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You are prohibited from making this PDF publicly available. isIt illegal to post this copyrighted PDF on any website. J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ article. Facultythe financialdisclosure appearsat theendof anyreported relevant personalfinancialrelationships. staff CME Institute the Health.Nomemberof of Mental pharmaceutical companies andtheNational Institute and Institute, whichreceives research funding from multiple Sunovion, andworks withtheMGHClinical Trials Network is sponsored by Teva, Actavis, and Alkermes, Otsuka, works with theMGHNational Pregnancy Registry, which GeneralHospital(MGH)employee,as aMassachusetts Committee for Educational for Activities and, Medscape; Steering the Committee for Janssen;hasbeenamemberof Data Safety andMonitoring Independent the member of Alkermes, andSunovion;boards hasbeena for Otsuka, advisory the from hasbeenamemberof JayMac and Sage; Freeman, MD, Editor inChief, hasreceived research funding interest that were identified. thepastyear, In P. Marlene interest. 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Physicians Category of 1AMAPRA shouldclaim fordesignates amaximum CMEactivity thisjournal-based The ofPhysicians CMEInstitute Postgraduate Press, Inc., Credit Designation physicians. to provide continuing medicaleducation for Council for Continuing Education Medical Press, Inc.,isaccredited by theAccreditation The ofPhysicians CMEInstitute Postgraduate Accreditation Statement youAfter shouldbeableto: studyingthisarticle, CME Objective A $10processing fee willapply. questions inthePosttest, andcomplete theEvaluation. To obtaincredit, answer correctly read the thearticle, needs withdesired results. areActivities plannedusingaprocess that linksidentified throughout eachvolume.topics of onavariety CME articles ofprovidingwith thepurpose readers of withacurriculum educational needsofCMEparticipants, the assessment of are for selected creditArticles designation basedonan CME Background • prescribing major depressive disorder usingthelatest data to guide Try to address cognitive impairmentsinpatients with Review Article Fl, Toronto, ON M5B 1M4, Canada ([email protected]) 1M4, M5B Toronto, ON Canada Fl, 193 6th Yonge St, Hospital, St Michael’s Program, Studies &Depression Suicide Canada J Clin Psychiatry 2020;81(4):19r13200 J ClinPsychiatry impairment inMDD. for cognitivetherapeutics definitive results regarding of theefficacy measures ofcognitive would behelpfulto performance obtainmore various agents are mixed. Further research at objective looking demonstrated procognitive effectsinMDD, butthefindingsbetween Conclusions: Present-day antidepressants andotheragents have depression. have alsodemonstrated significant positive effectsoncognition in agents, suchasmodafinil, amphetamines, anderythropoietin, norepinephrine reuptake inhibitors. Several non-antidepressant relative to serotonin selective reuptake inhibitors andserotonin- have demonstrated procognitive effectsinMDDpopulations do nothave procognitive effects, whilevortioxetine andbupropion Results: Overall, studiesdemonstrated antidepressants that tricyclic were resolved through athird reviewer. assessed andscreened by 2independent reviewers. Discrepancies Extraction: Data The ofresearch data andquality paperswere included inthissystematic review. were were assessed, articles eligible53 full-text and26articles to be or -5diagnosis ofMDD. total, In 2,045research paperswere screened, Participants were agedbetween 18and65years andhadaDSM-III,-IV, of antidepressants andothertherapeutic agents inMDDpopulations. Selection: Study The studiesincludedinthisreview were clinicaltrials Disorder,” “depress*,” “cognit*,” and “therapeutics” were used. publication was notrestricted. The search terms Depressive“Major PsycINFO, onMay 7,2019. andEmbasethrough Ovid The year of Sources: Data We adatabase conducted search ofMEDLINE, adults withmajordepressive disorder (MDD). therapeutic agents for thetreatment ofcognitive impairmentin Objective: To ofantidepressants review theefficacy andother J.Michelle Blumberg, BScH A Systematic Review Major Depressive Disorder: Therapeutic Agents in Antidepressants and Other ofProcognitive Effects e d c b a © Copyright 2020Physicians Postgraduate Press, Inc. To https://doi.org/10.4088/JCP.19r13200 share: systematic review. Psychiatry JClin a disorder: depressive major in agents therapeutic other and antidepressants cite: To and ShaneJ. McInerney, MD, MB, MSc, MRCPsych Ontario, Canada * ABSTRACT Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Toronto, Ontario, Hospital, St Michael’s Institute, Knowledge Shing Ka Li Centre for Depression and Suicide Studies, St Michael’s Hospital, Toronto, Hospital, St Michael’s Studies, Suicide and Depression for Centre University Hospital Galway, Hospital University Galway, Ireland Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Toronto, of Toronto, Ontario, University Psychiatry, of Department Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Toronto, of Toronto, Ontario, University Science, Medical of Institute Corresponding author: Blumberg MJ, Vaccarino SR, McInerney SJ. Procognitive effects of effects Procognitive SJ. McInerney SR, Vaccarino MJ, Blumberg © 2020Copyright Physicians Postgraduate Press, Inc. Sophie R. Vaccarino, BScH, Research Assistant, ASR ASR Assistant, Research BScH, Vaccarino, R. Sophie . 2020;81(4):19r13200. a ; Sophie R. ; Sophie Vaccarino, BScH a,c,d,e .

a,b, e1 * ; M of disability worldwide. psychosocial functioning. psychosocial that cognitive deficits inMDD are associated with impaired psychosocial functioning. psychosocial impairmentsthese are notably in associated with difficulties with impairments inmultiple cognitive domains and that there is strong suggesting evidence that MDD is associated affect approximatelyaffect two-thirds of individuals with MDD. Blumberg etal present despite remission or partial full of MDD symptoms. social functioning, and reducedsocial daily functioning. impairment and loss of occupational productivity, impaired a positive relationship self-reported cognitive between ( and Statistical Manual of Mental Disorders, Edition Fifth e2 For [email protected]. reprints orpermissions, contact ♦ andreview meta-analysis agents have not thoroughly been investigated. Asystematic procognitive of antidepressants effects and other therapeutic of antidepressants effects the on depressed the mood, Pharmacologic Treatments Depressive inMajor Disorder may contribute impairment to psychosocial the In particular, executive dysfunction tends to persist, which concentrating,with thinking, or making decisions. The occupational, domains. and social adequately interact with environment their across daily, functioning is understood as degree the to individuals which with moderate sizes. effect attention,speed, executive learning, function, and memory have demonstrated been also domains inthe of processing impairments on neuropsychological tests inMDD populations think orthink concentrate. changes in appetite, fatigue, and adiminished ability to psychophysiological changes, such as disturbed sleep, and/ormood anhedonia and presence the other of several MDD, though no significant difference classes the between on psychomotor and speed delayed inadults recall with reuptake inhibitors (NDRIs), have asignificant positive effect reuptake inhibitors (SNRIs), and norepinephrine-dopamine reuptake inhibitors (SSRIs), serotonin-norepinephrine such antidepressants as tricyclic (TCAs), serotonin selective experienced by with remitted those experienced MDD. It isIt illegal to post this copyrighted PDF on any website. DSM-5), ■ ■ ■ While extensive research conducted has been on ■ ■ ■ DSM-5 characterizes cognitive impairment as difficulty

