cognition as a target in major depression

European Neuropsychopharmacology (]]]]) ], ]]]–]]]

http://dx.doi.org/10924-977X/& 2015 E

nCorrespondenceof Neuroscience, HoBarcelona, Spain. Te

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Cognition as a target in major depression:New developments

Brisa Solé, Esther Jiménez, Anabel Martinez-Aran, Eduard Vietan

Barcelona Bipolar Disorders Program, Institute of Neurosciences, University of Barcelona, IDIBAPS,CIBERSAM, Barcelona, Catalonia, Spain

Received 29 July 2014; received in revised form 3 December 2014; accepted 23 December 2014

KEYWORDSCognition;Major depression;Monotherapy;Adjunctive treatment

0.1016/j.euroneurlsevier B.V. and E

to: Bipolar Disordespital Clinic of Barl.: +34 93 227 [email protected]

article as: Soléacology (2015), h

AbstractMajor depressive disorder (MDD) is a highly prevalent and disabling psychiatric illness oftenaccompanied of cognitive dysfunction which may persist even when patients achieve clinicalremission. Currently, cognitive deficits emerge as a potential target because they compromisethe functional outcome of depressed patients. The aim of this study was to review data forseveral potential pharmacological treatments targeting cognition in MDD, resulting frommonotherapy or adjunctive treatment. An extensive and systematic Pubmed/Medline searchof the published literature until March 2014 was conducted using a variety of search term tofind relevant articles. Bibliographies of retrieved papers were further examined for publicationsof interest. Searches were limited to articles available in English language. We describe studiesusing modafinil, lisdexamfetamine, ketamine, lanicemine, memantine, galantamine, donepe-zil, vortioxetine, intranasal oxytocin, omega-3, s-adenosyl-methionine, scopolamine anderythropoietin. From these articles, we determined that there are a number of promisingnew therapies, pharmacological agents or complementary medicines, but data are justemerging. Drugs and therapies targeting cognitive dysfunction in MDD should prove effectivein improving specific cognitive domains and functioning, while ruling out pseudospecificity.& 2015 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction

Major depressive disorder (MDD) is a highly prevalent anddisabling psychiatric disorder ranked as the first leading

o.2014.12.004CNP. All rights reserved.

r Program, Clinical Institutecelona, Villarroel, 170, 0803601; fax: +34 93 227 5795.s (E. Vieta).

, B., et al., Cognition as attp://dx.doi.org/10.1016/j.euron

cause of years lost due to disability (WHO, 2012; Catala-Lopez et al., 2013). This psychiatric condition is associatedwith higher rates of morbidity and mortality. In addition,the public health cost of this condition is quite high, in partdue to both the limited effectiveness and the long delay (upto 12 weeks) of conventionally antidepressant treatments(Kessler et al., 2003; Jick et al., 2004). Different studiesconclude that only 30–40% of patients that are optimallytreated with first line antidepressants achieve remission(Trivedi et al., 2006; Rush et al., 2011) and more than one

target in major depression: New developments. Europeaneuro.2014.12.004

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third of patients with depression are classified as treatment-resistant depression (TRD) (Souery et al., 2006), althoughthe rates may vary depending on the criteria used to defineTRD (Vieta and Colom, 2011; Posternak et al., 2004).

In this regard, most patients, including those consideredas good responders to antidepressant treatment, continuesuffering from residual subsyndromal symptomatology aswell as presenting persistent functional impairment, beingunable to achieving remission criteria. Some authors pointout that sleepiness, fatigue as well as executive dysfunc-tions constitute some of the most common residual symp-toms presented in this group of patients (Stahl and Grady,2003). Hence, the Diagnostic and Statistical Manual ofMental Disorders, Fifth Edition (DSM-5) included somecognitive symptoms, such as a diminished ability to thinkor concentrate, or indecisiveness, in the diagnostic criteriafor major depression, recognizing that cognitive impairmentis a core feature associated to this condition. Nonetheless,it should be remarked that cognitive difficulties may persistin patients even when depressive symptoms have abated ordisappeared, with small to medium effect sizes for memoryand medium to severe effect sizes for attention andexecutive function (Bora et al., 2013; Rock et al., 2013).

Despite the main cognitive dysfunctions in MDD are relatedto executive functions, attention, processing speed and mem-ory domains are also significantly impaired (Bora et al., 2013;Rock et al., 2013; McIntyre, 2013). These cognitive problemscompromise the individual's coping abilities and the likelihoodof successfully returning to work, which in turn exert a hugeimpact on functional recovery (Jaeger et al., 2006). In thissense, it is well known that cognitive function represents one ofthe best predictors of functional outcome in psychiatricpatients (Baune et al., 2010; Bonnin et al., 2014). For thisreason cognitive impairment emerges as a potential target forboth pharmacological and psychosocial treatments, with thefinal goal of improving functioning.

In order to deal with the aforementioned limitationsshown by current antidepressant drugs, the AmericanPsychiatric Association (APA) treatment guidelines recom-mend augmentation strategies added to antidepressanttreatment in those patients showing an inadequate resp-onse, since most of the proposed antidepressant monother-apy treatment strategies may not be effective enough toachieve full remission in a substantial group of patients.

So far, most of the widely prescribed antidepressantsagents target the aminergic system, however, evidencesuggests that depression is also associated with alterationsin other neurotransmitter systems (such as glutamatergictransmission), as well as to a loss of synaptic plasticity incircuits involved in regulating mood and emotions (Sanacoraet al., 2008; Kavalali and Monteggia, 2012). Therefore, itseems that the complexity of MDD entails more than themonoaminergic dysregulation. Currently, there is an incre-asing interest in the role of glutamatergic neurotransmittersystem in the pathophysiology of mood disorders and thedevelopment of novel and rapid-acting antidepressantdrugs. Additionally, there is an urgent clinical need fornew treatments that target cognitive enhancement sincemost current antidepressant medications have no directpro-cognitive effects – only indirect effects mediatedby mood improvement. In this line, the conventional anti-depressants available so far seem not to have enough robust

Please cite this article as: Solé, B., et al., Cognition as aNeuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euron

procognitive effects (McIntyre, 2013). The seroto-ninergic-noradrenergic reuptake inhibitors (SNRIs) seem tohave a better cognitive profile than serotonin reuptakeinhibitors (SSRIs) (Herrera-Guzman et al., 2009). Nonetheless,Baune and Renger, in a preliminary study, found that cognitiveeffects of SSRIs and selective serotonin reuptake enhancers(SSREs) were similar. They also reported that SSRIs cognitiveeffects were superior to those observed in the group ofpatients treated with tricylic antidepressants (Baune andRenger, 2014).

This systematic review focuses on those studies aimed toassess the cognitive effects resulting from both the combinationof different pharmacological agents and current antidepres-sants, as well as monotherapy, in MDD. Although our main focusof interest are objective cognitive measures, we have includedsome studies using subjective cognitive measures if the studywas considered of clinical relevance for testing new compoundsthat may influence cognitive variables. Even so, it is necessaryto keep in mind the distinction between self-reported/objec-tive cognitive measures given that the relationship betweenthem in patients with affective disorders is controversial andseveral studies have found that these variables are notassociated to a great extent (Svendsen et al., 2012). As Rosaand colleagues pointed out, probably, cognitive complaints arereferred to subjective experience of general cognitive problemsthat are not well characterized when reported by patients(Rosa et al., 2013).

