European Neuropsychopharmacology (2015) 25, 151–157
Cognition as a target in schizophrenia, bipolar disorder and depression 1.
This exciting issue of European Neuropsychopharmacology focuses on neurocognition across severe psychiatric disorders, particularly schizophrenia, bipolar disorder and major depressive disorder (MDD). In general, most clinical symptoms of psychiatric disorders, such as delusions, anxiety, irritability or insomnia, can be effectively treated by current psychopharmacological treatments. Nevertheless, cognitive deﬁcits, which represent core deﬁcits across severe mental disorders, do not improve and can even worsen over time. Cognitive dysfunction is a poorly controlled and highly relevant dimension of psychiatric disorders that goes beyond traditional diagnostic boundaries (Millan et al., 2012). Cognitive impairment should be considered a critical clinical and therapeutic target, and efforts to enhance cognition may lead to higher functioning and better quality of life for patients. The fact is that changes in speciﬁc cognitive domains can be seen across different diagnoses but it is extremely difﬁcult to establish which cognitive domains or areas and to which degrees are affected in the distinct disorders, since different cognitive proﬁles can be detected within diagnostic groups. More and more epidemiological, genetic, neuroimaging and neurocognitive studies show similarities between patients with schizophrenia and bipolar disorder. Cognitive deﬁcits seem qualitatively similar but quantitatively more severe in schizophrenia (Martinez-Aran et al., 2002, Daban et al., 2006). Cognitive deﬁcits have been studied to a much lesser extent in MDD. The study of the causes, consequences and potential prevention of cognitive impairment in psychiatric disorders is of great contemporary interest because cognitive impairment constitutes a core deﬁcit and because of its impact in the general functioning of the patients.
2. Are cognitive problems the same across conditions? A common criticism to this line of research is that cognitive deﬁcits appear to be unspeciﬁc. Indeed, cognitive impairment http://dx.doi.org/10.1016/j.euroneuro.2015.01.007 0924-977X/& 2015 Elsevier B.V. and ECNP. All rights reserved.
may be seen as a common pathway after brain damage caused by multiple different causes. Moreover, the tools that we use to measure cognitive performance may be too rudimentary to capture subtle differences across different conditions. Recently, attempts to provide a ﬁne grain analysis of cognitive deﬁcits have been made. Hence, attention can be affected in all disorders but in a different degree and deﬁcits may rely more on focused attention or on divided attention, depending on several factors that require further research. Something similar happens with regard to subdimensions of executive functions. In this line, patients with bipolar disorder may experience deﬁcits in speciﬁc subareas such as response inhibition whereas individuals with schizophrenia may show more generalized executive deﬁcits and people with depression may have problems with decision-making or initiating responses. There are discrepancies regarding memory and other cognitive domains, since memory seems to be affected in schizophrenia but it is not clear if it is equally affected in bipolar disorder or depression or in a lesser degree. Despite the evidence of a larger magnitude of cognitive impairment in schizophrenia as compared to affective psychoses, the literature provides evidence of a similar cognitive proﬁle across these disorders, so that the relative severity of impairments across different cognitive domains tends to be very similar in bipolar disorder, psychotic major depression and schizoaffective disorder as compared to that of schizophrenia, with the greatest impairment in verbal memory, and the least impairment in visual processing and general verbal ability (Reichenberg et al., 2009). Social cognition is a complex concept that involves multiple components and was thought to be more impaired in psychoses, especially in schizophrenia and autism spectrum disorders. However, recent research suggests that a subgroup of patients with bipolar disorders would also show difﬁculties in social cognition (Lahera et al., in press). This construct may be considered an important target in the treatment of mental disorders since enhancing social cognition may facilitate the treatment of affective symptoms and improve functional outcome (Samamé et al., 2012). For example, patients with severe psychiatric disorders share difﬁculties in cognitive control and goal representations such as to avoid eating a piece of cake or chocolate while on diet or maintaining points one wishes to
152 communicate in a conversation, taking relevant notes on a meeting or even to get a speciﬁc goal, such as going to the dentist or picking up children at school (Barch and Shefﬁeld, 2014). These problems also make more difﬁcult to beneﬁt from psychotherapy mainly due to attention, memory and executive deﬁcits. Recent ﬁndings reveal some barriers and inconsistencies in psychiatrists' routine clinical evaluation of cognitive function in schizophrenia, bipolar disorder and MDD (Belgaied et al., 2014). Current challenges in the assessment of cognition across psychiatric conditions include the lack of consensus on neurocognitive batteries and standardized, valid measures that are available in different languages. Multicenter follow-up studies including large samples of patients would be helpful in order to understand the course of cognitive deﬁcits across conditions from the earlier stages of the illness. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) was developed for clinical trial research in schizophrenia (Nuechterlein et al., 2008). More recently, the International Society for Bipolar Disorders (ISBD) Cognition Committee aimed to summarize the existing literature on cognitive functioning in bipolar disorder, to identify cognitive measures that show maximal impairment in bipolar disorder, to evaluate the suitability of the MCCB for use in bipolar disorders, and to propose a preliminary cognitive battery that could be applicable for international use in bipolar disorders research. The proposed ISBD Battery for Assessment of Neurocognition (ISBD-BANC) represents a preliminary cognitive battery that would be expected to have utility across a range of the multiple neuropsychological research contexts in the ﬁeld of bipolar disorders. The battery would be appropriate for broad research applications where a screening of cognitive abilities is required or where repeated assessments are necessary (e.g., treatment effects and clinical trials) as well as with the use of the MCCB in schizophrenia (Yatham et al., 2010). Nevertheless, no consensus is yet available in the ﬁeld of MDD. Efforts in this line would be helpful in order to compare performance across conditions and clarify cognitive proﬁles (Russo et al., 2015). Probably, the use of consensus batteries such as MCCB would allow the comparison between different diagnostic groups in research and clinical practice. We can not forget the relevance of including self-reports or speciﬁc measures to assess subjective cognitive deﬁcits even though there is not always a correspondence between subjective and objective cognitive impairment (MartinezAran et al., 2005; Burdick et al., 2005; Rosa et al., 2013; Durand et al., 2015), because these measures may be useful in predicting functional outcome. Interview-based assessments based on the use of short instruments such as the the Schizophrenia Cognition Rating Scale (SCoRS) may be useful as clinical measure of cognitive treatment response and to be used in clinical trials as a co-primary measure with functional relevance since it is related to real-world functioning and sensitive to cognitive beneﬁt (Keefe et al., 2015). New approaches highlight the cognitive variability in psychotic disorders taking into account that cognitive deﬁcits are core features of affective and non-affective psychosis (these terms may be a bit confusing and overlapping, since there are patients with affective disorders but without psychotic symptoms). However, substantial variability may be seen in terms of
A. Martinez-Aran, E. Vieta cognitive areas- both within and between diagnostic groups. In this context, cluster analysis provides an opportunity to group subjects using a cross-diagnostic cluster analysis (Lewandowski et al., 2014). Another current approach is to study the cognitive development of subjects with schizophrenia, bipolar disorder or depression, which involves the neurocognitive assessment of offspring or people at high risk for developing mental disorders to ascertain whether neurodevelopmental abnormalities may explain cognitive impairment in these individuals. Studies at ﬁrst episodes of the illness have been increased in the last two decades and longitudinal studies have appeared on scene looking for cognitive changes and progression or not of cognitive deﬁcits. In this regard, neurodevelopmental abnormalities may partly separate bipolar disorder from schizophrenia. Probably a subgroup of bipolar patients do not share neurodevelopmental anomalies with schizophrenia so that some of these patients, with no premorbid cognitive dysfunction can function at supranormal level (Burdick et al., 2014; Bora, 2015), whereas developmental trajectories in other individual with bipolar disorder may be similar to those of patients with schizophrenia suggesting that these premorbid deﬁcits may be result of problems in acquisition of cognitive abilities rather than cognitive decline.
Cognition and functioning
One of the great challenges in the treatment of psychiatric disorders is to achieve functional recovery beyond clinical remission. In schizophrenia, cognitive factors may constitute better independent predictors of functioning than psychotic symptoms (Bowie et al., 2010; Lewandowski et al., 2013). Similarly, more recently, cognitive deﬁcits have been considered better predictors of functioning and disability than affective symptoms, even though persistent subclinical symptoms, and especially depressive subsyndromal symptoms, have an important impact on the psychosocial functioning in patients with bipolar disorder (Sanchez-Moreno et al., 2009, Bonnin et al., 2010, 2012; Rosa et al., 2010). Since the relationship between improvement in speciﬁc neurocognitive tasks and the functional outcomes is not well established, the inclusion of measures to assess functioning as a primary outcome of pharmacological and non-pharmacological interventions in the context of clinical trials should be taken into consideration (Torrent et al., 2013; Bonnin et al., 2014). With regard to cognition trials in schizophrenia one of the main reasons for crisis in this area is the absence of well developed and well-validated coprimary measures (Nutt et al., 2013). The use of speciﬁc neurocognitive measures as well as composite neurocognitive indexes are needed to establish the efﬁcacy of cognitive remediation or cognitive enhancers. Other forms of enhancing cognition and functioning including education and psychical exercise should be promoted (Greer et al., 2015). Therefore, the use of instruments measuring functioning and disability are required to assess the efﬁcacy of interventions combining pharmacological and psychological therapeutic strategies in new trial designs including more innovative techniques, such as virtual reality. The impact of cognitive reserve on neurocognitive and long-term psychosocial functioning has been recently
Cognition as a target in schizophrenia, bipolar disorder and depression applied to psychiatric disorders. Cognitive reserve may be deﬁned as the capacity of an adult brain to cope with brain pathology to minimize cognitive symptomatology (Stern, 2002; De la Serna et al., 2013; Forcada et al., 2015), so it may be protective against cognitive and functional decline. Cognitive enhancement should be considered in young people with early onset schizophrenia, bipolar disorder or depression. Moreover, implementing programs that enhance cognitive reserve in the early stages of the disease or in those at risk for developing the disease may minimize the decline on cognitive and psychosocial functioning in the future.
