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

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

www.elsevier.com/locate/euroneuro

Cognition as a target in schizophrenia, bipolardisorder and depression

1. Introduction

This exciting issue of European Neuropsychopharmacologyfocuses on neurocognition across severe psychiatric disor-ders, particularly schizophrenia, bipolar disorder and majordepressive disorder (MDD). In general, most clinical symp-toms of psychiatric disorders, such as delusions, anxiety,irritability or insomnia, can be effectively treated bycurrent psychopharmacological treatments. Nevertheless,cognitive deficits, which represent core deficits acrosssevere mental disorders, do not improve and can evenworsen over time. Cognitive dysfunction is a poorly con-trolled and highly relevant dimension of psychiatric dis-orders that goes beyond traditional diagnostic boundaries(Millan et al., 2012). Cognitive impairment should beconsidered a critical clinical and therapeutic target, andefforts to enhance cognition may lead to higher functioningand better quality of life for patients. The fact is thatchanges in specific cognitive domains can be seen acrossdifferent diagnoses but it is extremely difficult to establishwhich cognitive domains or areas and to which degrees areaffected in the distinct disorders, since different cognitiveprofiles can be detected within diagnostic groups.

More and more epidemiological, genetic, neuroimaging andneurocognitive studies show similarities between patients withschizophrenia and bipolar disorder. Cognitive deficits seemqualitatively similar but quantitatively more severe in schizo-phrenia (Martinez-Aran et al., 2002, Daban et al., 2006).Cognitive deficits have been studied to a much lesser extentin MDD. The study of the causes, consequences and potentialprevention of cognitive impairment in psychiatric disorders is ofgreat contemporary interest because cognitive impairmentconstitutes a core deficit and because of its impact in thegeneral functioning of the patients.

2. Are cognitive problems the same acrossconditions?

A common criticism to this line of research is that cognitivedeficits appear to be unspecific. Indeed, cognitive impairment

0.1016/j.euroneuro.2015.01.007lsevier B.V. and ECNP. All rights reserved.

may be seen as a common pathway after brain damage causedby multiple different causes. Moreover, the tools that we use tomeasure cognitive performance may be too rudimentary tocapture subtle differences across different conditions. Recently,attempts to provide a fine grain analysis of cognitive deficitshave been made. Hence, attention can be affected in alldisorders but in a different degree and deficits may rely moreon focused attention or on divided attention, depending onseveral factors that require further research. Something similarhappens with regard to subdimensions of executive functions. Inthis line, patients with bipolar disorder may experience deficitsin specific subareas such as response inhibition whereas indivi-duals with schizophrenia may show more generalized executivedeficits and people with depression may have problems withdecision-making or initiating responses. There are discrepanciesregarding memory and other cognitive domains, since memoryseems to be affected in schizophrenia but it is not clear if it isequally affected in bipolar disorder or depression or in a lesserdegree. Despite the evidence of a larger magnitude of cognitiveimpairment in schizophrenia as compared to affective psy-choses, the literature provides evidence of a similar cognitiveprofile across these disorders, so that the relative severity ofimpairments across different cognitive domains tends to be verysimilar in bipolar disorder, psychotic major depression andschizoaffective disorder as compared to that of schizophrenia,with the greatest impairment in verbal memory, and the leastimpairment in visual processing and general verbal ability(Reichenberg et al., 2009).

Social cognition is a complex concept that involves multiplecomponents and was thought to be more impaired in psychoses,especially in schizophrenia and autism spectrum disorders.However, recent research suggests that a subgroup of patientswith bipolar disorders would also show difficulties in socialcognition (Lahera et al., in press). This construct may beconsidered an important target in the treatment of mentaldisorders since enhancing social cognition may facilitate thetreatment of affective symptoms and improve functional out-come (Samamé et al., 2012). For example, patients with severepsychiatric disorders share difficulties in cognitive control andgoal representations such as to avoid eating a piece of cake orchocolate while on diet or maintaining points one wishes to

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communicate in a conversation, taking relevant notes on ameeting or even to get a specific goal, such as going to thedentist or picking up children at school (Barch and Sheffield,2014). These problems also make more difficult to benefit frompsychotherapy mainly due to attention, memory and executivedeficits.