2. Experimental procedures

To identify relevant studies, we performed a PubMed search of newtreatments for cognitive dysfunction in human studies with majordepressive disorder until March 2014, using the following keywords:“depression” or “major depression” cross-referenced with “cogni-tion” or “cognn”. The same keywords were cross-referenced withdifferent pharmacological agents which were considered that couldinfluence cognitive function as well as new agents that were foundin articles reviewed, such as: “aniracetam”, “bitopertin”, “DHEA”,“D-cycloserine”, “donepezil”, “D-serine”, “dextromethorphan”,“encelicline”, “erythropoietin”, “galantamine”, “GLYX-13”, “intra-nasal oxytocin”, “ketamine”, “lixdexamfetamine”, “lanicemine”,“lurasidone”, “memantine”, “metyrapone”, “mifepristone”, “MK-0657”, “modafinil”, “n-acetyl-cysteine”, “NRX-1047”, “omega-3”,“pramipexole”, “propofol”, “riluzole”, “rivastigmine”, “s-adenosylmethionine”, “ropinirole”, “sarcosine”, “scopolamine”, “tamoxi-fen”, “traxoprodil”, “vilazodone”, “vortioxetine”. Complementingthe database search, pertinent review articles and reference listsfrom identified articles were hand-searched for additional studieseligible for inclusion in this review not previously identified.

The inclusion criteria for studies were the following:

1.

taeur

Studies conducted on humans where participants were adultswith diagnoses of MDD.

2.
Exploring changes in cognitive functions as primary or secondaryoutcome.
3.
A randomized, or quasi-randomized controlled trial or an openstudy assessing any cognitive measure or social cognition.
4.
English language original articles.The exclusion criteria were:
1.
Preclinical studies (such as animal studies).
2.
Studies with participants with a diagnosis of depression
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3Cognition in major depression

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secondary to other illness (i.e. post-stroke depression, schizo-phrenia, bipolar disorder, or any neurological disease such asmultiple sclerosis, dementia or Parkinson disease).

3.
Case-report studies.
Following the inclusion and exclusion criteria, 26 studies provid-ing data from pharmacological trials on cognitive function indepressed patients were found and were included in this review.We group the compounds into one section with compounds thatmight have a potential procognitive effect based on their neuro-biological mechanism and other section with compounds that exertan antidepressant effect with different profile of cognitive effects.The main findings of these original studies are reviewed below anddata extracted from them are illustrated in a table (see Table 1),gathering the following information: (a) pharmacological agent;(b) name of the first author and year of publication; (c) core samplecharacteristics (sample size, distribution); (d) cognitive measures asprimary or secondary outcome; (e) randomized or not randomizedstudy; (f) double-blind or not; (g) main neurocognitive findings; and(h) neurocognitive tests employed.

3. Results

3.1. Compounds with potential procognitiveeffect

3.1.1. ModafinilModafinil is an agent with stimulant-like properties, withoutthe abuse and dependence potential of stimulants. Thisdrug obtained the Food and Drug Administration approvalfor treating excessive sleepiness in narcolepsy as a wake-promoting agent. Modafinil exerts a multimodal actiontargeting several neurotransmitter systems (such as, cate-cholaminergic, serotonergic glutamatergic, gamma amino-butyric acid, orexin and histaminergic systems) (Minzenbergand Carter, 2008). Regarding the orexinergic and histami-nergic effects, they seem to be related with the alertnessimprovement in sleep disturbances, whilst the noradrener-gic action may be more associated with the cognitive-enhancing effects (Muller et al., 2004). Modafinil hasdemonstrated potential procognitive effects in healthyvoluntaries and it has been investigated in some clinicalpopulations (Minzenberg and Carter, 2008). Nowadays,modafinil is considered as an effective augmentation strat-egy for both acute unipolar or bipolar depressive episodes(Goss et al., 2013). However, with regard to its procognitiveeffects in patients with major depression, only an 4-weekopen-label study has been published some years ago(DeBattista et al., 2004). The study enrolled 35 patients,with a history of major depression with partial response on astable therapeutic dose of an antidepressant treatment,who received modafinil as an augmentation strategy. Con-cerning neuropsychological assessment a battery was admi-nistered assessing attention, visuomotor processing speed,working memory and executive functions, where only theStroop Interference test scores showed a significant impr-ovement from baseline to endpoint. Authors concluded thatmodafinil administration did not appear to adversely affectneurocognition, in fact, it may even improve some cognitivefunctions.

lease cite this article as: Solé, B., et al., Cognition as aeuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euron

Hence, further research focusing on analyze the procog-nitive effects of this pharmacological treatment in unipolardepression may be useful.

3.1.2. MemantineMemantine is a noncompetitive, voltage-dependent NMDA-receptor antagonist approved for the treatment of moder-ate to severe Alzheimer disease. The modulation of gluta-mate neurotransmission seems to be associated withantidepressant response and some studies have demon-strated that memantine may exert a positive impact onmood regulation (Sani et al., 2012). Memantine have alsobeen reported to have effects on the monoamine system,specifically on the serotonergic system (Johnson andKotermanski, 2006). Overall, despite interesting preclinicaldata, results concerning the use of memantine for thetreatment of major depression are not encouraging due todiscrepancies from the different studies (Ferguson andShingleton, 2007; Zarate et al., 2006a, 2006b). A rando-mized double-blind trial, which failed to demonstrate abenefit of memantine as augmentation antidepressantstrategy, gathered cognitive variables as secondary out-comes, although, as far as we know, the results have notbeen published yet (Smith et al., 2013).

The co-occurrence of alcohol dependence with MDD iscommon and the pharmacological approach to this comorbidcondition is still difficult and controversial (Kessler et al.,1997; Nunes and Levin, 2004). It is well known that alcoholacts on NMDA glutamate receptors and memantine mayhave neuroprotective properties that may be beneficialagainst the neurotoxic effects of alcohol use (Krystalet al., 2003b). Muhonen and co-workers compared escita-lopram versus memantine in a group of comorbid patients ina randomized double-blind trial in order to examine theefficacy of these compounds with regard to depression andcognitive functioning among other variables (Muhonenet al., 2008). Both treatments reduced depressive sympto-matology suggesting a potential efficacy of escitalopramand memantine for alcohol dependent depressed patients,however, with regard to neurocognitive functions, neithersignificant changes during the study period nor differencesbetween groups were observed.

3.1.3. GalantamineGalantamine is a cholinergic agent, a relatively weakacetylcholinesterase inhibitor and potent nicotinic receptormodulator. Due to its additional allosteric potentiatingeffects at nicotinic receptors, it has been suggested thatthis drug also affects other neurotransmitter systems suchas monoamines, glutamate, and γ-aminobutyric acid(GABA). Additionally, some animal models of psychiatricdisorders (not tested in behavioral models of depression)have shown that muscarinic receptor activation throughincreased brain acetylcholine levels appears to mediate, atleast in some extent, anti-psychotic effects and theimprovement of cognitive dysfunction (Ago et al., 2011).

With regard to this drug, only two randomized, double-blind placebo-controlled trials have been conducted andboth studies failed to demonstrate a significant benefit ofgalantamine augmentation of antidepressants in cognitivefunctioning when compared to placebo (Holtzheimer et al.,





Table 1 Main characteristics of studies.

Pharmacologicalcompounds

Author Subjects Primary/Secondaryoutcomemeasure

Randomized Double-blind

Main finding Cognitive measures

Compound with potential procognitive effectModafinil DeBattista et al. (2004) MDD with partial

response=31Secondary – – Significant improvement in the

Stroop Interference Test(executive function) was seenat 4 weeks, as an adjunctivetreatment of depressedpatients.

CWST; WAIS-III Letter Number,Digit Span; TMT-A, TMT-B.