for MDDpatients withcognitive impairment. far,So vortioxetine seemsto beaviabletreatment option pharmaceutical agents for cognitive impairmentinMDD. to inform future research investigating thebenefitsof A review ofallpotential therapeutic agents isnecessary treatment optionsare understudiedandlimited. in populations withmajordepressive disorder (MDD), Despite thecommon persistence ofcognitive impairment million people and is currently leading cause the ajor depressive disorder (MDD) over affects 300 2 MDD is characterized by amarked change in Clinical PointsClinical 2 Cognitive impairment is estimated to 15 4,5 1 According to Diagnostic the concluded that antidepressants, 12 Moreover, deficits remain these Additionally, studies show 11 It is well established 10 Psychosocial 7–9 commonly commonly 7,13,14 2 However, Thus, 3 6

“antidepressant agent,” “antidepressant,” “procognitive Disorder” OR “depress* 7, 2019,using following the search terms: “Major Depressive PsycINFO, and was conducted through Embase Ovid on May Search Methods agentssuccessful for treating cognitive impairment inMDD. most for need the future of studies assessing efficacy the provide article will this information practical regarding the antidepressant and non-antidepressant agents. Accordingly, of procognitive the efficacy of to offer overview adetailed relation to cognitive improvements. Thus, aims review this measure, examine we outcomes will functional and their pharmacologic discussed agents.the outcome As asecondary give procognitive amore ofthe realistic effects assessment of objective study measures andthis only will is akey strength of such as amphetamines, patients with depression. is that evidence bupropion improves cognitive functioning in between reported andbetween cognitive actual impairment themselves to low validity, considering relationship weak the cognitive improvements on participant based self-reports lend objective measures of cognition. Previous studies reporting and other therapeutic agents in MDD, on with afocus of is toreview examine antidepressants overall the efficacy current systematicTherefore,the objective of primary the priority as it is strongly related impairment. to psychosocial phenomenon inMDD and should considered be atreatment The Current Review lack of objective measures of cognitive functioning. samplesmall sizes,heterogeneous cognitive measures, and positive findings; however, studies these are limited by their agentstherapeutic inMDD populationsof have obtained To date, looking at trials clinical procognitive the effects have investigated been for cognitive their inMDD. effects depressive symptomatology. strongthe relationship cognitive between complaints and Administration for its procognitive effects. first antidepressantthe by recognized USFood and the Drug review, explore we which will current inthe review. have conducted previous been since publication the this of cognition and outcomes. functional Finally, trials clinical new the paper did not investigate relationshipthe between bupropion, as well as non-antidepressant agents. Additionally, toThis exclusion led the of antidepressants, certain such as antidepressants, TCAs, and multimodal antidepressants. reuptake inhibitors, noradrenergic serotonergic and specific following categories: SSRIs, SNRIs, serotonin antagonist and monoamineaction being modulation in1orthe more of studies of antidepressants mechanism with primary the of of antidepressants was found. Yet, that included review only METHODS A comprehensive database search of MEDLINE, Cognitive impairment is an important yet understudied Vortioxetine, amultimodal serotonergic antidepressant, is © 2020Copyright Physicians Postgraduate Press, Inc. J ClinPsychiatry 81:4,July/August 2020 ” AND“cognit* 18 17 erythropoietin, and erythropoietin, modafinil, More recently, adjunctive agents, 21 Consequently, of use the ” AND“therapeutics,” 16 Moreover, there 20 and and 19

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ Evaluations (GRADE) checklist. of Recommendations, Assessment, Development, and ofAssessment Quality Exclusion Criteria CriteriaInclusion through discussion with coauthor S.J.M. eligibility. The authors resolved discrepancies all independently search the assessed results for included articles. Authorsthe of M.J.B. and S.R.V. papers were from identified reference the section termsthe “cognition” and “depression.” Additional addition, ClinicalTrials.gov was searched, using for any remaining duplicates by author M.J.B. In Resultsfunction. were manually screened then automatically using by “deduplicate” the Ovid OR “procognitive.” Duplicates were removed treatment,” “clinical trial,” “psychostimulant,” 70% of participants enrolled studies inthe completed trial. the given, detection bias could not considered. be A minimum of regarding blinding the of outcome assessments were not bias could not excluded. be Additionally, because details bias;which selection minimized however, performance open-label studies, participants received same the treatment, double-blind, treatment randomization procedures. In the biasselection and performance used biases they because and active-comparator studies had alow potential for It isIt illegal to post this copyrighted PDF on any website. The quality of papers using was Grading assessed the 6. 5. 4. 3. 2. 1. 5. 4. 3. 2. 1. MDD. was not excluded, as it is acommon comorbidity of posttraumatic stress comorbid disorder; anxiety psychotic disorders, substance disorder, use or attention-deficit/hyperactivity disorder (ADHD), psychiatric disorders, such as bipolar disorder, Studies participants inwhich met criteria for other suicide risk. Studies including participants with concurrent outcome measures. Studies that included only subjective cognitive intervention investigated. being Studies psychotherapy inwhich was primary the Naturalistic studies. trials. Single-dose There was no restriction on year of publication. writtenArticles inEnglish. -11 criteria for MDD. International Classification of (ICD Disease and 65years of age met who DSM-III, -IVor −5or human participantsStudies 18 between of functioning. Studies measuring objective cognitive antidepressant agents) on cognition. interventions (antidepressant and non- of assessing pharmacologic effects the trials Randomized controlled and open-label 22,23 All placebo-controlled All or )-10 or Abbreviations: NA a endasscheduled? Did thetrials outcome ofinterest? Were consistently forthe datareported reporting Selective enrolled intrialsincludedtheanalysis? Were more than80%ofparticipants bias Reporting Was there blindingofoutcome assessment? bias Detection Was there blindingofparticipants? Performance bias Was random sequence generation used? bias Selection Item GRADE Table Criteria 1.GRADE Checklist Based onreferences 22and23. included afemale-only sample and another study the includedthe studies. It is important to note that one study of 42.The average proportion of females was 65%across of subjects ranged from 24 to 56 years, with an average age duration ranged from 1week to 24months. The mean age and 4had asample sizegreater than 200(Figure 2).Study than 50people, 9included asample 50and sizebetween 200, MDD participants: 13studies includedless asample sizeof comparator studies. Sample from sizes varied 17 to 598 (RCTs),trials 7were and 6were open-label trials, active 26articles, 13were randomizedthese controlled 2018. Of Studies the Description of populations, and inappropriate age of study population. lack of objective measures of cognition, nondepressed study (Figurereview 1).Studies were excluded for reasons such as forassessed eligibility, and 26were included systematic inthe and additional search articles were 53full-text methods, criteria for included the studies. studies prematurely. ended Table 1summarizes GRADE the demonstrating alow reporting selective bias. Nonethe of studies reported significant and nonsignificant results, 70% an acceptable rate on study the based population. All Although GRADE the 80%apt, criteria deem we considered review werereview unable to conclude that TCAs are at efficacious Tricyclic Antidepressants and non-antidepressant agents. TCAs, SSRIs and other serotonergic agents, SNRIs, NDRIs, a male-only sample. We study classified medications as RESULTS The included articleswere published 1982and between throughOf 2,045articlesidentified database the search Cognition. In general, studies the included in this = not applicable, NR © 2020Copyright Physicians Postgraduate Press, Inc. Procognitive Effects of Therapeutic Agents inMDD = not reported, RCT a All trials endedasscheduled All trials Open-label: yes comparator andactive studies:yes RCT Peselow etal1991(NR) Did notmeetcriteria: Open-label: unclear comparator andactive studies:unclear RCT Open-label: no comparator andactive studies:yes RCT Open-label: NA comparator andactive studies:yes RCT Herrera-Guzmán etal2008(77%) Herrera-Guzmán Wesnes etal2017(NR) etal2009(72%) Herrera-Guzmán Greer etal2014(70%) Bastos etal2013(74%) etal1992(NR) Spring = randomized controlled trial. Results 25 27 29 26 24 32 included 30 28

