Review Article It is illegal to post this copyrighted PDF on any website. CME Background Articles are selected for credit designation based on an Procognitive Effects of assessment of the educational needs of CME participants, Antidepressants and Other with the purpose of providing readers with a curriculum of CME articles on a variety of topics throughout each volume. Therapeutic Agents in Activities are planned using a process that links identified needs with desired results. Major Depressive Disorder: To obtain credit, read the article, correctly answer the questions in the Posttest, and complete the Evaluation. A Systematic Review A $10 processing fee will apply. Michelle J. Blumberg, BScHa; Sophie R. Vaccarino, BScHa,b,*; CME Objective and Shane J. McInerney, MD, MB, MSc, MRCPsycha,c,d,e After studying this article, you should be able to: • Try to address cognitive impairments in patients with ABSTRACT major depressive disorder using the latest data to guide prescribing Objective: To review the efficacy of antidepressants and other therapeutic agents for the treatment of cognitive impairment in Accreditation Statement adults with major depressive disorder (MDD). The CME Institute of Physicians Postgraduate Data Sources: We conducted a database search of MEDLINE, Press, Inc., is accredited by the Accreditation PsycINFO, and Embase through Ovid on May 7, 2019. The year of Council for Continuing Medical Education publication was not restricted. The search terms “Major Depressive to provide continuing medical education for Disorder,” “depress*,” “cognit*,” and “therapeutics” were used. physicians. Study Selection: The studies included in this review were clinical trials Credit Designation of antidepressants and other therapeutic agents in MDD populations. The CME Institute of Physicians Postgraduate Press, Inc., Participants were aged between 18 and 65 years and had a DSM-III, -IV, designates this journal-based CME activity for a maximum or -5 diagnosis of MDD. In total, 2,045 research papers were screened, of 1 AMA PRA Category 1 Credit™. Physicians should claim 53 full-text articles were assessed, and 26 articles were eligible to be only the credit commensurate with the extent of their included in this systematic review. participation in the activity. Data Extraction: The data and quality of research papers were Note: The American Academy of Physician Assistants (AAPA) assessed and screened by 2 independent reviewers. Discrepancies accepts certificates of participation for educational activities were resolved through a third reviewer. certified for AMA PRA Category 1 Credit™ from organizations Results: Overall, studies demonstrated that tricyclic antidepressants accredited by ACCME or a recognized state medical society. do not have procognitive effects, while vortioxetine and bupropion Physician assistants may receive a maximum of 1 hour of have demonstrated procognitive effects in MDD populations Category I credit for completing this program. relative to selective serotonin reuptake inhibitors and serotonin- norepinephrine reuptake inhibitors. Several non-antidepressant Release, Expiration, and Review Dates agents, such as modafinil, amphetamines, and erythropoietin, This educational activity was published in July 2020 and is have also demonstrated significant positive effects on cognition in eligible for AMA PRA Category 1 Credit™ through August 31, depression. 2022. The latest review of this material was July 2020. Conclusions: Present-day antidepressants and other agents have Financial Disclosure demonstrated procognitive effects in MDD, but the findings between All individuals in a position to influence the content of this various agents are mixed. Further research looking at objective activity were asked to complete a statement regarding measures of cognitive performance would be helpful to obtain more all relevant personal financial relationships between definitive results regarding the efficacy of therapeutics for cognitive themselves or their spouse/partner and any commercial impairment in MDD. interest. The CME Institute has resolved any conflicts of J Clin Psychiatry 2020;81(4):19r13200 interest that were identified. In the past year, Marlene P. Freeman, MD, Editor in Chief, has received research funding To cite: Blumberg MJ, Vaccarino SR, McInerney SJ. Procognitive effects of from JayMac and Sage; has been a member of the advisory antidepressants and other therapeutic agents in major depressive disorder: a boards for Otsuka, Alkermes, and Sunovion; has been a systematic review. J Clin Psychiatry. 