Memantine Muhonen et al. (2008) Memantine=29Escitalopram=29(MDD+Alcoholdependence)

Primary √ √ No cognitive changes in bothgroups.

CERAD; MMSE

Galantamine(GLTM)

Matthews et al. (2013) GLTM=12Placebo=18(MDD; BDdepressed type;SZA depressedtype)

Primary √ √ GLMT may be protectiveagainst impairment inretention of new learningduring ECT. The GLTM groupscored significantly higher atdischarge than did the controlgroup for the Delayed MemoryIndex.

RBANS; 3MS; WASI (vocabulary,matrix reasoning)

Holtzheimer et al. (2008)(pilot, proof-of-concept study)

GLTM=19Placebo=19(older adults)

Coprimary √ √ Authors failed to demonstratea benefit of GLTMaugmentation ofantidepressant medication inolder adults. Both groupsshowed improvement incognitive functioning overtime, but there was nostatistically significant groupby time interaction.

RBANS; MMSE

Elgamal and MacQueen (2008)(pilot study)

GLTM=10Placebo =10 MDD(not in an acuteepisode)

Coprimary √ √ Patients had a numericimprovement on cognitivemeasures although there wereno statistically significantdifferences.

CVLT; TMT-A, TMT-B; Ruff 2 and7 Selective Attention Test;Digit Span Test; DSST; COWAT

Matthews et al. (2008) (pilotstudy-ECT)

GLTM=9 NoGLTM=8(consecutive ECT

Coprimary � � GLTM may reduce cognitiveimpairment during ECT,especially with regards to newlearning.

3MS

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patients: MDD,BD, SZA)

Donepezil Pelton et al. (2008) (pilot studyPhase A: Open AD treatment/Phase B: Donepezil vs placebo/Phase C: Extended opendonepezil)

Donepezil=12Placebo=9(elderlydepressed,cognitiveimpaired)

Primary √ √ Patients with donepezil showedimprovement in memory.

BSRT; digit symbol WAIS-III;TMT-A, TMT-B; CFL

Reynolds et al. (2011) (Open ADtreatment with supportivedepression care managementto establish eligibility for(b) the randomized, placebo-controlled maintenance phaseof treatment (2 years))

Donepezil=67Placebo=63(Cognitivelynormal=73/MCI=57) (elderly)

Primary √ √ Whether donepezil should beused as augmentation in themaintenance treatment oflate-life depression dependsupon a careful weighing of risksand benefits in those with MCI.Donepezil appears to have noclear benefit in cognitivelyintact patients, for preventingprogression to MCI/dementia orrecurrence of depression.

TMT-A, TMT-B; Digit Symbol,Block Design; GroovedPegboard; Modified ROFC;Simple Drawings; BNT; Spot-the-Word; Letter Fluency;Animal Fluency; LogicalMemory; CVLT; Stroop NST;Executive Interview; WCST

Vortioxetine McIntyre et al. (2014) VRTX 10 mg=195VRTX 20 mg=207Placebo=196

Primary √ √ Vortioxetine significantlyimproved objective andsubjective measures ofcognition. Their effects werelargely independent of itseffect on improving depressivesymptoms.

DSST; RAVLT; TMT-A,TMT-B;Stroop; SRT; CRT; PDQ

Katona et al. (2012) VRTX=156Duloxetine=151Placebo=145(elderly MDD)

Secondary √ √ Patients showed a positiveeffect compared to placebo inprocessing speed and verballearning and memory.

MMSE; RAVLT;DSST

Erytrophoietin(EPO)

Miskowiak et al. (2010) EPO=10Placebo=9

Secondary √ √ EPO modulates the neural andcognitive processing ofemotional facial expression indepressed patients.

fMRI paradigm of facialexpression recognition

Miskowiak et al. (2014) EPO=18Placebo=21(TRD)

Secondary √ √ Sustained enhancement inmemory recall and inrecognition task after EPOrepeated administrations asadjunctive treatment.

RAVLT

Compounds with antidepressant effect and different profile of cognitive effectsLisdexamfetamine

(LXD)Madhoo et al. (2014) LXD=60

Placebo=59 (MDDPrimary √ √ LDX augmentation significantly

improved executive functionBRIEF-A

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Table 1 (continued )

Pharmacologicalcompounds

Author Subjects Primary/Secondaryoutcomemeasure

Randomized Double-blind

Main finding Cognitive measures

+executivedysfunction)

and depressive symptoms inpatients with mild MDD.

Ketamine Shiroma et al. (2014) TRD=13 Coprimary – – Significant improvements invisual memory, simple andworking memory after sixketamine infusions. However,neurocognitive changes wereaccounted for by improvementin the severity of depressivesymptoms. Performance inattention at baseline was asignificant predictor of changein severity of depressivesymptoms.

CogState battery

Diamond et al. (2014) TRD=28 (3infusions= 15;6 infusions=13)(unipolar orbipolar patients)

Secondary – – Ketamine was not associatedwith memory impairment after3 or 6 ketamine infusions

AMI-SF; AFT; Story Recall test;ECT-MQ

Murrough et al. (2014) TRD=25 Post-hocsubanalysisPrimary

� � Potential baselineneurocognitive predictor ofketamine response. An inverserelationship between cognitiveeffects of ketamine andantidepressant efficacy.

Estimated premorbid IQ;current IQ; MATRICS (MCCB).

Rasmussen et al. (2014) Ketamine=21Methohexital=17Non-psychoticMDE (unipolar orbipolar)

Coprimary √ √ No significant differences incognitive outcomes betweenthe two groups. Ketamine didnot diminish the cognitive sideeffects.

MMSE

Yoosefi et al. (2014) Ketamine=15Thiopental=14

Secondary √ √ Ketamine during ECT was welltolerated. Patients mayexperience better cognitiveperformance when comparedwith thiopental. Persistency ofthe beneficial effects.

MMSE (before first ECT, 48after–before second session-,3 to 7 days after the 6th ECT,1 month after the 6th)

Loo et al. (2012) Ketamine=22Placebo=24

Primary √ √ The addition of ketamine tothiopentone during anesthesia

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(unipolar orBipolar patients)

for ECT did not decreasecognitive impairment.

CFT; HVLT; COWAT; SDMT; Woodcock Johnson Cross-Out Test;AMI-SF; NART

Intranasal oxytocin(OT)

Macdonald et al. (2013)(crossover study)

17 depressedmale (OT orplacebo)

Secondary √ √ OT improved performance onthe RMET (social cognition).

RMET

Pincus et al. (2010) (crossoverstudy)

Unmedicateddepressed=8Healthycontrols=9 (OT orplacebo)

Secondary √ √ OT has a differential effectupon the brain of depressed orhealthy subjects in a mentalattribution task and enhancescognitive and emotionalappraisal.

RMET; fMRI

Omega-3 Rogers et al. (2008) EPA+DHA=96Placebo=94(individuals withdepressed mood)

Secondary √ √ No evidence effects ofsupplementation on anymeasure of cognitive function.

Simple RT; lexical decision;digit-symbol substitution WAIS-III; impulsivity; N-Back

Antypa et al. (2012) Omega-3=36Placebo=35(recovereddepressedindividuals)

Coprimary √ √ Only small effects of omega-3supplementation on aspects ofemotional decision-making, noton other cognitive functions.

Affective Go/No-Go task;Attentional Go/No-Go task; 15Word test; Facial Expressionrecognition task; Decision-making (gambling) task

S-adenosylmethionine(SAME)

Levkovitz et al. (2012) SAME=27Placebo=19

Post-hocsubanalysisprimary

√ √ Adjunctive SAME may beeffective in improving memory-related symptoms in TRDpatients.