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You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. in functional capacityin functional (P depression (mean HDRS of escitalopram treatment inindividuals with moderate verbal fluency.verbal escitalopram was associated with significant worsening of executive functioning. However, study this found also that processing memory, verbal speed, nonverbal memory, and significant improvements inmeasures of attention and mediated by depression (r =0.44, severity (N weeks (N not associated improvement. with functional moderateexperiencing levels of depression. with improvements incognitive functioning inindividuals findings, demonstrating that vortioxetine is associated functioning. significant improvements inmultiple domains of cognitive sample and had no placebo-controlled group. caution study this because included female-only asmall correlation was obtained (r 8 weeks of vortioxetine or escitalopram treatment, apartial a consequence of depressive symptom improvement. vortioxetine on was cognition, adirect effect rather than cognition. suggest that fluoxetine not does have on significant effects a large sample, and lasted 24 months. Therefore, results these former studies study as this was placebo-controlled, included [BDI] score depressed individuals Depression (mean Beck Inventory cognitive performance over inasample time of moderately was not associated with a significant improvement in J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ Other, more recent studies RCT larger HDRS (RT)time inindividuals with severe depression (mean treatment significantly improved attention and reaction depression (mean MADRS followingtreatment inparticipants 8weeks with of moderate those taking vortioxetine taking those (r with change capacity functional inperformance-based for change incognitive performance was positively correlated of vortioxetine on functional outcomes, it was found that capacity.functional obtain significant results for of vortioxetine effect the on between cognitivebetween performance and capacity. functional DSST and amoderate functioning, reflecting relationship attention. measure of executive of functioning, processing, speed and obtained on Digit the Symbol Substitution Test (DSST), a size, d effect improving cognition. global The largest sizes (Cohen effect mg/d and 20mg/d) were significantly superior to in placebo It isIt illegal to post this copyrighted PDF on any website.

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P EmploymentLam Absence and Productivity [d =1.35, Scale improvements outcomes infunctional (measured using the desvenlafaxine treatment resulted insignificant individuals with severe depression (mean HDRS depression (mean MADRS =31.7). (mean depression and included alarge sample of participants with moderate into consideration as it is only the placebo-controlled study ( and were memory moderated by change indepressive severity individuals with moderate depression (mean HDRS declarative memory, or and visual motor were skills found in (N of reboxetine.efficacy After 1week of reboxetine treatment and Norepinephrine Reuptake Inhibitors Serotonin andNorepinephrine Reuptake Inhibitors separate from escitalopram on measures. these (WM); however,memory duloxetine did not significantly increases inmental processing variables speed and working Moreover, duloxetine was associated with significant HDRS =19.1). (N and after memory 12weeks of open-label treatment memory,visual decision and making, learning verbal improvements domains inthe of psychomotor speed, of attention and RT. was significantly associated with improvements on measures another study (N This due could be to short the study duration. Conversely, treatment, participants (N Reuptake Inhibitors Norepinephrine-Dopamine placebo. RCT (N functioning, processing and speed, attention inan 8-week duloxetine didnot separate from on placebo tests of executive moderate depression (mean MADRS and cognition global (d =0.43, improvements incognitive flexibility, processing speed, with desvenlafaxine was associated with significant at compared baseline with less to impairment. those greater for individuals were who more cognitively impaired to escitalopram, after 24 weeks (N significant improvements memory, in episodic compared ess lcb (N =429). placebo versus MADRS were found inseverely depressed individuals (mean of depression was not provided. (mean HDRS P <.001]). Health and Work Performance Questionnaire [d r

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= 01; hea Dsblt Sae [ Scale Disability Sheehan .001]; 41), no significant improvements incognitive flexibility, 21) inindividuals with moderate depression (mean © 2020Copyright Physicians Postgraduate Press, Inc. 36 = = P 40 The results of the latterthe study The results should taken of be 508) comparing to vortioxetine its and efficacy 35.2) treated with 8 weeks of levomilnacipran35.2) treated with 8weeks of <.004). Procognitive Effects of Therapeutic Agents inMDD 27 = However, improvements learning in verbal 24.8) significantly improved on measures = 27 68) found that after 8weeks, reboxetine 41 Duloxetine associated with was also Information regarding sample severity 29

