Depression May Be a Dementia Prodrome

Nancy A. Melville

July 05, 2016

A gradual increase in depressive symptoms, as opposed to more stable symptoms, is linked to an increased risk of developing dementia, new research shows.

A longitudinal study conducted by investigators at Erasmus Medical Center in Rotterdam, the Netherlands, showed that dementia risk differed with different courses of depression, such that individuals with depressive symptoms that increased over time were more likely to develop dementia. This finding, the investigators note, suggests that depression may be a prodrome of dementia.

"By leveraging repeated measures of depressive symptoms over an 11-year period, our study is the first to our knowledge to assess the course of depression in relation to risk of dementia," the authors, led by M. Arfan Ikram, MD, PhD, write.

The findings were published in the July issue of Lancet Psychiatry.

According to investigators, the link between late-life depressive symptoms and incident dementia has been studied extensively, but the relationship has typically been assessed at a single time point.

"Such an approach neglects the course of depression, which, given its remitting and relapsing nature, might provide further insights into the complex association of depression with dementia. We therefore repeatedly measured depressive symptoms in a population of adults over a decade to study the subsequent risk of dementia," they write.

For the study, Dr Ikram and colleagues evaluated data from the the Rotterdam Study, which included information on depressive symptoms in a sample of individuals aged 55 years and older in the Dutch population over an 11-year period, from 1993 to 2004.

The study included 3325 participants. The median age of the participants was 74 years; 60% were women; and 434 participants developed incident dementia.

Patients were categorized according to one of five trajectories of depressive symptoms, as determined on the basis of scores on the Dutch version of the Center for Epidemiology Depression Scale (CES-D). Patients were categorized as having stable, low scores; scores that were moderately high but then decreased; scores that were initially low, then increased, then decreased; scores that were initially low but then steadily increased; and scores that were initially high and that remained so.

The strongest association with the development of dementia was seen among patients with increasing depressive symptoms, in comparision with patients with the low depressive symptom trajectory (hazard ratio [HR] 1.42; P = .024).

Conversely, no association with dementia risk was seen in patients who had a high degree of depressive symptoms at a single time point, followed by remission.

The stronger association seen with increasing depressive symptoms remained after adjusting for factors that included incident stroke (HR, 1.58; P = .004), placing a restriction on Alzheimer's disease as an outcome (HR, 1.44; P = .034), and accounting for mortality as a competing risk (HR, 1.45; P = .019).

"By repeatedly measuring depressive symptoms we noted the appearance and steady increase of depressive symptoms several years before the clinical diagnosis of dementia, probably as part of the dementia prodome," the authors note.

Adjustment for the use of antidepressants was associated with a reduction in the risk for dementia by approximately 10% in groups with high, increasing, and decreasing trajectories of depressive symptoms.

Although the mechanisms of the relation with antidepressant use are not well understood, the authors note that theories include "impairment of the cognitive-reserve capacity and reduced cholinergic activity due to the long-term use of antidepressants, which has been shown to increase beta-amyloid concentrations in animal models."

The overall findings are consistent with the hypothesis that depressive symptoms in older persons may represent a prodrome or an early stage of dementia, the authors write.

Currently, the strongest evidence of mechanisms linking depression and dementia, described in a large, systematic review published in the British Journal of Psychiatry in 2013, points to vascular risk factors, notes Simone Reppermund, PhD, of the Department of Developmental Disability and the Centre for Healthy Brain Ageing, at the University of New South Wales, in Sydney, Australia, in a commentary published with the study.

"Evidence exists for a bidirectional relationship between vascular disease and late-life depression; findings from some studies support an association between depression and subsequent vascular disease, and others provide evidence that vascular disease promotes the development of depression," Dr Reppermund writes.

In studies, depression and dementia have been linked with regard to social interaction and other lifestyle factors, Dr Reppermund notes. He also indicates the importance of differentiating between late-onset and early-onset depression.

The new findings "have brought us one step closer to answering whether depression is a risk factor for dementia or vice versa," Dr Reppermund adds.

The study received funding from the Erasmus Medical Center; ZonMw; the Netherlands Ministry of Education Culture and Science; and the Netherlands Ministry for Health, Welfare and Sports. The authors and Dr Reppermund have disclosed no relevant financial relationships.

Lancet Psychiatry. 2016;7:593-595, 628-635. Abstract, Commentary

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