Treatments for cognitive dysfunction
The attempts to ﬁnd drugs that treat clinical and cognitive symptoms at the same time have been disappointing. In schizophrenia, the CATIE study showed small improvements in cognition and little differential advantage of any drug over the other (Keefe et al., 2007). In bipolar disorder, the positive effects of drugs on mood and psychotic symptoms may carry some indirect positive impact on cognition, but also cognitive side-effects related to extrapyramidal, sedative, anticholinergic, and blunting mechanisms of drugs such as lithium, anticonvulsants or antipsychotics (Vieta, 2009). In MDD, antidepressants are not free of cognitive sideeffects either (Popovic et al., 2015). Only vortioxetine (McIntyre et al., 2014) and lurasidone (Harvey et al., 2013) may have some advantage over other compounds as regards to their cognitive properties, but this has to be conﬁrmed in further studies that rule out pseudospeciﬁcity of cognitive enhancing effects. The controversy on the effects of psychotropic drugs on cognition will not stop until the proper clinical trials have been conducted. Some studies point at mild or moderate adverse effects on psychomotor performance and verbal memory in lithium treated patients (Wingo et al., 2009; Mora et al., 2014) whereas other studies highlight the potential neuroprotective effects of lithium (Fountoulakis et al., 2008). Fewer studies have evaluated the effects of valproate on cognition, taking into account that lithium and valproate are the most widely used mood stabilizers in bipolar disorder. It is interesting to analyze the cognitive deﬁcits found in patients with early bipolar disorder treated with lithium or valproate to dilucidate the potential differences on the cognitive performance between patients treated with these mood stabilizers (Muralidharan et al., 2015). The study of the effects of medication on neurocognitive performance on the ﬁeld of MDD requires further research (Solé et al., 2015b). Recommendations for future research in the ﬁeld are provided including collaborative studies with larger samples, observational follow-up studies, as well as randomized clinical trials comparing headto-head neurocognitive impact of different medications (Balanzá-Martínez et al., 2010; Torrent et al., 2011). More attention in future research should be paid to which compounds seem promising as direct cognitive enhancers and which can be used to reduce cognitive side-effects. Changing the paradigm for drug development in Central Nervous System to avoid the declining assay sensitivity of clinical trials and moving toward hard outcomes, such as
biomarkers, and ecological measures of functional beneﬁts is one of the main objectives (Vieta, 2014). Generally, neurocognitive changes have been assessed immediately after intervention (pharmacological or non-pharmacological) but not so often over the long term and rarely in remitted patients at baseline. Psychological interventions may procure changes in cognition and functioning as well. In this regard, longitudinal studies are needed to establish maintenance of positive changes on cognition and generalization to everyday functioning over time. Different programs of cognitive remediation therapy have demonstrated their efﬁcacy through meta-analyses in schizophrenia (McGurk et al., 2007; Wykes et al., 2011). In bipolar disorder, there is a lack of studies focused on cognitive remediation, with some preliminary data showing improvements in the occupational functioning and subclinical symptoms (Deckersbach et al., 2010). More recently, in a randomized controlled trial, bipolar patients who received Functional Remediation improved their general functioning (Torrent et al., 2013) and verbal memory at 6-month followup after intervention (Bonnin et al., in press) compared to patients in the treatment as usual group. Moreover, in that clinical trial, patients with bipolar II disorder seemed to obtain beneﬁts from Functional Remediation intervention not only in functional improvements but also in reduction of depressive subclinical symptoms compared to that of patients receiving psychoeducation and treatment as usual (Solé et al., 2015a). Very little research has been conducted on cognitive remediation in other conditions such as schizoaffective disorders (Anaya et al., 2012; Fuentes-Durá et al., 2012). Optimizing and individualizing pharmacological treatment by small changes in dose or type of medication is good practice. It is usually directed to minimize side effects, subsyndromal symptoms and to reduce relapse. A positive impact on cognitive problems should also be an objective (Goodwin et al., 2008). New agents aiming at enhancing cognition together with cognitive training would be required in order to treat cognitive dysfunctions in schizophrenia, bipolar disorder and MDD. The combination of pro-cognitive enhancers and cognitive remediation programs together with psychosocial interventions would be needed in the earlier stages of severe psychiatric disorders to prevent cognitive impairment and poor functional outcome. Pro-cognitive drugs may be effective when delivered together with cognitive remediation or other rehabilitative programs as synergic facilitators (Nutt et al., 2013).