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on a test of executive functioning, wasof associated with modafinil significant improvements 14 weeks of the study (N the 14 weeks of HDRS in individuals with treatment-resistant depression (mean and memory recall recognition more memory than placebo duration and sample small size. of positive attributed findings could be to short the study Blumberg etal influenced psychosocial functioning. psychosocial influenced found that change inimmediate directly memory verbal composite memory. of and memory verbal nonverbal memory, but not WMor was associated with significant improvements on measures in individuals with moderate depression (mean HDRS bupropion to escitalopram foundbupropion that 8weeks of but not 120mg, was associated with improved cognition. MADRS =12.3). (mean inclusion of astudy population levels with mild of depression findings on composite cognition due could be to the e6 For [email protected]. reprints orpermissions, contact ♦ antidepressant agents are outlined in Table 3. (mean MADRS in participants (N Finally, following 12 weeks of intranasal insulin treatment a sample with depression mild (mean HDRS after 8weeks of open-label administration (N improvements inexecutive functioning and memory verbal (mean HDRS augmentation therapy inmoderately depressed participants Non-AntidepressantOther Agents MADRS =18.3). mean HDRS =14.1; (mean depression Moreover, participants levels these mild of experienced to findings to generalize females these withdifficult MDD. However, study this included a male-only sample, making it and on placebo composite cognition. was no difference lisdexamfetamine between dimesylate functioning were found compared to however, placebo; there patients (N dimesylate augmentation to SSRI therapy inremitted MDD Non-Antidepressant Agents: Psychostimulants antidepressant agents are outlined inTable 2. greater than that found with escitalopram. measures; however, improvement this was not significantly significant improvements on were functional observed nonresponders. improvementspeed; was greater inresponders versus of and memory some measures of mental processing neurocognitive tests showed such improvements. It isIt illegal to post this copyrighted PDF on any website. Eight weeks administration of erythropoietin enhanced An open-label study (N The details of of studies non- assessing efficacy the l Cognition. An open-label study (N Cognition. Followinglisdexamfetamine 9weeks of ofThe details of studies all assessing efficacy the outcomes. Functional -Theanine, an amino acid, was associated with significant

= 20); these effects were effects maintained20); these over entire the = = 59), significant improvements in executive = 30 21.4; mean BDI Astudy (N 25.9), no effects on25.9), no effects cognition were found. = 43 35) with treatment-resistant depression Followingbupropion, 8weeks of = = 39). 90) found that 60mg of caffeine, = 46 36) comparing of effects the = 20.6) found that 4weeks 43 18 44 The lack of positive though no other = 43 31) of modafinil The same study 44 = The lack = 12.5). = 20) in 23.4) 23.4) 45 32 13

acid [GABA]), (ie, dopamine [DA], norepinephrine [NE],γ-aminobutyric to its ability to modulate range a wide of neurotransmitters specifically. Vortioxetine’s is likely procognitive due efficacy vortioxetine to target could used be cognitive impairment in functional capacity.in functional vortioxetine were positively correlated with improvements actions. Improvements incognitive functioning with functioning. MDD is consistently associated with impaired global acceptability rates than other antidepressants. efficacious TCAs, such as amitriptyline and clomipramine, have lower warranted as studies have consistently demonstrated that of TCAson for efficacy the cognitive impairment is not different results across studies. Nevertheless, research further differing objective measures of cognition may which explain on capacity. functional Moreover, studies these included of TCAsstudies assessing investigated efficacy the effect their samplesmall sizeand short study duration, the and none of studies that examined TCAs were limited by relatively their directly improve memory. symptom measures, suggesting that imipramine didnot were tasks and obtained memory depressive also between significantly improved memory, significant correlations While individuals imipramine taking experienced antidepressants demonstrated that TCAs are not procognitive. Tricyclic Antidepressants measures of cognition inadults with MDD were assessed. ofassessing pharmaceutical effects the agents on objective relieving cognitive impairment inMDD. Specifically, studies of various antidepressants and other therapeutic agents for of depressive symptom improvement, direct and independent, rather than an epiphenomenon Vortioxetine’s on effect cognition appears largely to be previously demonstrated in elderly patients with MDD. of evidence the vortioxetine’s procognitive efficacy with MDD. and duloxetine, at improving cognitive impairments inadults inferior to other antidepressants, new such as vortioxetine However, recent studies have found that escitalopram is and nonverbal memory, but worsened fluency. verbal functioning, attention, processing memory, verbal speed, newer antidepressant, was correlated with improved executive positive on cognitive effects functioning. Escitalopram, a procognitive, but that newer serotonergic agents may exert that older SSRIs, such as fluoxetine and fluvoxamine, are not Serotonergic Agents SerotoninSelective Reuptake Inhibitors and may have significant on adverse memory. effects DISCUSSION Overall, studies assessing the efficacy of tricyclic tricyclic of studiesOverall, assessing efficacy the systematic was to review assess efficacy this the The aim of The results obtained included inthe studies extended In general, studies the included suggest review inthis © 2020Copyright Physicians Postgraduate Press, Inc. 28,35 50 Thus, among serotonergic agents, vortioxetine 49 inaddition to its multimodal serotonergic J ClinPsychiatry 81:4,July/August 2020 7 This finding is important, as 24 Furthermore, amitriptyline 34 suggesting that 25 Eligible Eligible 47 31 48

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Table 2. Summary of Studies Investigating the Effects of Antidepressant Agents on Cognitive Measures Study (by Main Drug Type Study Medication N Mean Proportion Investigated) (Dosage) (end) Age (y) Female Duration Design Diagnosis Outcome Measures Results Limitations Tricyclic Antidepressants (TCAs) Peselow et al Imipramine (IMI; 71 49 50% 4 wk Open-label MDD (HDRS≥ 16) Cognition: digit span; After 4 weeks, IMI significantly associated Short study duration 199124 150–300 mg/d) superspan digits; with improvements in implicit memory No placebo Buschke; fragmented (P < .002), short- and long-term memory pictures (P = .05), and retrieval efficiency from remote memory (P< .05) Significant correlations between HDRS, MADRS, and memory tasks (

© 2020Copyright Physicians Postgraduate Press, Inc. (P = .014), verbal memory (LM I, =P .049; LM II, P= .005), nonverbal memory (P = .041), and EF (P= .004) Escitalopram associated with significant Procognitive Effects of Therapeutic Agents inMDD worsening in verbal fluency (=P .003) McIntyre et al Vortioxetine (10 598 45 66% 8 wk RCT MDD (MADRS≥ 26), Cognition: DSST, RAVLT, After 8 weeks, both doses significantly Exclusion of individuals 201434 mg/d or 20 mg/d) current MDE≥ 3 TMT-A/B, Stroop test, superior to placebo on composite with milder baseline months SRT, CRT cognition (P< .001) severity Processing speed, working memory, and visuospatial processing had the largest effect size (d= 0.51 for 10 mg/d; d= 0.52 for 20 mg) Vieta et al Vortioxetine (10–20 99 48 75% 8 wk RCT (active MDD (MADRS≥ 22), Cognition: DSST, After 8 weeks, cognitive test scores No placebo 201835 mg/d), escitalopram comparator) inadequate response TMT-A/B, Stroop, SRT, improved in both treatment groups; no (10–20 mg/d) to ≥ 6 weeks of SSRI CRT, RAVLT significant differences between groups or SNRI Functioning: FAST, Vortioxetine did not significantly improve UPSA-B functional capacity Correlation between functional capacity and executive functioning, processing speed, and attention (DSST, =P .006)

(continued)

e7 Blumberg etal e8 For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Table 2 (continued).