CPFQ

Scopolamine Furey and Drevets (2006)(crossover study)

Placebo/scopolamine=10Scopolamine/placebo=9 (MDDor BD)

Notspecified

√ √ The effect of scopolamine inselective attention task wasrelatively small.

Computerized selectiveattention task

MDD=Major Depressive Disorder; MDE=Major Depressive Episode; TRD=Treatment Resistant Depression; IQ= Intelligence Quotient; BD=bipolar disorder; SZA=schizoaffective; MCI=MildCognitive Impairment; CWST=Color Word Stroop Test; WAIS=Wechsler Adult Intelligence Test; TMT=Trail Making Test; MATRICS (MCCB)=Matrics Consensus Cognitive Battery; MMSE=MiniMental State Examination; CFT=Medical College of Georgia Complex Figure; HVLT=Hopkins Verbal Learning Test; COWAT=Controlled Oral Word Association Test; SDMT=Symbol DigitModalities Test; AMI-SF=Autobiographical Memory Interview-shortform; AFT=Autobiographical Fluency Task; ECT-MQ=ECT Memory Questionnaire; NART=National Adult Reading Test;DSST=Digit Symbol Substitution Test; RAVLT=Rey Auditory Verbal Learning Test; SRT=simple reaction time task; CRT=choice reaction time task; PDQ=Perceived Deficits Questionnaire;RBANS=Repeatable Battery for the Assessment of Neuropsychological Status; 3MS=Modified Mental Status Examination; WASI=Wechsler Abbreviated Scale of Intelligence;CVLT=California Verbal Learning Test; CERAD=consortium to Establish a Registry for Alzheimer's Disease cognitive test battery; BRIEF-A=Behavior Rating Inventory of ExecutiveFunction-Adult Version; BSRT=Buschke Selective Reminding Test; CFL=verbal fluency; Modified ROFC=Rey-Osterreith Figure Copy; BNT=Boston Naming Test; Stroop NST=StroopNeuropsychological Screening Test;WCST=Wisconsin Card Sorting Test, WMS=Wechsler Memory Scale; BVMT-R=Brief Visual Memory Test-Revised; SST=Syndrome Short Test; STGI=ShortTest For General Intelligence; NCT=Zahlen-Verbindungs-Test; REP=nonvalidated Reproduction List with Concept Clusters; VL=nonvalidated Vocabulary List; RMET=Reading the mind inthe eyes test; CPFQ=self-rated cognitive and physical symptoms questionnaire.

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2008; Elgamal and MacQueen, 2008). Some considerationsneed to be mentioned concerning these studies. First, bothstudies used small samples. In addition, the first study onlyenrolled older adults, whilst the latter included patientsranging from 40 to 80 years. Another limitation is related tothe high discontinuation rate observed in the galantaminegroup from the study carried out by Hotzheimer. Hence, itmay be useful to test galantamine in a homogeneous sampleof young adult patients in order to test the efficacy of thisdrug enhancing, since late-life depression could implyspecific pathophysiological characteristics that would beoften related to prodromal symptoms of dementia.

Besides, it should be mentioned that Galantamine has alsobeen evaluated as a pharmacological strategy to mitigatecognitive side effects derived from ECT (Matthews et al.,2013). This study which included MDD, bipolar and schizoaf-fective patients, reported that patients who received galan-tamine were protected against impairment in retention ofnew learning during ECT. Replications with larger and morehomogeneous samples are needed to reinforce these findings.As far as we know, no more clinical trials of galantamine arecurrently being carried out.

3.1.4. DonepezilDonepezil is a longer acting, orally available, reversiblecholinesterase inhibitor, indicated for treating mild tomoderate Alzheimer disease.

Regarding this pharmacological agent, only two rando-mized, double-blind, placebo-controlled studies have beenpublished with neurocognition as a primary outcome. Bothstudies enrolled patients with late-life depression and someof them presenting with Mild Cognitive Impairment (MCI). Itis worth to mention that there is an increased likelihood ofconversion to dementia in patients with co-occurrence,which is highly prevalent.

In the first pilot study, where all the depressed older adultswere cognitive impaired, a short-term improvement in theverbal memory domain was found in patients treated withadjunctive donepezil to antidepressant treatment (Peltonet al., 2008). These results raise the possibility that combinedtreatment may be considered in patients when cognitiveimpairment and depression co-occurs, since cholinergic neuro-transmission may be involved in cognitive dysfunction asso-ciated with depression. The second one was conducted withelderly outpatients. In this study authors included, on one hand,a group of non-cognitively affected patients to test whetherdonepezil protects against MCI and, on the other hand, patientswith MCI in order to test for cognitive improvement ondonepezil (Reynolds III et al., 2011). Authors found a temporarypositive effect of donepezil on global cognition, executivefunctions and memory. Nonetheless, some issues should betaken into account: (1) donepezil as an augmentation treat-ment also led to higher rates of recurrent depressive episodesand (2) do not appear to clear benefit for preventing progres-sion to dementia or recurrence of depression in cognitivelyintact remitted patients and, finally, (3) in the case of MCIpatients, the addition of donepezil seems to prevent dementiabut it could also increase the risk of depressive relapse.According to these observations, authors suggested that itmay be necessary to weigh up risks and benefits for thecombined treatment with donepezil in patients with MCI.


Therefore, the available evidence does not suggest aclear benefit for donepezil as an adjunctive therapy toantidepressants for cognitive enhancement for depressedolder patients. Currently, a clinical trial (NCT01658228) isbeing carried out aiming at assessing a large sample ofcognitively impaired depressed patients with combinedtreatment of antidepressant and donepezil as cognitiveenhancer treatment.

Therefore, it would be interesting to test donepezil inyoung adult depressed patients without MCI.

3.1.5. VortioxetineVortioxetine (Lu AA21004) is a new multimodal antidepres-sant, acting via the combination of a direct effect onreceptor activity and serotonin (5-HT) reuptake inhibition.It is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist, anda 5-HT transporter inhibitor. First, Katona and colleaguesdemonstrated the efficacy of vortioxetine on both depres-sive symptoms and cognitive function in elderly depressedpatients (Katona et al., 2012). In this study, where cognitionwas considered as a secondary efficacy outcome, patientson vortioxetine showed a positive effect compared toplacebo group in processing speed, verbal learning andmemory. Recently, another group of authors has extendedthe investigation in adult MDD patients with cognition as aprimary outcome (McIntyre et al., 2014). Patients wererandomized to two different doses of vortioxetine orplacebo. The improvement of vortioxetine was evident onthe both primary outcomes measures of attention andprocessing speed (DSST, Digit Symbol Substitution Test) aswell as verbal learning and memory (RAVLT, Rey AuditoryVerbal Learning Test). The improvement was also noted onother secondary measures of cognition. The authors sug-gested that both vortioxetine doses significantly improvedobjective and subjective measures of cognition indepen-dently of its effects on improving depressive symptoms,based on the results of a path and subgroup analyses wherethe mood improvement that patients showed simulta-neously was controlled for. Therefore, it seemed reasonableto assume that these antidepressant and procognitiveeffects work via distinct mechanisms. However, it is worthto mention that a path analysis has its own limitations.

Probably, some recently completed clinical trials, orother ongoing studies, will provide new data about thetruly direct procognitive effects of vortioxetine in the nearfuture (NCT01564862, NCT01607125, NCT02279953, NCT02272517, NCT02279966). Some of these studies, which recruitsubjects remitted from depression and healthy controls, willhelp to explore if vortioxetine will lead to improvedcognitive function in the absence of depression, that is,with a direct procognitive effect.