In this issue
Several hot questions on neurocognition in severe psychiatric disorders are treated in this issue of European Neuropsychopharmacology. One of the main goals in the management of psychiatric disorders is to prevent or reduce cognitive impairment by studying factors involved in neurocognitive performance, instruments to assess cognition, cognitive side effects of current drugs, potential cognitive enhancers and the role of new psychological interventions. All these elements appear in this special issue on cognition as a target. In this issue, Bora (2015) provides support, throughout a wide review of literature, to the idea of a common trajectory of cognitive deﬁcits from childhood to adulthood in individuals
A. Martinez-Aran, E. Vieta
with schizophrenia and many patients with bipolar disorder with neurodevelopmental abnormalities. This author makes a proposal to explain the dual nature of association between cognitive functioning and risk for bipolar disorder, since at least a subgroup of patients with bipolar disorder would outperform many healthy controls in scholar or vocational achievement. Moreover, some cognitive domains like verbal memory can be affected differentially along the course of schizophrenia and bipolar disorder (Czepielewski et al., 2015), suggesting that verbal episodic memory would be impaired early in the course of schizophrenia whereas deﬁcits in this area would be more evident in late-stage bipolar disorder. One of the main relevant points offered in this research is that both, individuals with schizophrenia and bipolar disorder seem to maintain the ability to learn, which opens a new avenue for cognitive and functional remediation techniques. This special issue pays attention to the importance of measuring cognition by using reliable and valid clinical measures to be considered as co-primary measures of functional relevance, such as the Schizophrenia Cognition Rating Scale (Keefe et al., 2015). The lack of correspondence between objective and subjective cognitive deﬁcits is pointed at the study by Durand et al. (2015), indicating that performance-based measures of cognitive functioning and functionality should be considered the gold-standard of functioning assessment in treatment research. Several clinical factors are presented as being associated with cognitive impairment, such as subclinical depression and sleep disturbances in bipolar disorder (Volkert et al., 2015), or suicidal ideation in MDD (Lara et al., 2015). More recent constructs have been incorporated in psychiatry and especially in severe psychiatric disorders such as cognitive reserve because of its implications on neurocognition and general functioning. This topic is analyzed in the work by Forcada et al., (2015) being the ﬁrst study, to our knowledge, investigating the impact of cognitive reserve on cognition and functioning in bipolar disorder. The effects of current treatments for bipolar disorders on cognition are addressed in a study comparing lithium and valproate in remitted early bipolar I disorder patients after a ﬁrst manic episode (Muralidharan et al., 2015) The treatments for cognitive deﬁcits, including physical exercise, in MDD are discussed in two articles (Solé et al., 2015b; Greer et al., 2015) Another article highlights the efﬁcacy of novel interventions such as functional remediation for patients with bipolar II disorder at improving functioning and subsyndromal symptoms (Solé et al., 2015a). Finally, new potential agents to enhance cognition, such as oxitocin and its efﬁcacy in the improvement of social cognition deﬁcits in affective and psychotic disorders are pointed out by Perez-Rodriguez et al., (2015).
The way ahead
Cognitive problems are present across different psychiatric conditions but they may vary quantitatively depending on the severity and characteristics of the underlying illness. It is not clear if onset and progression differs between diagnostic groups. Some preliminary ﬁndings suggest that neurocognitive functioning in patients with childhood or adolescent onset schizophrenia and bipolar disorder do not improve over time,
showing similar cognitive proﬁles at a two-year follow-up after a ﬁrst episode of psychosis (Bombin et al., 2013). Moreover, a social cognition problem may be expressed in different ways depending on the condition, that is, social cognition may be deﬁcient in schizophrenia or autism whereas may be excessive or distorted in borderline personality disorder (Perez-Rodriguez et al., 2015). The potential use of social cognition as an endopenotype should be examined by studying individuals at high risk and their relatives, and taken into account as a therapeutic target in mental illnesses. In general, cognitive deﬁcits represent a target when the main goal is functional recovery. In this regard, ﬁrst steps have been done, with DSM-5 psychosis committee proposal of a dimensional assessment of cognition, in order to raise attention to the need for additional treatments speciﬁcally targeting cognitive symptoms, such as cognitive and functional remediation and cognitive enhancing drugs. Psychosocial interventions, such as cognitive and functional remediation, may improve cognitive dysfunction in mental illnesses. Cognitive remediation may help to reduce disability and resultant health and social care costs (Wykes et al., 2011; Reeder et al., 2014). Recent studies have shown that functional remediation, based on cognitive enhancement, may be helpful in patients with bipolar disorder (Torrent et al., 2013; Solé et al., 2015a). However, very few studies have speciﬁcally addressed the efﬁcacy of cognitive remediation in depressed patients with MDD (Anaya et al., 2012; Baune and Renger, 2014). Exercise as a procognitive intervention is also worth studying. Lastly, studies on combination of pharmacological treatments and CR should be considered to enhance cognition, so combining pharmacological compounds with cognitive training may be feasible in clinical trials. Finally, enhancing cognitive reserve may be helpful to prevent the impact of cognitive deﬁcits on functional outcome particularly in the earlier stages of the illness.