Study (by Main Drug Type Study Medication N Mean Proportion Investigated) (Dosage) (end) Age (y) Female Duration Design Diagnosis Outcome Measures Results Limitations Mahableshwarkar Vortioxetine (10 or 508 45 65% 8 wk RCT MDD (MADRS≥ 26), Cognition: DSST, After 8 weeks, vortioxetine led to Lack of formalized et al 201536 20 mg/d), duloxetine subjective reports TMT-A/B, Stroop test, significant improvements in tests of inclusion criteria for (60 mg/d) of cognitive Groton Maze Learning EF, processing speed, and attention cognitive dysfunction dysfunction, acute Test, Detection Task, (P < .001); duloxetine did not separate MDE≥ 3 months Identification Task, from placebo One-Back Vortioxetine led to improvements in Functioning: UPSA, WLQ functional capacity (P< .001) Baune et al Vortioxetine (10 134 46 66% 8 wk RCT MDD (MADRS≥ 26), Cognition: DSST, After 8 weeks, neither treatment separated 20187 mg/d), paroxetine current MDE≥ 3 TMT-A/B, Stroop test, from placebo on executive functioning, (20 mg/d) months SRT, CRT processing speed, or attention Functioning: FAST, Vortioxetine separated from placebo on UPSA-B composite cognition (P= .024) No significant improvement on functional capacity, but cognition positively correlated with functional capacity (r = 0.213, P= .024)

Richardson et al Fluoxetine, 37 NR 68% 6 wk RCT (active MDD (HDRS> 20 and RAVLT After 6 weeks, significant differences No placebo 199437 amitriptyline (doses comparator) BDI > 20) obtained in verbal learning scores not specified) between the drug groups, favoring fluoxetine (P= .0002) Bastos et al Fluoxetine (FLU; 202 30 62% 24 mo RCT MDD or depressive Cognition: similarities, After 24 months, FLU did not lead to Homogeneity of 201326 20–60 mg/d) disorder NOS (BDI digit span, letter- significant improvements in cognitive participant sample 20–35) number sequencing, performance over time digit-symbol coding, © 2020Copyright Physicians Postgraduate Press, Inc. matrix reasoning, picture arrangement Keegan et al Fluoxetine (20–80 37 44 66% 6 wk RCT (active MDD (HDRS-21≥ 20 Cognition: RAVLT After 6 weeks, FLU led to significant No placebo 199138 mg/d), amitriptyline comparator) and BDI≥ 20) improvements on a test of verbal memory (100–250 mg/d) (P = .001); AMI did not

J ClinPsychiatry 81:4,July/August 2020 Koetsier et al Imipramine 116 52 55% 4 wk RCT MDD (HDRS> 13) Cognition: CPT After 4 weeks, both treatments led to Short study duration 200239 (200–300 μg/L), significant improvements in attention No placebo fluvoxamine (P < .01) and RT (P< .01) (150–200 μg/L) Fluvoxamine led to a significant decrease in omission errors (P< .01); IMI did not Attention positively correlated with depression in the fluvoxamine group (r = 0.44, P< .05) (continued)

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Table 2 (continued). Study (by Main Drug Type Study Medication N Mean Proportion Investigated) (Dosage) (end) Age (y) Female Duration Design Diagnosis Outcome Measures Results Limitations Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), Norepinephrine Reuptake Inhibitors Lam et al Desvenlafaxine 36 39 55% 8 wk Open-label Outpatients, MDD Cognition: CNSVS, NCI After 8 weeks, desvenlafaxine associated Functional capacity 201640 (flexible, 50–100 (MADRS≥ 23), Functioning: LEAPS, with significant improvements in based on self-report mg/d) subjective cognitive HPQ, SDS cognitive flexibility (d= 0.60, P< .001), Open-label design complaints processing speed (d= 0.57, P< .001), (BC-CCI≥ 6) and global cognition (d= 0.43, P= .003) After 8 weeks, functional outcomes improved (P< .001) Cognitive-improvement group (measured by NCI) had significantly better outcomes on depressive and functional outcomes than those who did not experience cognitive improvement Greer et al Duloxetine (30–120 21 31.3 67% 12 wk Open-label MDD (HDRS-17≥ 16; Cognition: IDS item 15, After 12 weeks, duloxetine associated withSmall sample size 201427 mg/d) CGI-S≥ 4), reported CANTAB improvements in RT, VRM (

Wesnes et al Levomilnacipran 429 45 65% 8 wk RCT MDD (MADRS≥ 30), Cognition: digit After 8 weeks, significantly greater Baseline MDD Procognitive Effects of Therapeutic Agents inMDD 201729 extended-release current MDE≥ 4 vigilance, SRT, CRT, POA, improvements in attention and RT found characteristics not (40–120 mg/d) weeks COA, cognitive RT, RT with levomilnacipran in the intent to consistent across variability treat (ITT) population and in the higher cognitive impairment cognitive impairment groups (

20) Cognition: CDR test After 8 weeks, reboxetine led to significantMean age and 200341 mg/d), paroxetine battery, COA factor improvements in attention and proportion female NR (20–40 mg/d) score, Combined Speed performance speed (P< .05) factors Paroxetine did not lead to significant improvements on any cognitive measure Göder et al Citalopram (9–27 41 31 76% 1 wk Active MDD (HDRS-17≥ 15) Cognition: TMT-A/B, shift Neither treatment led to significant Short study duration 201142 mg/d), reboxetine comparator of attention, fluency test, improvements on cognitive tests No placebo (4–8 mg/d) study final acquisition, recall,

retention, mirror tracing e9 (continued) Blumberg etal e10 For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website.

