Cognitive remission: a novel objective for the treatment of major depression?

BMC Medicine, Jan 2016

Background Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD. Discussion Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. Summary The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to ‘cognitive remission’, which may aid functional recovery in MDD.

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Cognitive remission: a novel objective for the treatment of major depression?

Bortolato et al. BMC Medicine Cognitive remission: a novel objective for the treatment of major depression? Beatrice Bortolato 3 4 Kamilla W. Miskowiak 2 4 Cristiano A. Köhler 0 1 4 Michael Maes 4 7 8 Brisa S. Fernandes 4 6 8 Michael Berk 4 5 8 André F. Carvalho 0 1 4 0 Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty Medicine, Federal University of Ceará , Rua Prof. Costa Mendes 1608, 4° andar, Fortaleza, CE 60430-040 , Brazil 1 Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty Medicine, Federal University of Ceará , Rua Prof. Costa Mendes 1608, 4° andar, Fortaleza, CE 60430-040 , Brazil 2 Psychiatric Centre Copenhagen, Copenhagen University Hospital , Rigshospitalet, Copenhagen , Denmark 3 Department of Neurosciences, University of Padova , Padova , Italy 4 Competing interests MB has received a grant/research support from Bristol Myers Squibb, Eli Lilly , Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis , Mayne Pharma, Servier and Woolworths, and has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly , Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay, and Wyeth as well as serving 5 Orygen, The National Centre of Excellence in Youth Mental Health, Department of Psychiatry and The Florey Institute of Neuroscience and Mental Health, University of Melbourne , Parkville , Australia 6 Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, UFRGS , Porto Alegre , Brazil 7 Department of Psychiatry, Faculty of Medicine, Chulalongkorn University , Bangkok , Thailand 8 Deakin University, School of Medicine, IMPACT Strategic Research Centre , Geelong , Australia Background: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD. Discussion: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. Summary: The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD. Antidepressants; Cognition; Cognitive enhancers; Erythropoietin; Lisdexamfetamine dimesylate; Major depression; Novel targets; Vortioxetine; Psychiatry Background Major depressive disorder (MDD) is a prevalent and disabling condition with a high frequency of non-recovery and recurrence, leading to substantial mortality and morbidity [ 1–3 ]. Only a subset of individuals with MDD (30–40 %) reach symptomatic remission after adequate treatment with a first-line antidepressant, and many patients do not reach premorbid levels of psychosocial functioning, such that a significant proportion of patients present residual symptoms. Cognitive symptoms are acknowledged clinical manifestations of MDD, with fatigue, sleepiness, and executive dysfunction being among the most frequently reported residual manifestations of MDD [ 4 ]. The ICD-10 and DSM-5 diagnostic criteria consider items such as ‘reduced concentration and attention’ and ‘diminished ability to think or concentrate’, respectively, in relation to MDD. On average, the standardized effect size of cognitive impairment in a first major depressive episode (MDE) compared to that in healthy controls is approximately 0.3. Accordingly, a meta-analysis of 13 studies in 644 symptomatic patients with first-episode depression versus 570 healthy controls showed significant impai (...truncated)


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Beatrice Bortolato, Kamilla Miskowiak, Cristiano Köhler, Michael Maes, Brisa Fernandes, Michael Berk, André Carvalho. Cognitive remission: a novel objective for the treatment of major depression?, BMC Medicine, 2016, pp. 9, 14, DOI: 10.1186/s12916-016-0560-3