Recent findings reveal some barriers and inconsistencies inpsychiatrists' routine clinical evaluation of cognitive function inschizophrenia, bipolar disorder and MDD (Belgaied et al., 2014).Current challenges in the assessment of cognition acrosspsychiatric conditions include the lack of consensus on neuro-cognitive batteries and standardized, valid measures that areavailable in different languages. Multicenter follow-up studiesincluding large samples of patients would be helpful in order tounderstand the course of cognitive deficits across conditionsfrom the earlier stages of the illness. The Measurement andTreatment Research to Improve Cognition in Schizophrenia(MATRICS) Consensus Cognitive Battery (MCCB) was developedfor clinical trial research in schizophrenia (Nuechterlein et al.,2008). More recently, the International Society for BipolarDisorders (ISBD) Cognition Committee aimed to summarizethe existing literature on cognitive functioning in bipolardisorder, to identify cognitive measures that show maximalimpairment in bipolar disorder, to evaluate the suitability ofthe MCCB for use in bipolar disorders, and to propose apreliminary cognitive battery that could be applicable forinternational use in bipolar disorders research. The proposedISBD Battery for Assessment of Neurocognition (ISBD-BANC)represents a preliminary cognitive battery that would beexpected to have utility across a range of the multipleneuropsychological research contexts in the field of bipolardisorders. The battery would be appropriate for broad researchapplications where a screening of cognitive abilities is requiredor where repeated assessments are necessary (e.g., treatmenteffects and clinical trials) as well as with the use of the MCCB inschizophrenia (Yatham et al., 2010). Nevertheless, no consen-sus is yet available in the field of MDD. Efforts in this line wouldbe helpful in order to compare performance across conditionsand clarify cognitive profiles (Russo et al., 2015). Probably, theuse of consensus batteries such as MCCB would allow thecomparison between different diagnostic groups in researchand clinical practice.

We can not forget the relevance of including self-reportsor specific measures to assess subjective cognitive deficitseven though there is not always a correspondence betweensubjective and objective cognitive impairment (Martinez-Aran et al., 2005; Burdick et al., 2005; Rosa et al., 2013;Durand et al., 2015), because these measures may be usefulin predicting functional outcome. Interview-based assess-ments based on the use of short instruments such as the theSchizophrenia Cognition Rating Scale (SCoRS) may be usefulas clinical measure of cognitive treatment response and tobe used in clinical trials as a co-primary measure withfunctional relevance since it is related to real-world func-tioning and sensitive to cognitive benefit (Keefe et al.,2015).

New approaches highlight the cognitive variability in psycho-tic disorders taking into account that cognitive deficits are corefeatures of affective and non-affective psychosis (these termsmay be a bit confusing and overlapping, since there arepatients with affective disorders but without psychotic symp-toms). However, substantial variability may be seen in terms of

cognitive areas- both within and between diagnostic groups. Inthis context, cluster analysis provides an opportunity to groupsubjects using a cross-diagnostic cluster analysis (Lewandowskiet al., 2014).

Another current approach is to study the cognitive devel-opment of subjects with schizophrenia, bipolar disorder ordepression, which involves the neurocognitive assessment ofoffspring or people at high risk for developing mentaldisorders to ascertain whether neurodevelopmental abnorm-alities may explain cognitive impairment in these individuals.Studies at first episodes of the illness have been increased inthe last two decades and longitudinal studies have appearedon scene looking for cognitive changes and progression or notof cognitive deficits. In this regard, neurodevelopmentalabnormalities may partly separate bipolar disorder fromschizophrenia. Probably a subgroup of bipolar patients donot share neurodevelopmental anomalies with schizophreniaso that some of these patients, with no premorbid cognitivedysfunction can function at supranormal level (Burdick et al.,2014; Bora, 2015), whereas developmental trajectories inother individual with bipolar disorder may be similar to thoseof patients with schizophrenia suggesting that these pre-morbid deficits may be result of problems in acquisition ofcognitive abilities rather than cognitive decline.

3. Cognition and functioning

One of the great challenges in the treatment of psychiatricdisorders is to achieve functional recovery beyond clinicalremission. In schizophrenia, cognitive factors may constitutebetter independent predictors of functioning than psychoticsymptoms (Bowie et al., 2010; Lewandowski et al., 2013).Similarly, more recently, cognitive deficits have been consid-ered better predictors of functioning and disability thanaffective symptoms, even though persistent subclinical symp-toms, and especially depressive subsyndromal symptoms, havean important impact on the psychosocial functioning inpatients with bipolar disorder (Sanchez-Moreno et al., 2009,Bonnin et al., 2010, 2012; Rosa et al., 2010).