3.1.6. ErythropoietinErythropoietin (EPO), also known for its effects on bloodcells and as a treatment of anemia, is also produced in thebrain. Results from both animal models and neuropsychia-tric patients, suggested that this compound presents neuro-trophic and neuroprotective effects and would improvecognitive functioning (Siren et al., 2009). Indeed, it hasbeen reported that EPO would present antiapoptotic,






antioxidant and anti-inflammatory properties and preclini-cal studies have shown that these actions contribute to anantidepressant-like effects and improvement of cognitivefunction together with enhanced hippocampal plasticity andlong-term potentiation.

Miskowiak and colleagues demonstrated that a single highdose of EPO enhances memory and executive functions(Miskowiak et al., 2012). They also found that EPO mod-ulates the neural and cognitive processing of emotionalfacial expression in depressed patients (Miskowiak et al.,2010). Later, in a randomized double-blind placebo-con-trolled study with TRD patients, authors found a sustainedimprovement in verbal learning and memory after repeatedEPO administrations as adjunctive treatment (8 weeklyinfusions of 1 ml recombinant EPO—doses of 40,000 UI)versus saline infusions (Miskowiak et al., 2014). AlthoughEPO did not demonstrate superiority over placebo regardingdepressive symptoms in the Hamilton Depression RatingScale (HDRS), which was the primary outcome, patientstreated with EPO showed a reduction in other relatedmeasures such as the Beck Depression Inventory (BDI).Moreover, when some patients who showed unexpectedsymptom improvement before trial start were excludedfrom exploratory analyses, a higher clear effect on primaryoutcome was found. Concerning cognitive function, authorssuggested that EPO has direct, mood-independent effectson verbal memory. Interestingly, there were no correlationsbetween the changes in red blood cells and memory and thememory-effect persisted after normalization of red bloodcells. This suggests that the cognitive effects were at leastpartially independent of hematological actions.

Further studies with larger samples of TRD to analyze theantidepressant effects of EPO are needed, since the latterstudy was not enough empowered to detect a clinicallyrelevant difference in the primary outcome variable (HDRS).

The clinical application of EPO is limited by its hemato-poietic actions, which increase the risk of hypertension andblood clotting, so a careful safety monitoring would benecessary (Miskowiak et al., 2014). Other disadvantages ofEPO are related with its unclear potential risk of promotingmalignant tumor growth as well as the intravenously orsubcutaneously delivery. However, research focused ondeveloping derivates of EPO without hematopoietic activityand other alternative administration (i.e. the intranasalEPO) routes are being carried out (Miskowiak et al., 2012).

3.2. Other compounds with antidepressant effectand different profiles of cognitive effects

3.2.1. LisdexamfetamineLisdexamfetamine Dimesylate (LDX) is a pharmacologicallyinactive prodrug of D-amphetamine which has beenapproved for treating attention-deficit/hyperactivity disor-der (ADHD). It modulates dopamine and norepinephrinesystems, which in turn are critical to maintain executivefunctions mediated by the prefrontal cortex (Arnsten andLi, 2005). In addition, this drug administered as an augmen-tation therapy to antidepressants has demonstrated toeffectively reduce depressive symptomatology in poorresponders to escitalopram (Trivedi et al., 2013).


Recently, Madhoo and colleagues evaluated the efficacyof LDX augmentation of selective serotonin reuptake inhi-bitor (SSRI) monotherapy in a randomized, double-blind,placebo-controlled, parallel-group study for treating execu-tive dysfunction in partially or fully remitted MDD patientswith self-reported executive dysfunction (Madhoo et al.,2014). In this study, the primary outcome was the change inthe Self-report BRIEF-A from baseline to endpoint. Secon-darily, changes in the Informant Report BRIEF-A and neu-ropsychological test performance were also analyzed. Inaddition to an improvement of residual depressive sympto-matology, patients treated with LDX displayed a greaterexecutive improvement in the two BRIEF-A reports whencompared to placebo, however the improvement in theneuropsychological tests did not achieve statistical signifi-cant levels. Although these results should be interpretedcautiously since these derived from subjective cognitivemeasures, these are of clinical relevance to be mentionedsince is the only one study that assesses cognitive effects ofLDX in depression. Future studies analyzing the potentialprocognitive profile of LDX augmentation treatment usingobjective cognitive measures are needed.

3.2.2. KetamineKetamine is a high-affinity, noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist that hasdemonstrated a rapid antidepressant effect even withinhours in patients with TRD. In addition, ketamine exerts arobust impact on reducing suicidal ideation which mightoccur independently of its antidepressant effect (Blier,2013). This drug, usually used as an anesthetic agent, hasthe disadvantage of inducing negative neurocognitiveeffects as well as transient dissociative and psychotomi-metic effects at subanesthetic doses. However, it should beremarked that, at the doses usually used in depressedpatients, most of them generally resolved within minutesor first hours following drug cessation. Some studies haveassessed the clinical utility of ketamine as an anestheticagent for electroconvulsive therapy (ECT) with the interestthat it could improve the antidepressant efficacy of ECT andsome of them have analyzed if ketamine could exert aprotective role against the neurocognitive side effects ofECT, with inconsistent findings. The rationale for thesestudies is based on that one postulated mechanism forcognitive impairment is excitotoxic damage related toexcessive glutamatergic transmission through the NMDAreceptor during ECT. In this regard, several lines of evidencesuggests that ketamine, an NMDA antagonist, may haveneuroprotective effects, including in a ECT treatmentcontext (Hudetz and Pagel, 2010; MacPherson and Loo,2008), supported at the same time by indirect and briefpreliminary clinical reports (Krystal et al., 2003a; McDanielet al., 2006).

On one hand, in a randomized double-blind clinical trial,Yossemi and co-authors found a better cognitive perfor-mance in patients receiving ECT with ketamine whencompared to patients from the thiopental group, whichremains stable even one month later (Yoosefi et al., 2014).In contrast, Rasmussen and colleagues suggested thatketamine did not diminish the cognitive impairment sinceno significant differences between depressive patients





B. Solé et al.10

receiving ketamine or methohexital were found (Rasmussenet al., 2014). Similarly, Loo and colleagues also reportedthat adding ketamine or placebo to thiopentone did notreduce cognitive side effects (Loo et al., 2012). Never-theless, it is difficult to draw conclusions regarding the useof ketamine in ECT since conflicting results may be relatedto methodological differences (e.g. ketamine doses, anes-thetic combinations, type of ECT administration—bilateral/unilateral, time of assessment as well as sample character-istics—bipolar/unipolar depression). Furthermore, ketamineis also associated with difficulty to treat patients in aclinical setting, not in a hospital (Sanacora et al., 2014).

Moreover, recently Murrough et al. (2014) assessedneurocognitive functioning in a group of 25 TRD patientsbefore and after a 40 min intravenous infusion of ketaminein an open-label fashion. The authors found that thebaseline neurocognitive performance may be a predictorof ketamine response (lower levels of neurocognitiveperformance were associated with an increased antide-pressant response). They also reported an inverse correla-tion between the altered cognitive effects of ketamine andits antidepressant efficacy, that is, when negative cogni-tive side effects occur following ketamine, it carried lowerresponse rate. In this study, ketamine was not associatedwith an overall significant neurocognitive decline; only aminimal impairment in memory recall was observed afteradministration of the drug. Afterwards, when patientswere categorized based on presence/absence of dimin-ished cognitive performance following the ketamine adm-inistration, patients who had negative cognitive effectswere more associated with nonresponse to the antidepres-sant effects of ketamine. Similarly, two studies did not finda cognitive decline in TRD patients after several serialinfusions (three or six) of ketamine (Shiroma et al., 2014;Diamond et al., 2014), neither in a 4-week follow-up.Moreover, Shiroma and colleagues found an associationbetween a baseline attention performance and an anti-depressant improvement after a series of ketamine infu-sions (Shiroma et al., 2014). It would be necessary to assessmore long-term neurocognitve effects of ketamine admi-nistered at low doses to evaluate the safety of ketamine onneurocognition to be considered as a potential treatmentfor TRD (Murrough et al., 2014).