Table 2 (continued). Study (by Main Drug Type Study Medication N Mean Proportion Investigated) (Dosage) (end) Age (y) Female Duration Design Diagnosis Outcome Measures Results Limitations Norepinephrine Dopamine Reuptake Inhibitors Herrera-Guzmán Bupropion 20 24 92% 8 wk Open-label MDD (HDRS-17≥ 18) Cognition: CANTAB, After 8 weeks, bupropion associated Small sample size et al 200830 sustained-release WAIS-III digit span, DMS, with significant improvement on tests Open-label design (150 mg/d) SSP, RAVLT, PRM, PAL, of episodic memory (P< .04), visual SRM, processing speed, learning, and memory (P= .028, P= .029) MTS, RT, RVP, Stroop test, Memory improvement was greater COWAT, set shift, SWM, in responders than nonresponders SOC (P < .05) Soczynska et al Bupropion 36 38 53% 8 wk RCT (active MDD (HDRS-17≥ 16), Cognition: CVLT-II, After 8 weeks, bupropion led to significantNo placebo 201443 extended-release comparator) current MDE measures from the improvements in verbal (=P .001) and (150–300 mg/d), WMS-III, BVMT-R nonverbal memory (P< .001) but not in escitalopram (10–20 Functioning: SDS, EWPS working or composite memory mg/d) Both treatments led to significant improvements in global functioning (P < .001) and work productivity © 2020Copyright Physicians Postgraduate Press, Inc. (P = .045) Improvements in immediate verbal memory exerted a direct influence on improvements in global functioning (P = .006) Abbreviations: BC-CCI = British Columbia Cognitive Complaints Inventory; BDI = Beck Depression Inventory; BVMT-R = Brief Visuospatial Memory Test—Revised; CANTAB = Cambridge Neuropsychological Test Automated Battery; CDR = Cognitive Drug Research (cognitive battery); CGI-S = Clinical Global Impression scale—Severity of Illness; CNSVS = CNS Vital Signs; COA = Continuity Of Attention; COWAT = Controlled Oral Word Association

J ClinPsychiatry 81:4,July/August 2020 Test; CPT = Continuous Performance Test; CRT = Choice RT Task; CVLT = California Verbal Learning Test; DMS = Delayed Matching to Sample; DSST = Digit Symbol Substitution Test; EF = executive function; EWPS = Endicott Work Productivity Scale; FAST = Functional Analysis Screening Tool; HDRS = Hamilton Depression Rating Scale; HPQ = Health and Work Performance Questionnaire; IDS = Inventory for Depressive Symptomatology; LEAPS = Lam Employment Absence and Productivity Scale; LM I, LM II = Logical Memory I, Logical Memory II; MADRS = Montgomery-Asberg Depression Scale; MDD = major depressive disorder; MDE = major depressive episode; MTS = Match to Sample Visual Search; NCI = Neurocognitive Index; NOS = not otherwise specified; NR = not reported; PAL = Paired Associates Learning; POA = Power Of Attention; PRM = Pattern Recognition Memory; RAVLT = Rey Auditory Verbal Learning Test; RCT = randomized controlled trial; RT = reaction time; RVP = rapid visual information processing; SDS = Sheehan Disability Scale; SOC = Stockings of Cambridge; SRM = Spatial Recognition Memory; SRT = Simple RT Test; SSP = Spatial Span; SWM = Spatial Working Memory; TMT = Trail Making Test; UPSA-B = University of California, San Diego Performance-Based Skills Assessment (Brief); VRM = verbal recognition memory; WAIS-III = Wechsler Adult Intelligence Scale; WLQ = Work Limitations Questionnaire; WMS = Wechsler Memory Scale.

Table 3. Summary of Studies Investigating the Effects of Non-Antidepressant Agents on Cognitive Measures Study (by Main Mean Drug Type Study Medication N Age Proportion Investigated) (Dosage) (end) (y) Female Duration Design Diagnosis Outcome Measures Results Limitations Psychostimulants Madhoo et al Lisdexamfetamine 59 40 69% 9 wk RCT MADRS≥ 18, self-reported Cognition: BRIEF-A After 9 weeks, no significant differences 201418 dimesylate (LDX; executive dysfunction informant-report, NCI in cognition between LDX and placebo 20–70 mg/d) derived from CNSVS LDX significantly improved participant- reported EF (P= .0006) Liu et al Caffeine (60 or 90 41 0% 4 wk RCT Current MDE (HDRS= 10–18; Cognition: MoCA Cognition significantly increased after 60 Male-only sample 201732 120 mg/d) MADRS= 14–24) mg caffeine but not 120 mg (

16), complaints Cognition: Stroop After 4 weeks, modafinil associated with Short study duration 200444 (100–400 mg/d) of hypersomnia, fatigue, daytime test, WAIS-III, TMT-A/Bsignificant improvements in EF (

© 2020Copyright Physicians Postgraduate Press, Inc. improvements in verbal memory (P = .005) and EF (P= .016) Miskowiak et Erythropoietin 39 43 69% 14 wk RCT MDD (HDRS-17> 17), treatment Cognition: RAVLT After 14 weeks, erythropoietin led to Did not screen or exclude al 201446 (40,000 IU) resistance based on the TRAQ Functioning: GAF, significant improvements in recall comorbid Axis II disorder Procognitive Effects of Therapeutic Agents inMDD QOL (P = .02) Erythropoietin significantly improved recognition memory vs placebo (P = .03) Cha et al Intranasal insulin 35 47 63% 12 wk RCT MDD (HDRS-17≥ 20), TRD Cognition: CVLT-II, No significant improvements on overall Included patients with 201713 (1.6 mL/d) (nonresponse to ≥2 treatments) D-KEFS (verbal mood, neurocognitive function, or self- TRD; many other studies fluency, TMT-A/B, reported quality of life did not DSST, CFQ), CANTAB Abbreviations: BACS = Brief Assessment of Cognition in Schizophrenia, BRIEF-A = Behavior Rating Inventory of Executive Function for Adults, CANTAB = Cambridge Neuropsychological Test Automated Battery, CFQ = Cognitive Failures Questionnaire, CNSVS = CNS Vital Signs, CVLT = California Verbal Learning Test, D-KEFS = Delis-Kaplan Executive Function System, DSST = Digit Symbol Substitution Test, EF = executive function, GAF = Global Assessment of Functioning, HDRS = Hamilton Depression Rating Scale, MADRS = Montgomery-Asberg Depression Rating Scale, MDD = major depressive disorder, MDE = major depressive episode, MoCA = Montreal Cognitive Assessment, NCI = Neurocognitive Index, QOL = quality of life, RAVLT = Rey Auditory Verbal Learning Test, RCT = randomized controlled trial, TMT = Trail Making Test, TRAQ = Treatment Response to Antidepressants Questionnaire, TRD = treatment-resistant depression, WAIS-III = Wechsler Adult Intelligence Scale, WMS = Wechsler Memory Scale.