Role of funding source None
Contributors All the authors have been sufﬁciently involved in the submitted study and have approved the ﬁnal paper.
Conﬂicts of interest Dr. Vieta has received grants, CME-related honoraria, or consulting fees from Alexza, Almirall, AstraZeneca, Bristol-Myers Squibb, 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), theStanley Medical Research Institute, United Biosource Corporation, and Wyeth.Dr. Martinez-Aran has served as speaker or advisor for the following companies: Bristol-Myers Squibb, Otsuka, Lundbeck and Pﬁzer.
Cognition as a target in schizophrenia, bipolar disorder and depression
Acknowledgments The authors thank the support of the CIBERSAM, the Spanish Ministry of Economy and Competitiveness, Plan Nacional de I +D +I y coﬁnanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (PI11/00637, PI12/00912), the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya to the Bipolar Disorders Group (2014 SGR 398). Dr. Anabel Martinez-Aran's project is supported in part by a 2013 NARSAD (20288), Independent Investigator Grant from the Brain & Behavior Research Foundation.
References Anaya, C., Martinez Aran, A., Ayuso-Mateos, J.L., Wykes, T., Vieta, E., Scott, J., 2012. A systematic review of cognitive remediation for schizo-affective and affective disorders. J. Affect. Disord. 142, 13–21. Balanzá-Martínez, V., Selva, G., Martinez Aran, A., Prickaerts, J., Salazar, J., González-Pinto, A., Vieta, E., Tabarés-Seisdedos, R., 2010. Neurocognition in bipolar disorders-a closer look at comorbidities and medications. Eur. J. Pharmacol. 626, 87–96. Barch, DM., Shefﬁeld, JM., 2014. Cognitive impairments in psychotic disorders, common mechanisms and measurement. World Psychiatry 13, 224–232. Baune, BT., Renger, L., 2014. Pharmacological and nonpharmacological interventions to improve cognitive dysfunction and functional ability in clinical depression-a systematic review. Psychiatry Res. 219, 25–50. Belgaied, W., Samp, J., Vimont, A., Rémuzat, C., Aballéa, S., El Hammi, E., Kooli, A., Toumi, M., Akhras, K., 2014. Routine clinical assessment of cognitive functioning in schizophrenia, major depressive disorder, and bipolar disorder. Eur.Neuropsychopharmacol. 24, 133–141. Bombin, I., Mayoral, M., Castro-Fornieles, J., Gonzalez-Pinto, A., de la Serna, E., Rapado-Castro, M., Barbeito, S., Parellada, M., Baeza, I., Graell, M., Payá, B., Arango, C., 2013. Neuropsychological evidence for abnormal neurodevelopment associated with early-onset psychoses. Psychol. Med. 43, 757–768. Bonnin, C.M., Torrent, C., Arango, C., Amann, B.L., Solé, B., González-Pinto, A., Crespo, J.M., Tabarés-Seisdedos, R., Reinares, M., Ayuso-Mateos, J.L., García-Portilla, M.P., Ibáñez, A., Salamero, M., Vieta, E., Martínez-Aran, A., the CIBERSAM Functional Remediation Group., 2015. One-year follow-up of functional remediation in bipolar disorder: neurocognitive and functional outcome. Br J Psychiatry, in press. Bonnin, C.M., Martinez-Aran, A., Torrent, C., Pacchiarotti, I., Rosa, A.R., Franco, C., Murru, A., Sanchez-Moreno, J., Vieta, E., 2010. Clinical and neurocognitive predictors of functional outcome in bipolar euthymic patients, a long-term, follow-up study. J. Affect. Disord. 121, 156–160. Bonnin, C.M., Sanchez-Moreno, J., Martinez-Aran, A., Solé, B., Reinares, M., Rosa, A.R., Goikolea, J.M., Benabarre, A., AyusoMateos, J.L., Ferrer, M., Vieta, E., Torrent, C., 2012. Subthreshold symptoms in bipolar disorder, impact on neurocognition, quality of life and disability. J. Affect. Disord. 136, 650–659. Bonnin, C.M., Torrent, C., Vieta, E., Martinez-Aran, A., 2014. Restoring functioning in bipolar disorder, functional remediation. Harv. Rev. Psychiatry 22, 326–330. Bora, E., 2015. Developmental trajectory of cognitive impairment in bipolar disorder, comparison with schizophrenia. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/j.euroneuro.2014.09.007 (2014 Sep 16. pii, S0924-977X(14)00259-4), this issue. Bowie, C.R., Depp, C., McGrath, J.A., Wolyniec, P., Mausbach, B.T., Thornquist, M.H., Luke, J., Patterson, T.L., Harvey, P.D., Pulver, A.E., 2010. Prediction of real-world functional disability in