Moreover, some of the aforementioned studies assessedcognition using a simple cognitive measure (the MMSE) andonly a few studies have analyzed the neurocognitive effectsof Ketamine as primary outcome by means of a comprehen-sive neuropsychological battery.

We expect that some of the ongoing clinical trials(NCT01700829, NCT01881763, NCT01260649, NCT02012335,NCT01441505) would give further evidence of the role ofketamine in the treatment of depression and its potentialneuroprotective effects.

3.2.3. LanicemineLanicemine, also known as AZD6765, is a low-trappingN-methyl-D-aspartate (NMDA) channel blocker which mightbe a potential novel glutamatergic-based therapeutics forthe treatment of refractory affective disorders withoutpresenting the acute psychotomimetic, dissociative sideeffects attributed to ketamine.


Results from different studies confirm the antidepressanteffect of this pharmacological agent as an adjunctivetreatment (single or repeated doses) in both patientsexperiencing a moderate-to-severe MDD and TRD. In thissense, Zarate and colleagues found a rapid antidepressanteffect of lanicemine in TRD patients with a single intrave-nous dose of 150 mg of lanicemine but with a short-prolonged action (Zarate et al., 2013). In contrast, theyfound a more robust and sustained effect of ketamine inTRD patients in a previous study (Zarate et al., 2006a).

So far, no clinical meaningful effects on cognitive vari-ables have been reported concerning the use of lanicemine.A phase IIA, double-blind, randomized study conducted inTRD patients with single doses of 100 mg of laniceminewhere cognitive variables were assessed as secondary out-comes did not found differences between the two arms(lanicemine versus placebo) (Sanacora et al., 2014). Furtherstudies with this compound will be necessary to confirm thesupposed antidepressant efficacy of lanicemine as well as itslower cognitive side effects when compared to ketamine.Unfortunately, lanicemine's clinical development has beenrecently stopped after a failed phase III study.

3.2.4. Intranasal oxytocinIt has been observed that oxytocin, a neuropeptide, isinvolved in social–emotional functioning, such as emotionrecognition, memory for faces, interpersonal trust, etc. andin promoting prosocial behaviors (Ellenbogen et al., 2013).Despite many questions still remains to be answered abouthow intranasal oxytocin (OT) acts, in recent years anincreased interest on OT and its impact on the treatmentof several clinical populations has emerged (e.g. autism,social anxiety, postnatal depression, obsessive-compulsiveproblems, schizophrenia, borderline personality disorderand post-traumatic stress). The doses of OT administeredin studies assessing OT could range from 15 IU to more than7000 IU, and also included a great variety of outcomes (forexample, related with social cognition, emotional recogni-tion, social behaviour, etc.). However, some authors havepointed out that, at the moment, the pharmacotherapeuticuse of OT seems less effective in several psychiatricdisorders, being the individuals diagnosed with autism orrelated disorders who might profit most from the adjunctapplication of OT (Bakermans-Kranenburg and van, 2013).

In a pilot study assessing the OTeffects in male depressedpatients in a psychotherapeutic setting, authors found thatOT improved social cognition through the performance onthe Reading the Mind in the Eyes Test (RMET), a testdeveloped to assess emotional mental attribution (Macdonaldet al., 2013). To the contrary to what was expected, patients onOT, experienced increased levels of anxiety, but interpretedmore accurately the states of mind from visual facial cues thanplacebo group. Other authors studied the influence of a singledose of OT on functional brain activity using an fMRI paradigm,with a randomized double-blind crossover design, comparingunmedicated depressed females with matched healthy controlsubjects (Pincus et al., 2010). Obtained results suggest that OTacts in a different way in depressed patients and healthycontrols. The former showed an increased activation in primaryemotional circuits such as the cingulated and insula whencompared to healthy subjects. Moreover, depressed subjects






showed a slower speed of response when received OTwhereasthe healthy subjects presented faster reaction times. It shouldbe mentioned that oxytocin did not affect the accuracy ofresponses in either group.

Apart from that, in a study carried out with a sample ofuniversity students with high levels of depressive symptomswhich did not meet MDD criteria, the authors found that,those patients on OT presented more difficulties to inhibitthe processing of sad faces in a negative affective priming(NAP) task (Ellenbogen et al., 2013). This was an unex-pected finding for the authors since no global effect oninhibition has been proved concerning OT administration.However, other studies has demonstrated that OT effectsmay vary due to individual differences and on the context(Guastella and MacLeod, 2012; Bartz et al., 2011). Onepossible explanation to their results could be related to anincreasing empathy toward others.

The effect of OT has also been explored in other clinicalpopulations, such as mothers with postnatal depression andassessing sensitive parenting, with an improvement in therelationship between mothers and their infants (Mah et al.,2013).

3.2.5. Omega-3During the last few years, there has been a growing interestabout the benefits and practical use of long chain omega-3fatty acids since beneficial effects for mood disorders hasbeen described. In this sense, it has been suggested that alow dietary intake of them may be related with an increasedrisk for some psychiatric disorders, particularly for depres-sion. Levels of omega-3 polyunsaturated fatty acids (PUFAs)have been found to be depleted in MDD patients in an acuteepisode. For instance, DHA is associated with neural mem-brane stability and with serotonin and dopamine transmis-sion, which in turn has been traditionally linked todepression pathophysiology (Chalon, 2006).

A double-blind randomized controlled trial assessed theeffects of n-3 LCPUFA supplementation on mood and cogni-tion, as primary and secondary outcomes, respectively(Rogers et al., 2008). This study failed to provide anyevidence of positive effects on depressed mood or oncognitive domains (visual probe task, speed of informationprocessing, reasoning, impulsivity and working memory)among people with mild to moderate depression. It isnecessary to mention that this trial recruited patients fromgeneral population presenting depressed mood, althoughnone of them met criteria for major depression in a clinicalsetting neither followed any antidepressant treatment.These data comport with a meta-analysis carried out byAppleton and co-authors which showed a limited effect of n-3 long-chain polyunsaturated fatty acids on depressed mood(Appleton et al., 2006). However, a recent update meta-analysis by Appleton and colleagues supports the efficacy ofomega-3 on depressed mood but heterogeneity is still anissue to draw firm conclusions, as other authors also pointedout (Lin and Su, 2007). It seems that a distinguishing effectof PUFAs between patients diagnosed of depression andindividuals with depressed mood (without diagnosis) mayexist: there is some evidence suggesting a positive effect ofn-3 PUFA supplementation for the first group whereas thereis no evidence for the latter (Appleton et al., 2010).


Therefore, currently there is a growing debate about therole of PUFAs on depression.

Moreover, Antypa and colleagues have tested the effectsof n-3 PUFA supplementation on emotional informationprocessing and mood in remitted depressed patients in adouble-blind randomized design (Antypa et al., 2012). Theyfound a small effect of omega-3 supplementation on aspectsof emotional decision-making, however, they did not findany influence in other neutral cognitive domains such asattention and memory.