2020;81(4):19r13200. member of the Independent Data Safety and Monitoring To share: https://doi.org/10.4088/JCP.19r13200 Committee for Janssen; has been a member of the Steering © Copyright 2020 Physicians Postgraduate Press, Inc. Committee for Educational Activities for Medscape; and, a as a Massachusetts General Hospital (MGH) employee, Centre for Depression and Suicide Studies, St Michael’s Hospital, Toronto, Ontario, Canada works with the MGH National Pregnancy Registry, which bInstitute of Medical Science, University of Toronto, Toronto, Ontario, Canada You are prohibited from making this publicly PDF available. You is sponsored by Teva, Alkermes, Otsuka, Actavis, and cLi Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Sunovion, and works with the MGH Clinical Trials Network Canada and Institute, which receives research funding from multiple dDepartment of Psychiatry, University of Toronto, Toronto, Ontario, Canada pharmaceutical companies and the National Institute eUniversity Hospital Galway, Galway, Ireland of Mental Health. No member of the CME Institute staff *Corresponding author: Sophie R. Vaccarino, BScH, Research Assistant, ASR reported any relevant personal financial relationships. Suicide & Depression Studies Program, St Michael’s Hospital, 193 Yonge St, 6th Faculty financial disclosure appears at the end of the Fl, Toronto, ON M5B 1M4, Canada ([email protected]). article. For reprints or permissions, contact [email protected]. ♦ © 2020 Copyright Physicians Postgraduate Press, Inc. J Clin Psychiatry 81:4, July/August 2020 e1 Blumberg et al It is illegal to post this copyrighted PDF on any website. Clinical Points of antidepressants was found. Yet, that review included only studies of antidepressants with the primary mechanism of ■ Despite the common persistence of cognitive impairment action being monoamine modulation in 1 or more of the in populations with major depressive disorder (MDD), following categories: SSRIs, SNRIs, serotonin antagonist and treatment options are understudied and limited. reuptake inhibitors, noradrenergic and specific serotonergic ■ A review of all potential therapeutic agents is necessary antidepressants, TCAs, and multimodal antidepressants. to inform future research investigating the benefits of This led to the exclusion of certain antidepressants, such as pharmaceutical agents for cognitive impairment in MDD. bupropion, as well as non-antidepressant agents. Additionally, So far, vortioxetine seems to be a viable treatment option ■ the paper did not investigate the relationship between for MDD patients with cognitive impairment. cognition and functional outcomes. Finally, new clinical trials have been conducted since the publication of this previous review, which we will explore in the current review. ajor depressive disorder (MDD) affects over 300 Vortioxetine, a multimodal serotonergic antidepressant, is million people and is currently the leading cause the first antidepressant recognized by the US Food and Drug Mof disability worldwide.1 According to the Diagnostic Administration for its procognitive effects.16 Moreover, there and Statistical Manual of Mental Disorders, Fifth Edition is evidence that bupropion improves cognitive functioning in (DSM-5),2 MDD is characterized by a marked change in patients with depression.17 More recently, adjunctive agents, mood and/or anhedonia and the presence of several other such as amphetamines,18 erythropoietin, and modafinil,19 psychophysiological changes, such as disturbed sleep, have been investigated for their cognitive effects in MDD. changes in appetite, fatigue, and a diminished ability to To date, clinical trials looking at the procognitive effects think or concentrate.2 Cognitive impairment is estimated to of therapeutic agents in MDD populations have obtained affect approximately two-thirds of individuals with MDD.3 positive findings; however, these studies are limited by their The DSM-5 characterizes cognitive impairment as difficulty small sample sizes, heterogeneous cognitive measures, and with thinking, concentrating, or making decisions.2 However, lack of objective measures of cognitive functioning. impairments on neuropsychological tests in MDD populations have also been demonstrated in the domains of processing The Current Review speed, attention, executive function, learning, and memory Cognitive impairment is an important yet understudied with moderate effect sizes.4,5 Moreover, these deficits remain phenomenon in MDD and should be considered a treatment present despite full or partial remission of MDD symptoms.6 priority as it is strongly related to psychosocial impairment. In particular, executive dysfunction tends to persist, which Therefore, the primary objective of the current systematic may contribute to the psychosocial impairment7–9 commonly review is to examine the overall efficacy of antidepressants experienced by those with remitted MDD.10 Psychosocial