chronic mental disorders, a comparison of schizophrenia and bipolar disorder. Am. J. Psychiatry 167, 1116–1124. Burdick, K.E., Endick, C.J., Goldberg, J.F., 2005. Assessing cognitive deﬁcits in bipolar disorder, are self-reports valid? Psychiatry Res. 136, 43–50. Burdick, K.E., Russo, M., Frangou, S., Mahon, K., Braga, R.J., Shanahan, M., Malhotra, A.K., 2014. Empirical evidence for discrete neurocognitive subgroups in bipolar disorder, clinical implications. Psychol. Med. 44, 3083–3096. Czepielewski, L.S., Massuda, R., Goi, P., Sulzbach-Vianna, M., Reckziegel, R., Costanzi, M., Kapczinski, F., Rosa, A.R., Gama, C.S., 2015. Verbal episodic memory along the course of schizophrenia and bipolar disorder, A new perspective. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/j.euroneuro.2014.09.006 (2014 Sep 16. pii, S0924-977X(14)00258-2), this issue. Daban, C., Martinez-Aran, A., Torrent, C., Tabarés-Seisdedos, R., Balanzá-Martínez, V., Salazar-Fraile, J., Selva-Vera, G., Vieta, E., 2006. Speciﬁcity of cognitive deﬁcits in bipolar disorder versus schizophrenia. A systematic review. Psychother. Psychosom. 75, 72–84. De la Serna, E., Andrés-Perpiñá, S., Puig, O., Baeza, I., Bombin, I., Bartrés-Faz, D., Arango, C., Gonzalez-Pinto, A., Parellada, M., Mayoral, M., Graell, M., Otero, S., Guardia, J., Castro-Fornieles, J., 2013. Cognitive reserve as a predictor of two year neuropsychological performance in early onset ﬁrst-episode schizophrenia. Schizophr. Res. 143, 125–131. Deckersbach, T., Nierenberg, A.A., Kessler, R., Lund, H.G., Ametrano, R.M., Sachs, G., Rauch, S.L., Dougherty, D., 2010. RESEARCH: cognitive rehabilitation for bipolar disorder: an open trial for employed patients with residual depressive symptoms. CNS Neurosci. Ther. 16, 298–307. Durand, D., Strassnig, M., Sabbag, S., Gould, F., Twamley, E.W., Patterson, T.L., Harvey, P.D., 2015. Factors inﬂuencing selfassessment of cognition and functioning in schizophrenia: implications for treatment studies. Eur. Neuropsychopharmacol. http: //dx.doi.org/10.1016/j.euroneuro.2014.07.008 (2014 Jul 25. pii: S0924-977X(14)00205-3), this issue. Forcada, I., Mur, M., Mora, E., Vieta, E., Bartrés-Faz, D., Portella, M.J., 2015. The inﬂuence of cognitive reserve on psychosocial and neuropsychological functioning in bipolar disorder. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/j.euroneuro.2014.07.018 (2014 Aug 15. pii: S0924-977X(14)00232-6), this issue. Fountoulakis, K.N., Vieta, E., Bouras, C., Notaridis, G., Giannakopoulos, P., Kaprinis, G., Akiskal, H., 2008. A systematic review of existing data on long-term lithium therapy: neuroprotective or neurotoxic? Int. J. Neuropsychopharmacol. 11, 269–287. Fuentes-Durá, I., Balanzá-Martínez, V., Ruiz-Ruiz, J.C., Martinez-Aran, A., Girón, M., Solé, B., Sanchez-Moreno, J., Gómez-Beneyto, M., Vieta, E., Tabarés-Seisdedos, R., 2012. Neurocognitive training in patients with bipolar disorders: current status and perspectives. Psychother. Psychosom. 81, 250–252. Goodwin, G.M., Martinez-Aran, A., Glahn, D.C., Vieta, E., 2008. Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? Eur. Neuropsychopharmacol. 18, 787–793. Greer, T.L., Grannemann, B.D., Chansard, M., Karim, A.I., Trivedi, M.H., 2015. Dose-dependent changes in cognitive function with exercise augmentation for major depression: results from the TREAD study. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/j.euroneuro. 2014.10.001 (2014 Oct 18. pii: S0924-977X(14)00277-6), this issue. Harvey, P.D., Siu, C.O., Hsu, J., Cucchiaro, J., Maruff, P., Loebel, A., 2013. Effect of lurasidone on neurocognitive performance in patients with schizophrenia: a short-term placebo- and activecontrolled study followed by a 6-month double-blind extension. Eur. Neuropsychopharmacol. 23 (11), 1373–1382. http://dx.doi. org/10.1016/j.euroneuro.2013.08.003. Epub 2013 Aug 27. Keefe, R.S., Bilder, R.M., Davis, S.M., Harvey, P.D., Palmer, B.W., Gold, J.M., Meltzer, H.Y., Green, M.F., Capuano, G., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O.,