3.2.6. S-adenosyl-methionineS-adenosyl-methionine (SAME) is a naturally occurring mole-cule in all living human cells with an important role incellular metabolism which serves as methyl donor in cellularmetabolism (Mischoulon and Fava, 2002). Currently, it isalso considered as a dietary supplement. Clinical trials havedemonstrated that parenteral SAME monotherapy is superiorto placebo and comparable to tricyclic antidepressants intreating depressed patients (Papakostas, 2009). In a pre-liminary study, it has been also demonstrated to be effec-tive as an oral adjunctive treatment for depressed patientswith low response to antidepressant (Papakostas et al.,2010). Nevertheless, similarly to what happens to otheraforementioned agents, one of the main clinical limitationsstems from the route of administration, since there is littleevidence concerning oral administration.

Despite different potential mechanisms of action have beenproposed, it remains unclear how SAME exerts its antidepres-sant action. It has been hypothesized that when SAME may alterthe fluidity of neural membrane trough methylation of plasmaphospholipids, it would affect the activity of proteins thattransverse the membrane, among them the monoamine recep-tors and transporters (Mischoulon and Fava, 2002).

Regarding cognitive function, the group of Papakostasprovided preliminary evidence on the ability to improverecall information and a trend toward a greater enhance-ment in word-finding in depressed patients treated with oraladjunctive SAME based on subjective self-reports measures(Levkovitz et al., 2012). The authors administered the CPFQ(Massachusetts General Hospital Cognitive and PhysicalFunctioning Questionnaire), validated as a reliable measureof cognitive and physical symptoms of MDD, however, itrelays on patients' self-report. As far as we know, no morestudies have evaluated the cognitive effects of SAME inMDD, therefore, it would be necessary to confirm thesefindings by using a comprehensive neuropsychological bat-tery in studies specifically designed to assess the effects ofSAME on cognitive function.

3.2.7. ScopolamineAs mentioned earlier, it is well known that hypersensivity ofthe cholinergic system play a role in the pathophysiology ofdepression. In this regard, scopolamine, which is a muscari-nic cholinergic receptor antagonist, produces a rapid andlong-lasting antidepressant effect (Drevets et al., 2013). Inaddition to the antagonist effects at muscarinic receptors,it modulates other neurotransmitter systems such as thedopaminergic, serotonergic and the neuropetide Y, as wellas it seems to involve modulation of NMDA receptorfunction.





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Furey and Drevets assessed the role of the cholinergicsystem in selective attention in a pilot study with anintravenous administration of scopolamine hydrobromide.They hypothesized that selective attention wouldimprove under antimuscarinic agents treatment (Fureyand Drevets, 2006). However, no significant overallchanges in the attention task were found when patientson scopolamine were compared with those on placebo.Hence, scopolamine seems to have a small impact onattention.

To the best of our knowledge, no more studies haveassessed the effects of scopolamine in depressed patients.

4. Discussion

We provide a descriptive overview about the availableresearch on different pharmacological agents that mightinfluence cognitive functions in patients with a MDD, eitheras monotherapy or as an adjunctive treatment. Despite thehigh number of promising new therapies, current evidenceis insufficient to support any augmentation strategy as atreatment recommendation for cognitive symptoms inmajor depressive disorder. Most of the reviewed agentsrequire further investigation.

Modafinil is currently considered an effective augmenta-tion treatment for major depressive disorder, but theircognitive effects in MDD have still been understudied,whereas there is some evidence suggesting that modafinilimproves cognition in other psychiatric conditions (i.e.ADHD children and schizophrenia). The same occurs withlixdexamfetamine, which seems to be effective not onlyreducing depressive symptomatology in some populationsof depressed patients, but also improving self-reportedcognitive measures of patients. However, more studiesfocused on objective cognitive measures are needed inorder to confirm the potential procognitive effects oflixdexamfetamine.

At the moment, agents targeting the glutamatergic systememerge as a promising intervention for mood symptoms, since agrowing body of evidence implicates this system in thepathophysiology of depression. In addition, it should beremarked that NMDA receptors are also involved in executiveprocessing and learning/memory, among other cognitive func-tions. With regard to ketamine, several studies have studiedtheir cognitive side effects, for example, when administered asan anesthetic agent in ECT. Nevertheless, data indicating abetter cognitive profile of ketamine when compared to otheranesthetic agents is still limited and inconclusive. In the future,some ongoing clinical trials could help to elucidate thepotential cognitive effects of ketamine in ECT. Moreover, otherroutes of ketamine administration, as oral and intranasal, arecurrently being tested in TRD patients. Future randomizedplacebo-controlled studies with larger samples will be neededin order to determine the cognitive effects in a short ormedium-term of glutamatergic antagonist and, as some authorspointed out, it is necessary to examine if longer duration ofinfusions as well as higher doses could induce cognitive decline(Diamond et al., 2014). In fact, concerning safety, whereaslower doses of ketamine have been associated with neuropro-tection and neutotrophic effects, on the other side higher dosesof ketamine and longer duration of exposure have been


associated to neurotoxic effects and cognitive impairments.Therefore, more research is necessary before this can berecommended as a treatment.

Lanicemine might appear as an alternative pharmacologicaloption but the future of this drug is unclear given thediscontinuation of its clinical development in TRD. In view ofthe rapid antidepressant effect of ketamine, several newagents affecting the glutamate pathway are under investiga-tion, such as modulators of AMPA receptors, NMDA receptorsubunit GluN2B and metabotropic glutamate receptors(mGluRs). For instance, traxoprodil and MK-0657 are GluN2Bantagonists which have demonstrated efficacy in TRD(Preskorn et al., 2008; Ibrahim et al., 2012), although furtherstudies with larger samples are needed to support thesefindings. Moreover, as far as we know, no studies focused oncognitive effects of this group of agents in MDD have beenreported yet. Other compounds related to the glycine mod-ulatory site on the NMDA receptors, such as D-cycloserine andGLYX-13, have also led to a significant improvement indepressive symptomatology (Heresco-Levy et al., 2013;Burgdorf et al., 2013) and have great potential. In addition,due to the fact that mGluR seem to play a significant role indepression, some agents acting on them have been developed(i.e. MGS0039, LY341495, among others). In fact, one of them,the RO4432717, has shown positive effects on cognition insome preclinical models (Goeldner et al., 2013). Hopefully,the development of novel potential antidepressant treatmentstargeting this neural system in a near future provide us witheffective therapeutic tools not only for treating depression,but also with the cognitive impairment usually associated tothis clinical condition.

Data concerning potential cognitive benefits of meman-tine, galantamine and donepezil (all of them approved fortreating cognitive dysfunction in Alzheimer's disease) lacksubstantial efficacy as an augmentation treatment for MDD.Probably this fact has led few studies assessing cognition indepressed patients. Memantine, which also targets gluta-matergic system, has not demonstrated a clear efficacy indepression in RCT. On the other hand, the few existingstudies examining the cognitive performance of patientstreated with galantamine and donepezil were conductedwith older depressed adult patients and failed to demon-strate a clear cognitive benefit. While deficits in cholinergicfunction are related to the cognitive symptoms of depres-sion, several authors hypothesized that depressive patientsmay show a cholinergic hypersensitivity to depressogeniceffects of cholinoceptive agents (Dilsaver, 1986). To the bestof our knowledge, the effects of rivastigmine on thecognitive functioning of unipolar depressed patients havenot been evaluated.

Data derived from some clinical trials on scopolamine,another agent which acts on cholinergic system, suggestthat it could be considered as an effective adjunctivetreatment for patients with MDD. Only one study has sofar assessed the cognitive effects of scopolamine showing aminor impact on selective attention.

Vortioxetine is a promising new multimodal antidepres-sant which may improve cognitive function in depressedadults independently of its antidepressant effects (McIntyreet al., 2014). Several trials are currently ongoing to testthe precognitive effects of this compound in depressedpatients.