Since the relationship between improvement in specificneurocognitive tasks and the functional outcomes is not wellestablished, the inclusion of measures to assess functioningas a primary outcome of pharmacological and non-phar-macological interventions in the context of clinical trialsshould be taken into consideration (Torrent et al., 2013;Bonnin et al., 2014). With regard to cognition trials inschizophrenia one of the main reasons for crisis in this areais the absence of well developed and well-validated co-primary measures (Nutt et al., 2013). The use of specificneurocognitive measures as well as composite neurocognitiveindexes are needed to establish the efficacy of cognitiveremediation or cognitive enhancers. Other forms of enhan-cing cognition and functioning including education andpsychical exercise should be promoted (Greer et al., 2015).Therefore, the use of instruments measuring functioning anddisability are required to assess the efficacy of interventionscombining pharmacological and psychological therapeuticstrategies in new trial designs including more innovativetechniques, such as virtual reality.

The impact of cognitive reserve on neurocognitive andlong-term psychosocial functioning has been recently

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applied to psychiatric disorders. Cognitive reserve may bedefined as the capacity of an adult brain to cope with brainpathology to minimize cognitive symptomatology (Stern,2002; De la Serna et al., 2013; Forcada et al., 2015), so itmay be protective against cognitive and functional decline.Cognitive enhancement should be considered in youngpeople with early onset schizophrenia, bipolar disorder ordepression. Moreover, implementing programs that enhancecognitive reserve in the early stages of the disease or inthose at risk for developing the disease may minimize thedecline on cognitive and psychosocial functioning in thefuture.

4. Treatments for cognitive dysfunction

The attempts to find drugs that treat clinical and cognitivesymptoms at the same time have been disappointing. Inschizophrenia, the CATIE study showed small improvementsin cognition and little differential advantage of any drugover the other (Keefe et al., 2007). In bipolar disorder, thepositive effects of drugs on mood and psychotic symptomsmay carry some indirect positive impact on cognition, butalso cognitive side-effects related to extrapyramidal, seda-tive, anticholinergic, and blunting mechanisms of drugs suchas lithium, anticonvulsants or antipsychotics (Vieta, 2009).In MDD, antidepressants are not free of cognitive side-effects either (Popovic et al., 2015). Only vortioxetine(McIntyre et al., 2014) and lurasidone (Harvey et al.,2013) may have some advantage over other compounds asregards to their cognitive properties, but this has to beconfirmed in further studies that rule out pseudospecificityof cognitive enhancing effects.

The controversy on the effects of psychotropic drugs oncognition will not stop until the proper clinical trials havebeen conducted. Some studies point at mild or moderateadverse effects on psychomotor performance and verbalmemory in lithium treated patients (Wingo et al., 2009;Mora et al., 2014) whereas other studies highlight thepotential neuroprotective effects of lithium (Fountoulakiset al., 2008). Fewer studies have evaluated the effects ofvalproate on cognition, taking into account that lithium andvalproate are the most widely used mood stabilizers inbipolar disorder. It is interesting to analyze the cognitivedeficits found in patients with early bipolar disorder treatedwith lithium or valproate to dilucidate the potential differ-ences on the cognitive performance between patientstreated with these mood stabilizers (Muralidharan et al.,2015). The study of the effects of medication on neurocog-nitive performance on the field of MDD requires furtherresearch (Solé et al., 2015b). Recommendations for futureresearch in the field are provided including collaborativestudies with larger samples, observational follow-up stu-dies, as well as randomized clinical trials comparing head-to-head neurocognitive impact of different medications(Balanzá-Martínez et al., 2010; Torrent et al., 2011). Moreattention in future research should be paid to whichcompounds seem promising as direct cognitive enhancersand which can be used to reduce cognitive side-effects.Changing the paradigm for drug development in CentralNervous System to avoid the declining assay sensitivity ofclinical trials and moving toward hard outcomes, such as

biomarkers, and ecological measures of functional benefitsis one of the main objectives (Vieta, 2014).