156 Davis, J.A., Hsiao, J.K., Lieberman, J.A., CATIE Investigators, Neurocognitive Working Group, 2007. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch. Gen. Psychiatry. 64 (6), 633–647 (2007 Jun). Keefe, R.S., Davis, V.G., Spagnola, N.B., Hilt, D., Dgetluck, N., Ruse, S., Patterson, T.D., Narasimhan, M., Harvey, PD., 2015. Reliability, validity and treatment sensitivity of the Schizophrenia Cognition Rating Scale. Eur. Neuropsychopharmacol. http: //dx.doi.org/10.1016/j.euroneuro.2014.06.009 (2014 Jun 28. pii: S0924-977X(14)00177-1), this issue. Lahera, G., Herrera, S., Reinares, M., Benito, A., Rullas, M., González-Cases, J., Vieta, E., 2015. Hostile atributions in bipolar disorder and schizophrenia contribute to poor social functioning. Acta Psychiatr. Scand, in press. Lara, E., Olaya, B., Garin, N., Ayuso-Mateos, JL., Miret, M., Moneta, V., Haro, JM., 2015. Is cognitive impairment associated with suicidality? A population-based study. Eur. Neuropsychopharmacol.. http://dx. doi.org/10.1016/j.euroneuro.2014.08.010 (2014 Aug 21. pii: S0924977X(14)00244-2), this issue. Lewandowski, K.E., Cohen, B.M., Keshavan, M.S., Sperry, SH., Ongür, D., 2013. Neuropsychological functioning predicts community outcomes in affective and non-affective psychoses: a 6month follow-up. Schizophr. Res. 148, 34–37. Lewandowski, K.E., Sperry, S.H., Cohen, B.M., Ongür, D., 2014. Cognitive variability in psychotic disorders: a cross-diagnostic cluster analysis. Psychol. Med. 44, 3239–3248. Martinez-Aran, A., Penadés, R., Vieta, E., Colom, F., Reinares, M., Benabarre, A., Salamero, M., Gastó, C., 2002. Executive function in patients with remitted bipolar disorder and schizophrenia and its relationship with functional outcome. Psychother. Psychosom. 71, 39–46. Martinez-Aran, A., Vieta, E., Colom, F., Torrent, C., Reinares, M., Goikolea, J.M., Benabarre, A., Comes, M., Sanchez-Moreno, J., 2005. Do cognitive complaints in euthymic bipolar patients reﬂect objective cognitive impairment? Psychother. Psychosom. 74, 295–302. McGurk, S.R., Twamley, E.W., Sitzer, D.I., McHugo, G.J., Mueser, K.T., 2007. A meta-analysis of cognitive remediation in schizophrenia. Am. J. Psychiatry 164, 1791–1802. McIntyre, R.S., Lophaven, S., Olsen, C.K., 2014. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int. J. Neuropsychopharmacol. 17, 1557–1567. Millan, M.J., Agid, Y., Brüne, M., Bullmore, E.T., Carter, C.S., Clayton, N.S., Connor, R., Davis, S., Deakin, B., DeRubeis, R.J., Dubois, B., Geyer, M.A., Goodwin, G.M., Gorwood, P., Jay, T.M., Joëls, M., Mansuy, I.M., Meyer-Lindenberg, A., Murphy, D., Rolls, E., Saletu, B., Spedding, M., Sweeney, J., Whittington, M., Young, L.J., 2012. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat. Rev. Drug Discov. 11, 141–168. Mora, E., Portella, M.J., Forcada, I., Vieta, E., Mur, M., 2014. Persistence of cognitive impairment and its negative impact on psychosocial functioning in lithium-treated, euthymic bipolar patients: a 6-year follow-up study. Psychol. Med. 43, 1187–1196. Muralidharan, K., Kozicky, J.M., Bücker, J., Silveira, L.E., Torres, I.J., Yatham, L.N., 2015. Are cognitive deﬁcits similar in remitted early bipolar I disorder patients treated with lithium or valproate? Data from the STOP-EM study. Eur. Neuropsychopharmacol. http://dx. doi.org/10.1016/j.euroneuro.2014.09.005 (2014 Sep 16. pii: S0924977X(14)00256-9), this issue. Nuechterlein, K.H., Green, M.F., Kern, R.S., Baade, L.E., Barch, D.M., Cohen, J.D., Essock, S., Fenton, W.S., Frese 3rd, F.J., Gold, J.M., Goldberg, T., Heaton, R.K., Keefe, R.S., Kraemer, H., Mesholam-Gately, R., Seidman, L.J., Stover, E., Weinberger, D.R., Young, A.S., Zalcman, S., Marder, S.R., 2008. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am. J. Psychiatry 165, 203–213.