Antiglucocorticoid treatments are thought to attenuatedepressive symptoms in some diagnostic subtypes since thehypothalamic–pituitary–adrenocortical (HPA) axis dysregulationseems to play an important role on the pathophysiology ofdepression. Despite one might argue that these compoundscould improve cognitive functioning, no studies have evaluatedtheir cognitive effects, specifically in MDD patients. While theefficacy of mifepristone in depressed patients has been demon-strated in some small, double-blind, placebo-controlled studies,other studies failed to significantly separate mifepristone fromplacebo in depression (Schule et al., 2009). Furthermore,mifepristone seems to be more effective to treat psychosis inpsychotic depression than to have a consistent effect on coredepressive features. In a bipolar sample treated with theaforementioned drug, a spatial working memory improvementwas detected and this result was sustained at six weeks aftercessation of treatment (Watson et al., 2012). Whereas inbipolar disorder there are studies with positive results (Younget al., 2004; Watson et al., 2012; Dias et al., 2012), nopublished studies have assessed the cognitive properties ofmifepristone in major depressive samples. However, it shouldbe mentioned that, currently, there are some ongoing clinicaltrials with depressed patients which have been completed withnot yet published results. Other antiglucocorticoids have beenreviewed here (i.e. ketoconazole, metyrapone) but, as far aswe know, no studies have evaluated their cognitive effects ondepressed patients.

Apart from that, other augmentation strategies related todietary supplements, such as omega-3 and s-adenosylmethionine, are now being studied regarding their potentialeffects on cognition. Nevertheless, further studies will berequired to clarify their utility. Omega-3 seems to presentan effect improving emotional information processing(Antypa et al., 2012).

Similarly, intranasal oxytocin also could be implicated inemotional/social cognition. The inhibition of information withan emotional component may be related to the regulation ofnegative emotion, particularly, in depressed patients. A smallnumber of studies have addressed the effects of OT in clinicallydepressed patients. It is necessary to better understand howoxytocin influences cognition since it seems to be mediated bydifferent factors and contexts (Ebner et al., 2013). Furtherstudies in clinically depressed patients or remitted patients arewarranted.

Lastly, other pharmacological candidate for the managementof memory impairment in unipolar depression is erythropoietin(EPO). Although evidence is still scarce, EPO could represent anovel add-on strategy for patients with persistent cognitivedeficits. It should be remarked that there are some limitationsregarding its route of administration and its potential hemato-logical side effects lending to a necessary monitoring. That iswhy some other routes of administration are currently beinginvestigated.

As recommendations, one consideration derived from thisreview is that further clinical trials will be required in orderto assess cognitive function as a primary outcome. Cognitivefunction has been traditionally considered as a secondaryoutcome (Keefe et al., 2014) and most studies were notspecifically designed nor powered to assess the cognitiveeffects of the different pharmacological drugs covered inthis review. In the same line, longer follow-up studies ofcognitive changes in response to different pharmacological


treatments are required to better characterize the poten-tial procognitive profiles of each of them. In addition,studies with larger samples of depressed patients also arenecessary. Besides, some of the included studies (i.e.galantamine, donepezil) were conducted only with elderlydepressed samples. For this reason, it will be necessary toanalyze these drugs in depressed young populations sincethe former group presents with specific characteristics duethe risk of developing cognitive impairment associated todementia. Moreover, as other authors have previouslyproposed, it would be necessary to develop and employ anstandardized neuropsychological battery to assess cognitivefunctioning in unipolar depression in order to allow compar-isons between studies (Anaya et al., 2012; Baune andRenger, 2014). A critical issue, once a drug with clearprocognitive effects is identified or developed, will be toproof that improvements in cognition translate into betterpsychosocial functioning, and that those pro-functionaleffects are not pseudospecific (meaning that they areindependent from the improvement of mood). Tools suchas the FASTor the UPSA-B may be useful in that regard (Rosaet al., 2007; Mausbach et al., 2007).

It is worth to mention that despite non-pharmacologicalstrategies have not been included in the current review,psychosocial interventions, such as cognitive remediation(CR), might ameliorate cognitive dysfunction associated todepressive symptoms. Recent studies have shown that func-tional remediation, based on cognitive enhancement, may behelpful in patients with bipolar disorder (Torrent et al., 2013;Sole et al., 2014). However, very few studies have specificallyaddressed the efficacy of CR in depressed patients with MDD.Anaya and colleagues as well as, more recently, Baune andRenger, covered this topic (Anaya et al., 2012; Baune andRenger, 2014). Both reviews pointed out that, despite resultsare encouraging, additional studies are needed to properlyassess the effects of CR in depression. Furthermore, CRprograms specifically addressed to patients with MDD shouldbe developed. Exercise as a procognitive intervention is alsoworth studying. Lastly, studies on combination of pharmacolo-gical treatments and CR should be considered to enhancecognition in MDD.

One of the main limitations of our review is the use ofonly Pubmed database, which may have restricted thesearch to published, publicly available information. Sincethis is an extremely hot topic nowadays, there may beemerging data which has not been published yet that mightbe relevant to this topic.

In conclusion, currently there is an increased interest to findnew treatments targeting the cognitive impairment associatedto depression due to the clinical significance on functionaloutcome. A few agents in monotherapy or augmentationstrategies seem to reduce some cognitive impairment, but itis difficult to draw clear conclusions due the large variability ofstudies and some negative findings, so, further studies arewarranted.

Role of funding source

Supported by a grant from the Spanish Ministry of Economy andCompetitiveness (PI11/00637, PI12/00912) integrated into the PlanNacional de I+D+ I y cofinanciado por el ISCIII-Subdirección Generalde Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER);





B. Solé et al.14

CIBERSAM; and the Comissionat per a Universitats i Recerca del DIUEde la Generalitat de Catalunya (2014 SGR 398 to the BipolarDisorders Group) and with the support of the Esther KoplowitzCentre (CEK). Anabel Martinez-Aran's project is supported, in part,by a 2013 NARSAD, Independent Investigator Grant from the Brain &Behavior Research Foundation.

Contributors

All the authors have been sufficiently involved in the submittedstudy and have approved the final paper.

Conflict of interest

Dr. Martinez-Aran has served as speaker or advisor for the followingcompanies: Bristol-Myers Squibb, Otsuka, Lundbeck and Pfizer.

Dr. Vieta has received grants, CME-related honoraria, or consult-ing fees from Alexza, Almirall, AstraZeneca, Bristol-Myers Squibb,Cephalon, Eli Lilly, Ferrer, Forest Research Institute, GedeonRichter, GlaxoSmith-Kline, Janssen, Janssen-Cilag, Jazz, Johnson& Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer,Pierre-Fabre, Qualigen, Roche, Sanofi-Aventis, Schering-Plough,Servier, Shire, Solvay, Takeda, Teva, CIBERSAM, the Seventh Eur-opean Framework Programme (ENBREC), the Stanley MedicalResearch Institute, United Biosource Corporation, and Wyeth. Theother authors report no financial relationships with commercialinterests.

Acknowledgments

The authors thank the support of the Esther Koplowitz Centre (CEK)and of the Spanish Ministry of Economy and Competitiveness,Instituto de Salud Carlos III, CIBERSAM, the Spanish Ministry ofEducation and the Comissionat per a Universitats i Recerca del DIUEde la Generalitat de Catalunya to the Bipolar Disorders Group (2014SGR 398)and the 2013 NARSAD, Independent Investigator Grantfrom the Brain & Behavior Research Foundation (Grant no. 20288).

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cognition as a target in major depression

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