personal use only.
266
KRISHNAN
4. Salomon, A., Yeates, A. E., Burger, P. C., Heinz, R. 1987. Subcortical arterio sclerotic encephalopathy: Brainstem findings with MR imaging. Radiology 165:625-29 5. Krishnan, K. R. R., Goli,V., Ellinwood, E. H., France, R. P., Blazer, D. G., et al. 1988. Leukoencephalopathy in patients diagnosed as major depressive. Bioi. Psychiatry 23 : 519-22 6. Coffey, C. E., Figiel, G. S., Djang, W. T., Cress, M., Saunders, W. B., et al. 1988. Leukoencephalopathy in elderly depressed patients referred for ECT. BioI. Psychiatry 24: 143-61 7. Coffey, C. E., Figiel, G. S., Djang, W. T., Saunders, W. B., Weiner, R. D. 1989. White matter hyperintensity on mag netic resonance imaging: Clinical and neuroanatomic correlates in the depressed elderly. J. Neuropsychiatry I:
16.
17. 18.
-
19.
135-43
8. Coffey, C. E., Figiel, G. S., Djang, W. T., Weiner, R. D. 1990. Subcortical hyperintensity on magnetic resonance imaging: A comparison of normal and depressed elderly subjects. Am. J. Psy
20.
chiatry 147: 187-89
9. Figiel, G. S., Krishnan, K. R. R., Dorai swamy, P. M., Boyko, O. B., Nemeroff, C. B. 1990. Brain MRI subcortical struc tural changes in late onset depression. Bioi. Psychiatry 27(Suppl. 9A): 46 10. Tomlinson, B. E., Blessed, C., Roth, M. 1968. Observations of the brains of non demented old people. J. Neural. Sci. 7: 331-56 11. McDonald. W. M., Krishnan, K. R. R., Doraiswamy, P. M., Blazer, D. G. 1990. Subcortical hyperintensities in elderly subjects with mania. Bioi. Psychiatry 27(Suppl. 9A): 273 12. Breitner, J., Husain, M. M., Krishnan, K. R. R., Figiel, G. S., Boyko, O. B. 1990. Leukoencephalopathy on MR imaging in late onset schizophrenia. Bioi. Psychiatry 27(Suppl. 9A): 136 13. Caine, E. D., Shoulson, I. 1983. Psy chiatric syndrome in Huntington's dis ease. Am. J. Psychiatry 140: 728-33 14. Mendez, M. F., Adams, N. L., Lewan dowski, K. S. 1989. Neurobehavioral changes associated with caudate lesions. Neurology 39: 349-54 15. McDonald, W. M., Husain, M. M., Doraiswamy, P. M., Figie1, G. S.,
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