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Treating Cognitive Impairment In Depression: An Unmet Need.

R. Keefe
Published 2016 · Medicine

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Cognitive impairment is a substantial unmet need in patients with major depressive disorder. Patients with major depressive disorder perform an average of 0·5–0·7 standard deviations (SDs) lower than the general population on cognitive performance measures, and most people with the disorder complain about cognitive problems even after other symptoms of depression have remitted. Furthermore, cognitive impairment is signifi cantly associated with—and might partly cause— important elements of functional disability in major depressive disorder, including reduced occupational and psychosocial functioning. The Article by Carrie Shilyansky and colleagues in The Lancet Psychiatry clearly shows the extent of this unmet need. The results of this study are noteworthy, and several of the design features are excellent. The investigators enrolled more than 1000 participants into the study, and assessed 712 patients with major depressive disorder on a cognitive test battery before and after treatment. Because of its design and large sample size, the study is able to make legitimate comparisons of the cognitive eff ect of three commonly used antidepressant treatments. Although it is generally formidable to obtain proof of a null hypothesis in clinical studies, the large size of the sample increases the likelihood that the results are stable and could be replicated. Furthermore, the report includes a group of 336 age-matched and educationmatched healthy controls assessed during a similar time interval, allowing the investigators to estimate the common and expected improvement in test performance based solely on repeated testing. The authors correctly conclude that cognitive performance remains impaired and largely unchanged following antidepressant treatment, with cognitive performance in patients with major depressive disorder remaining 0·4 SD below that of controls in two tests. Even in patients whose symptoms of depression fully remit, cognitive performance on all nine tests (with a diff erence of 0·3 SD on four tests) remained worse than controls after treatment, which generally agrees with the published literature. How can we remedy the present dearth of treatment options for major depressive disorder? There have been some encouraging developments recently. Expert panels enlisted by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have concluded that cognitive impairment in major depressive disorder is a legitimate treatment target. Cognitive remediation strategies have been shown to improve cognition in major depressive disorder, and two pharmacological treatment strategies seem to have a small benefi cial eff ect. Adjunctive lisdexamfetamine led to improvement in cognitive behaviours in patients with remitted major depressive disorder, although cognitive test performance did not improve signifi cantly and the treatment is not being pursued for this indication. On the basis of a series of studies of diff erent patient populations with major depressive disorder, the EMA has approved the inclusion of language describing a modest cognitive benefi t in the summary of product characteri stics for the antidepressant vortioxetine, and a US FDA panel has voted to follow suit. However, the studies that support these results are based on a patchwork set of methods. Clear consensuses have been established for the design and conduct of clinical trials for cognitive impairment in schizophrenia and Alzheimer’s disease, but no such consensus exists for an indication of cognitive impairment in major depressive disorders. Investigators need guidance to answer several questions for this indication: is a previously approved comparator necessary? What size of benefi t is clinically meaningful? Is functional improvement also necessary? For how long should patients receive treatment to assess the possibility of a short-term benefi t that diminishes over time? A well-conceived and consistent set of guidelines is needed. Although eff orts have been initiated, a more formal pathway is necessary to stimulate research and treatment development, hopefully without the imposition of draconian restrictions that raise too high a hurdle to overcome for regulatory approval. One of the main controversies in cognition clinical trials concerns how cognitive change is measured. The performance-based cognitive test battery used in the study by Shilyansky and colleagues addressed a range of cognitive domains known to be impaired in major depressive disorder, such as verbal recall, executive functions, processing speed, working memory, response inhibition, and attention. One limitation of the study, which is reported in the appendix, is that the test–retest For the EMA see http://www.ema.europa.eu/ docs/en_GB/document_library/ EPAR_-_Summary_for_the_ public/human/002717/ WC500159448.pdf
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