Generally, neurocognitive changes have been assessed imme-diately after intervention (pharmacological or non-pharmaco-logical) but not so often over the long term and rarely inremitted patients at baseline. Psychological interventions mayprocure changes in cognition and functioning as well. In thisregard, longitudinal studies are needed to establish mainte-nance of positive changes on cognition and generalization toeveryday functioning over time. Different programs of cognitiveremediation therapy have demonstrated their efficacy throughmeta-analyses in schizophrenia (McGurk et al., 2007; Wykeset al., 2011). In bipolar disorder, there is a lack of studiesfocused on cognitive remediation, with some preliminary datashowing improvements in the occupational functioning andsubclinical symptoms (Deckersbach et al., 2010). More recently,in a randomized controlled trial, bipolar patients who receivedFunctional Remediation improved their general functioning(Torrent et al., 2013) and verbal memory at 6-month follow-up after intervention (Bonnin et al., in press) compared topatients in the treatment as usual group. Moreover, in thatclinical trial, patients with bipolar II disorder seemed to obtainbenefits from Functional Remediation intervention not only infunctional improvements but also in reduction of depressivesubclinical symptoms compared to that of patients receivingpsychoeducation and treatment as usual (Solé et al., 2015a).Very little research has been conducted on cognitive remedia-tion in other conditions such as schizoaffective disorders (Anayaet al., 2012; Fuentes-Durá et al., 2012).

Optimizing and individualizing pharmacological treat-ment by small changes in dose or type of medication isgood practice. It is usually directed to minimize sideeffects, subsyndromal symptoms and to reduce relapse. Apositive impact on cognitive problems should also be anobjective (Goodwin et al., 2008). New agents aiming atenhancing cognition together with cognitive training wouldbe required in order to treat cognitive dysfunctions inschizophrenia, bipolar disorder and MDD. The combinationof pro-cognitive enhancers and cognitive remediation pro-grams together with psychosocial interventions would beneeded in the earlier stages of severe psychiatric disordersto prevent cognitive impairment and poor functional out-come. Pro-cognitive drugs may be effective when deliveredtogether with cognitive remediation or other rehabilitativeprograms as synergic facilitators (Nutt et al., 2013).

5. In this issue

Several hot questions on neurocognition in severe psychia-tric disorders are treated in this issue of European Neurop-sychopharmacology. One of the main goals in the mana-gement of psychiatric disorders is to prevent or reducecognitive impairment by studying factors involved in neu-rocognitive performance, instruments to assess cognition,cognitive side effects of current drugs, potential cognitiveenhancers and the role of new psychological interventions.All these elements appear in this special issue on cognitionas a target.

In this issue, Bora (2015) provides support, throughout awide review of literature, to the idea of a common trajectoryof cognitive deficits from childhood to adulthood in individuals

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with schizophrenia and many patients with bipolar disorderwith neurodevelopmental abnormalities. This author makes aproposal to explain the dual nature of association betweencognitive functioning and risk for bipolar disorder, since atleast a subgroup of patients with bipolar disorder wouldoutperform many healthy controls in scholar or vocationalachievement. Moreover, some cognitive domains like verbalmemory can be affected differentially along the course ofschizophrenia and bipolar disorder (Czepielewski et al., 2015),suggesting that verbal episodic memory would be impairedearly in the course of schizophrenia whereas deficits in thisarea would be more evident in late-stage bipolar disorder. Oneof the main relevant points offered in this research is thatboth, individuals with schizophrenia and bipolar disorder seemto maintain the ability to learn, which opens a new avenue forcognitive and functional remediation techniques.

This special issue pays attention to the importance ofmeasuring cognition by using reliable and valid clinicalmeasures to be considered as co-primary measures offunctional relevance, such as the Schizophrenia CognitionRating Scale (Keefe et al., 2015). The lack of correspon-dence between objective and subjective cognitive deficits ispointed at the study by Durand et al. (2015), indicating thatperformance-based measures of cognitive functioning andfunctionality should be considered the gold-standard offunctioning assessment in treatment research. Severalclinical factors are presented as being associated withcognitive impairment, such as subclinical depression andsleep disturbances in bipolar disorder (Volkert et al., 2015),or suicidal ideation in MDD (Lara et al., 2015). More recentconstructs have been incorporated in psychiatry and espe-cially in severe psychiatric disorders such as cognitivereserve because of its implications on neurocognition andgeneral functioning. This topic is analyzed in the work byForcada et al., (2015) being the first study, to our knowl-edge, investigating the impact of cognitive reserve oncognition and functioning in bipolar disorder.