e11 significant improvement cognition. inglobal with recurrent MDD, found that duloxetine resulted ina placebo-controlled conducted trial, inan elderly population supports duloxetine’s procognitive adouble-blind, effects: inclusion criteria for due review this to improper age range) groups. Nevertheless, another study (which did not meet metabolite hydroxybupropion. inhibition of DA and NEby bupropion and its primary Commonly suggested mechanisms are reuptake the bupropion scarcely has been studied inhuman populations. and concurrent suicide risk. improved neurocognitive performance inpatients with MDD criteriameet for review, this foundbupropion that 8weeks of studiesOther support findings. One study, these didnot which on andcognition, memory processing specifically speed. studies, bupropion was shown to have on positive effects Blumberg etal the ratthe prefrontal cortex (PFC) in response to bupropion. study neurotransmitters foundthese elevated levels of in e12 For [email protected]. reprints orpermissions, contact ♦ improve executive deficits inMDD Noradrenergic reuptake inhibition PFC inthe is shown to functioning. in global bupropion treatment is associated with greater improvement suggested that improvement following memory inverbal noradrenergic enhance cognition. effects Reuptake Inhibitors Norepinephrine-Dopamine Finally, 2studies outcomesfunctional in individuals with MDD. and desvenlafaxine have inimproving shown efficacy cognitivebaseline functioning. Moreover, levomilnacipran for drug individualsthe withsuggesting poor utility the of found cognitivewith baseline higher in those impairments, functioning. For levomilnacipran, greater improvements were resulted in significant improvements in measures of cognitive levomilnacipran and desvenlafaxine, newer antidepressants, reboxetine) at improving cognition inMDD. For instance, both Norepinephrine Reuptake Inhibitors Serotonin andNorepinephrine Reuptake Inhibitors and cognitive and impairment functional inMDD. has consistently demonstrated its superiority at improving cognition. no significant improvements were found on measures of study comparing to vortioxetine its and efficacy placebo, multiple domains of cognitive functioning. However, ina on inanaturalistic memory study. bupropion shown has been to have superior to SSRIs effects to inclusion the of individuals with suicide risk. Additionally, the fact that fact the first2studies the cognitive measures andto heterogeneitythe the used of NE in response to bupropion administration. and found increased extracellular concentrations of DA and neurotransmitter levels nucleus inthe accumbens of mice that Porsolt the used animal of model depression measured It isIt illegal to post this copyrighted PDF on any website. Multiple studies, including inreview, this those have It hypothesized has been that antidepressants with potent Newer SNRIs are superior also to older SNRIs (eg,

36 Discrepancies studies between due could be 27,28 demonstrated that duloxetine improves 55,56 The mechanism of action of 54 This study was excluded due 57,58 27,28 17 One microdialysis study didnot include control 4 ; this was not; this found in 17 Among included 53 57 Another 29,51,52 29 57

individuals with remitted depression. significantly improved and memory episodic WMin found of ofuse asingle dose modafinil) that modafinil study didnot (which inclusion meet criteria due to its However, first study the 2included studiesthe investigating either of bupropion. psychoactive properties. dysfunction as an inclusion criterion. measures due could be to of use the self-reported executive cognition. The absence of positive results on objective lisdexamfetamine didnot significantly improve objective MDD. neurotransmitters may improve executive functioning in promoting agent that has stimulant-like properties. procognitivetheir efficacy. Modafinil is an wake- effective Non-AntidepressantOther Agents improvements inwork and life functioning. objective cognitive impairments and relationship their with studies investigate should further impact the of stimulants on cognition inadults with MDD. studies, one study found that low of doses caffeine enhanced by PFC the involved inmaintaining executive functions mediated increasing release. their blocks reuptake the of catecholamines, subsequently converted to active metabolite the d neurotransmitters. Specifically, lisdexamfetamine is to treattypically used ADHD, is able to regulate these life events. resultas they insignificant problems incoping with stressful functions, such as RT and attention. consensus that low of doses caffeine improve lower cognitive as attention. findings are These supported by general the functioning and WM, and lower cognitive abilities, such measureswhich cognitive higher functions, such as executive Montrealwerethe insubtests seen Cognitive Assessment, of on of effects the caffeine on cognitivehigher abilities. depressive symptoms. subjective executive dysfunction inpatients with residual For instance, lisdexamfetamine shown has been to ameliorate may able be to enhance cognitive functioning PFC. inthe the activity ofthe 6typical antidepressants inmice. Executive deficits function are interest of particular inMDD effectiveness at improving cognitive impairments in MDD. Non-Antidepressant Agents: Psychostimulants include cognitive measures that assess executive functioning. depressive episodes. shownbeen related to be to cumulative the duration of individuals with MDD since cognitive impairments have may not same the level of experience impairment as older of younger individuals (mean age Another stimulant, caffeine, is frequently for used its Finally, other therapeutic agents were investigated for There that is evidence lisdexamfetamine, a stimulant Stimulant agents have investigated been also for their © 2020Copyright Physicians Postgraduate Press, Inc. 18 18,60 61 ; consequently, agents that modulate these NEand DA are important neurotransmitters 5 Moreover, second the study J ClinPsychiatry 81:4,July/August 2020 63 61,62 43 However, among eligible studies, 32 included sample asmall (N Caffeine was found to enhance Consequently, lisdexamfetamine 32 Specifically, improvements = 24). Younger individuals 65 -amphetamine, which There is less research 66 Modafinil was also 64 Ofeligible 30 65 didnot Future Future 44 One One = 20) 59

