17 February 2006. In spite of numerous studies that have linked depression with dementia, no clear consensus has yet emerged about how the two are associated. Two papers published in the February Archives of General Psychiatry attempt to add some clarity. One concludes that there is no causative link between depressive symptoms and cognitive decline, while the other reports that a lifetime history of major depression is associated with accelerated cognitive decline in patients with Alzheimer disease (AD). These seemingly contradictory findings emphasize that there is still much to learn about depression and cognition. This sentiment is echoed in a perspective article, published in the same issue of the journal, on a recent NIMH conference that addressed how best to study the relationship between depression and AD.
Most experts in the field agree that there is a relationship between depression and AD. What is less obvious is whether that relationship is one of cause and effect and, if so, what comes first. One of the problems in studying dementia and depression is that people who lose some of their cognitive capabilities or have trouble remembering may, understandably, feel depressed, while those suffering from depression may not be as sharp in neuropsychological or cognitive tests than they would be otherwise. So depression may be a consequence of cognitive decline and vice versa. Mary Ganguli and colleagues at the University of Pittsburgh found as much when they followed more than 1,300 community-dwelling older adults for 8 years, measuring both dementia and symptoms of depression. They concluded that, over the short term, depression was a prodrome rather than an independent predictor of AD (see Chen et al., 1999).
In their latest paper, Ganguli and colleagues report a further four-year follow-up of those same people. This time the researchers asked if depression could predict cognitive decline whether or not subjects subsequently developed dementia. For the almost 1,100 people who remained dementia-free and the 174 people who eventually developed dementia, depression at baseline had no bearing on cognitive decline, the authors found, even though some of those subjects performed poorly in cognitive tests at baseline. In fact, only about 12 percent of the patients who had significant symptoms of depression at baseline went on to develop dementia. But perhaps more importantly, Ganguli and colleagues found that in the group that remained dementia-free, cognitive decline was practically non-existent despite the fact that a similar percentage of those subjects were also depressed at baseline. “Our findings suggest that substantial cognitive decline does not occur in the absence of incipient dementia and therefore cannot be attributed to depression,” write the authors.
At first blush, Vahram Haroutunian and colleagues at Mount Sinai School of Medicine, New York, seemed to arrive at a different conclusion. First author Michael Rapp and colleagues compared, postmortem, the psychiatric histories of 102 Alzheimer disease (AD) patients. Fifty of those patients had a lifetime history of major depressive disorder (MDD)—medical records indicating at least one prior MDD episode—and Rapp and colleagues found that those AD patients had had accelerated cognitive decline compared to those with no MDD history. Annualized rates of decline, measured by the Mini-Mental State Exam, were 1.86 and 1.15 for patients in the depression and non-depression groups, respectively. Despite standard errors that were almost as high as the means, the authors report that multivariate analysis (controlling for age, cause of death, sex, and education) indicated that depression had a statistically significant effect.
The authors also examined postmortem brain tissue samples for AD pathology and found higher levels of both neuritic plaques and neurofibrillary tangles in the hippocampus of patients with an MDD history. Again, standard errors were as high or higher than the mean numbers of both plaques and tangles. Even so, the authors report that both multivariate and univariate analyses show that the effect of major depression on these pathological hallmarks was statistically significant.
“I don’t find these studies to be inconsistent; they are just filling in different parts of the puzzle,” said Ganguli. It should be noted that her group’s study focused on a large cohort of elderly people randomly sampled from the voter registry in Pennsylvania, while Rapp and colleagues studied patients with AD who died in a nursing home. “No one disputes that there is a relationship between AD and depression,” said Ganguli.
The most important question, she suggested, is whether depression is a risk factor for dementia or whether it represents the leading edge of the disease. Her findings suggest the latter, but it must be emphasized that she was studying the relationship between cognitive decline and people with at least five symptoms of depression, not patients who have or had major depressive disorder, that is, clinical depression. She noted that there are other lines of evidence pointing to residual cognitive impairment in recurrent or chronic major depression even after the depression resolves.
Reconciling different approaches to studying the relationship between cognitive impairment and depression is a major issue that needs to be addressed, conclude David Steffens, Duke University School of Medicine, Durham, North Carolina, and colleagues in their summary of an NIMH conference titled Perspectives on Depression, Mild Cognitive Impairment, and Cognitive Decline. One of the most important recommendations to emerge from the conference is that investigators who primarily study depression and those who primarily study memory impairment should cooperate more closely. Steffens and colleagues emphasized the need for greater integration, for example, more measures of depression in cognitive studies and vice versa. But that can be technically and logistically challenging. “What is needed is a way to find the resources and the methods to combine and meld our research so that we may be able to pay equal attention to both cognition and depression in the same study,” suggested Ganguli.—Tom Fagan.
Ganguli M, Du Y, Dodge HH, Ratcliff GG, Chang C-CH. Depressive symptoms and cognitive decline in late life. Archives of General Psychiatry. February 2006;63:153-160. Abstract
Rapp MA, Schnaider-Beeri M, Grossman HT, Sano M, Perl DP, Purohit DP, Gorman JM, Haroutunian V. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch. Gen. Psychiatry. February 2006;63:161-167. Abstract
Steffens DC, Otey E, Alexopoulos GS, Butters MA, Cuthbert B, Ganguli M, Geda YE, Hendrie HC, Krishnan RR, Kumar A, Lopez OL, Lyketsos CG, Mast BT, Morris JC, Norton MC, Peavy GM, Petersen RC, Reynolds CF, Salloway S, Welsh-Bohmer KA, Yesavage J. Perspectives on depression, mild cognitive impairment, and cognitive decline. Arch. Gen. Psychiatry. February 2006;63:130-138. Abstract