The effects of current treatments for bipolar disorders oncognition are addressed in a study comparing lithium andvalproate in remitted early bipolar I disorder patients aftera first manic episode (Muralidharan et al., 2015) Thetreatments for cognitive deficits, including physical exer-cise, in MDD are discussed in two articles (Solé et al., 2015b;Greer et al., 2015) Another article highlights the efficacy ofnovel interventions such as functional remediation forpatients with bipolar II disorder at improving functioningand subsyndromal symptoms (Solé et al., 2015a). Finally,new potential agents to enhance cognition, such as oxitocinand its efficacy in the improvement of social cognitiondeficits in affective and psychotic disorders are pointedout by Perez-Rodriguez et al., (2015).

6. The way ahead

Cognitive problems are present across different psychiatricconditions but they may vary quantitatively depending on theseverity and characteristics of the underlying illness. It is notclear if onset and progression differs between diagnosticgroups. Some preliminary findings suggest that neurocognitivefunctioning in patients with childhood or adolescent onsetschizophrenia and bipolar disorder do not improve over time,

showing similar cognitive profiles at a two-year follow-up aftera first episode of psychosis (Bombin et al., 2013). Moreover, asocial cognition problem may be expressed in different waysdepending on the condition, that is, social cognition may bedeficient in schizophrenia or autism whereas may be excessiveor distorted in borderline personality disorder (Perez-Rodriguezet al., 2015). The potential use of social cognition as anendopenotype should be examined by studying individuals athigh risk and their relatives, and taken into account as atherapeutic target in mental illnesses. In general, cognitivedeficits represent a target when the main goal is functionalrecovery. In this regard, first steps have been done, with DSM-5psychosis committee proposal of a dimensional assessment ofcognition, in order to raise attention to the need for additionaltreatments specifically targeting cognitive symptoms, suchas cognitive and functional remediation and cognitive enha-ncing drugs.

Psychosocial interventions, such as cognitive and func-tional remediation, may improve cognitive dysfunction inmental illnesses. Cognitive remediation may help to reducedisability and resultant health and social care costs (Wykeset al., 2011; Reeder et al., 2014). Recent studies haveshown that functional remediation, based on cognitiveenhancement, may be helpful in patients with bipolardisorder (Torrent et al., 2013; Solé et al., 2015a). However,very few studies have specifically addressed the efficacy ofcognitive remediation in depressed patients with MDD(Anaya et al., 2012; Baune and Renger, 2014). Exercise asa procognitive intervention is also worth studying. Lastly,studies on combination of pharmacological treatments andCR should be considered to enhance cognition, so combiningpharmacological compounds with cognitive training may befeasible in clinical trials. Finally, enhancing cognitivereserve may be helpful to prevent the impact of cognitivedeficits on functional outcome particularly in the earlierstages of the illness.

Role of funding source

None

Contributors

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

Conflicts of interest

Dr. Vieta has received grants, CME-related honoraria, or con-sulting fees from Alexza, Almirall, AstraZeneca, Bristol-MyersSquibb, Cephalon, Eli Lilly, Ferrer, ForestResearch Institute,Gedeon Richter, 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 European Framework Programme (ENBREC), theS-tanley Medical Research Institute, United Biosource Corpora-tion, and Wyeth.Dr. Martinez-Aran has served as speaker oradvisor for the following companies: Bristol-Myers Squibb,Otsuka, Lundbeck and Pfizer.

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Acknowledgments

The authors thank the support of the CIBERSAM, the SpanishMinistry of Economy and Competitiveness, Plan Nacional de I+D+ I y cofinanciado por el ISCIII-Subdirección General de Evaluación yel Fondo Europeo de Desarrollo Regional (PI11/00637, PI12/00912),the Comissionat per a Universitats i Recerca del DIUE de laGeneralitat de Catalunya to the Bipolar Disorders Group (2014SGR 398). Dr. Anabel Martinez-Aran's project is supported in part bya 2013 NARSAD (20288), Independent Investigator Grant from theBrain & Behavior Research Foundation.

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Anabel Martinez-AranBipolar Disorders Unit, Department of Psychiatry, Instituteof Neuroscience, Hospital Clinic, University of Barcelona,

IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain

Eduard Vietan

Bipolar Disorders Unit, Department of Psychiatry, Instituteof Neuroscience, Hospital Clinic, University of Barcelona,

IDIBAPS, CIBERSAM, Barcelona, Catalonia, SpainE-mail address: evieta@clinic.ub.es

10 December 2014; accepted 8 January 2015

nCorrespondence to: Bipolar Disorder Program. Clinical Instituteof Neuroscience. Hospital Clinic of Barcelona, Villarroel, 170. 08036Barcelona, Spain.Tel.: +34 93 227 54 01; fax: +34 93 227 9228.