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. in bupropion studies may have psychomotor slowing due to cross blood-brain the barrier Systemicallyeffects. administered is able erythropoietin to (N However, study this was limited by its sample small size executive functioning, but not inother cognitive domains. was associated withmodafinil significant improvements in respond to bupropion. to respond psychomotor slowing are more likely and prescribed to be may bias choice drug and response. For instance, with those for agents. these increasing that likelihood positive the results are obtained Specifically, are newer drugs more likely investigated, to be may introduce bias favoring over newer drugs older ones. J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ havedrugs low acceptability rates. studiedbe for older because procognitive their efficacy studies currentlythese exist. few of outcomeas a primary measure would However, ideal. be very onfocus studies that include objective cognitive functioning cognitive domains that may impaired be inMDD. Astrict batteriesThese may not encompass broad the range of cognitivemeasure, batteries.brief resulting of use inthe include objective cognitive outcome functioning as aprimary outcomes. In addition, majority the of studies didnot and to make definitive conclusions regarding treatment heterogeneity to makes compare it difficult study results of objective measures included inthe used studies. This cognition. any conclusions regarding long-term treatment on effects short-term (ie, 4 weeks), ability restricts which the to make sizes across studies. Moreover, studies werethe many of results. There was asubstantial difference sample between experimenter bias, can which subsequently the influence toblinding study medication lack of canto lead patient and in our 26studies review. werethe open-label. A of Seven Limitations measures outcome as primary measures. larger samples, controlled and trials, objective cognitive agentscontinue usingthese to assess effectiveness the of are focusing on few trials Future clinical these. studies should ofprocognitive non-antidepressant efficacy agents as there It to make definitive is difficult conclusions regarding the deprivation.sleep found to counteract cognitive impairments associated with and recognition in MDD. memory study, was found erythropoietin to enhance memory recall limited by its sample small (N correlated with improved cognition; however, study the was neurotrophic inneuropsychiatric effects disorders. suggested to have psychotropic effects. an amino acid that is contained in green tea and has been It isIt illegal to post this copyrighted PDF on any website. Erythropoietin has also been explored been has also forErythropoietin its procognitive It important is also to note that patients’ symptom profiles Newer such drugs, as vortioxetine, are more likely to A key limitation was large the to review the diversity There were limitations several to studies the included = 31) and short study duration (4weeks). 67 DeBattista and colleagues 70 Consequently, sample populations 68 and neuroprotective exert and = 20) and open-label design. 46 Finally, l 47 Nevertheless, this 45

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depressed patients. are more cognitively impacted by than illness their unipolar homogenous study population and bipolar because patients participants with bipolar disorder. This was done to ensure a participants with objective cognitive impairments. limitation to studies that didnot limit sample their to show positive improvements. This introduces an important inparticipants are who observed impairedeffect and do who forin trials cognition, are they likely to weaken treatment the cognitive impairment. If unimpaired patients are included samples that may include participants without objective studies symptom inwhich profiles are not considered. recruitment bias and may show compared greater efficacy to impairment remain despite high remission. some agents show promising results, rates the of cognitive showalso promise, but more research Although is needed. for its procognitive SNRIs, effects; NRIs, and bupropion inconclusive. vortioxetine Overall, has greatest the support domains, results the of different studies are contradictory and some positive have effects found been for multiple cognitive objective measures of cognitive functioning. Although impairments in adults with MDD, on focus with a strict of antidepressantseffects the and other agents on cognitive meta-analysis on summarized the studies. research team. Future studies should consider conducting a was not conducted as it of was our not within expertise the agents. Ameta-analysis of use with the statistical methods therapeutic regardingevidence of procognitive the efficacy systematic was to review synthesizethis available best the meta-analysis However, would ideal. be of purpose the episodes, and cognitive impairments. for prescribing medications effective for patients with MDD help will review informMDD. cliniciansthis The findings of day pharmacologic treatments for cognitive impairment in The current offers review athorough of summary present- in cognitive functioning and depressive symptomatology. on outcomes functional and how relate these to improvements therapies tothese exploreit would beneficial be impact the of cognitive testing outcome as aprimary measure. Furthermore, non-antidepressant agents using standardized and objective continue to investigate of antidepressants effect the and current and residual Future MDD is difficult. studies should target.they Consequently, targeting cognitive deficits in may inregard differ also to cognitive which impairments in terms impairments, of experienced and therapeutic agents impaired cognition inMDD. Additionally, individuals differ include bipolar patients. studiedbeen for its procognitive in samples that efficacy may drugs missing.certain be For instance, ketamine has since information regarding procognitive the of effects severity ofseverity symptoms, causethe of cognitive impairment inMDD is complex: In systematic this review, we excluded studies that included In addition, included the studies include heterogenous In was to review investigate conclusion,this aim the of Finally, current the while is comprehensive, review a © 2020Copyright Physicians Postgraduate Press, Inc. 5 and presence of comorbidities Procognitive Effects of Therapeutic Agents inMDD 71 However, represents this alimitation 73 cumulative duration of depressive 72 4 all contribute all to 6 Nevertheless,

e13 3. 2. Blumberg etal e14 For [email protected]. reprints orpermissions, contact ♦ 13 12 11 10 9. 8. 7. 6. 5. 4. 1. and Blumberg Mss 5years. last the in Janssen from fees consulting Financial disclosure: depressive disorder. major in impairment cognitive of treatment the for Administration Drug and USFood the by approved insulin and intranasal are not erythropoietin, modafinil, lisdexamfetamine, bupropion, levomilnacipran, reboxetine, citalopram, fluoxetine, fluvoxamine, desvenlafaxine, escitalopram, vortioxetine, duloxetine, paroxetine, clovoxamine,imipramine, amitriptyline, knowledge, their of best the to that, determined have Disclosure of authors off-labelusage: The Published online: 2020. Submitted: Funding/support: article. the to relative disclose to interest commercial affiliations relationships withfinancial or any REFERENCES It isIt illegal to post this copyrighted PDF on any website. . . . .

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3. 2. 1. To obtaincredit, goto P to take thisPosttest andcomplete theEvaluation. osttest d. c. b. a. current evidence? would youof action take to improve Zahir’s cognitive symptoms, on the basis of treatment stopped regimen due to serious side effects.but quickly What course content for several months. Zahir’s previous physician added vortioxetine to his but he has complained of having trouble concentrating and remembering course successfully for his mood symptoms with bupropion extended release 300 mg/d, Zahir is a 25-year-old male university student with MDD. He has beentreated d. c. b. a. Escitalopram deficits in patients with MDD? Which antidepressant currently has the greatest for improving support cognitive d. c. b. a. found. should youWhat take, action according to current evidence? of life her quality affecting and daily functioning. No othersigns of dementia are the right words. She asks for your help in improving thesesymptoms, asthey are complaining of cognitive symptoms, specifically forgetfulness and trouble finding not experienced a major depressive episode in many years. Adriana comes to you disorder (MDD). She has been treated for with amitriptyline thelast decade and has Adriana is a 55-year-old woman previously diagnosed with major depressive Add lisdexamfetamine Add modafinil Add escitalopram Stop bupropion vortioxetine and only try Vortioxetine Bupropion sustained release Bupropion extended release Refer Adriana to acognitive training program Switch Adriana antidepressant to another tricylic agent, such as imipramine and recurrence of depression Taper off amitriptyline and monitor Adriana for improvements incognitive symptoms Add escitalopram to her treatment regimen (Keyword: August CME) © 2020Copyright Physicians Postgraduate Press, Inc. A $10processing fee is required. J ClinPsychiatry 81:4,July/August 2020

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