A. Martinez-Aran, E. Vieta Nutt, D., Gispen-de Wied, C.C., Arango, C., Keefe, R.S., Penadés, R., Murphy, D.G., Robbins, T.W., Sahakian, B.J., 2013. Cognition in schizophrenia: summary nice consultation meeting 2012. Eur. Neuropsychopharmacol. 23, 769–778. Perez-Rodriguez, M., Mahon, K., Russo, M., Ungar, A.K., Burdick, K.E., 2015. Oxytocin and social cognition in affective and psychotic disorders. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/ j.euroneuro.2014.07.012 (2014 Aug 1. pii: S0924-977X(14)00212-0), this issue. Popovic, D., Vieta, E., Fornaro, M., Perugi, G., 2015. Cognitive tolerability following successful long term treatment of major depression and anxiety disorders with SSRi antidepressants. J. Affect. Disord. 173, 211–215. Reeder, C., Harris, V., Pickles, A., Patel, A., Cella, M., Wykes, T., 2014. Does change in cognitive function predict change in costs of care for people with a schizophrenia diagnosis following cognitive remediation therapy? Schizophr. Bull. 40, 1472–1481. Reichenberg, A., Harvey, P.D., Bowie, C.R., Mojtabai, R., Rabinowitz, J., Heaton, R.K., Bromet, E., 2009. Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders. Schizophr. Bull. 35, 1022–1029. Rosa, A.R., Bonnin, C.M., Vázquez, G.H., Reinares, M., Solé, B., Tabarés-Seisdedos, R., Balanzá-Martínez, V., González-Pinto, A., Sanchez-Moreno, J., Vieta, E., 2010. Functional impairment in bipolar II disorder: is it as disabling as bipolar I? J. Affect. Disord. 127, 71–76. Rosa, A.R., Mercadé, C., Sanchez-Moreno, J., Solé, B., Mar Bonnin, C.M., Torrent, C., Grande, I., Sugranyes, G., Popovic, D., Salamero, M., Kapczinski, F., Vieta, E., Martinez-Aran, A., 2013. Validity and reliability of a rating scale on subjective cognitive deﬁcits in bipolar disorder (COBRA). J. Affect. Disord. 150, 29–36. Russo, M., Mahon, K., Burdick, K.E., 2015. Measuring cognitive function in MDD: Emerging assessment tools. Depress. Anxiety in press, http://dx.doi.org/10.1002/da.22297. Samamé, C., Martino, D.J., Strejilevich, S.A., 2012. Social cognition in euthymic bipolar disorder: systematic review and metaanalytic approach. Acta Psychiatr. Scand. 125, 266–280. Sanchez-Moreno, J., Martinez-Aran, A., Tabarés-Seisdedos, R., Torrent, C., Vieta, E., Ayuso-Mateos, JL., 2009. Functioning and disability in bipolar disorder: an extensive review. Psychother. Psychosom. 78, 285–297. Solé, B., Bonnin, C.M., Mayoral, M., Amann, B.L., Torres, I., González-Pinto, A., Jimenez, E., Crespo, J.M., Colom, F., Tabarés-Seisdedos, R., Reinares, M., Ayuso-Mateos, JL., Soria, S., Garcia-Portilla, M.P., Ibañez, A., Vieta, E., Martinez-Aran, A, Torrent, C, the CIBERSAM Functional Remediation Group, 2015. Functional remediation for patients with bipolar II disorder: Improvement of functioning and subsyndromal symptoms. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/j.euroneuro.2014.05.010 (2014a May 20. pii: S0924-977X(14)00148-5), this issue. Solé, B., Jimenez, E., Martinez-Aran, A., Vieta, E., (2015b). Cognition as a target in major depression: new developments. Eur. Neuropsychopharmacol. Stern, Y., 2002. What is cognitive reserve? Theory and research application of the reserve concept. J. Int. Neuropsychol. Soc. 8, 448–460. Torrent, C., Martinez-Aran, A., Daban, C., Amann, B., Balanzá-Martínez, V., Bonnin, C.M., Cruz, N., Franco, C., Tabarés-Seisdedos, R., Vieta, E., 2011. Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients. Compr. Psychiatry 52, 613–622. Torrent, C., Bonnin, C.M., Martinez-Aran, A., Valle, J., Amann, B.L., González-Pinto, A., Crespo, J.M., Ibáñez, A., Garcia-Portilla, M.P., Tabarés-Seisdedos, R., Arango, C., Colom, F., Solé, B., Pacchiarotti, I., Rosa, A.R., Ayuso-Mateos, J.L., Anaya, C., Fernández, P., Landín-Romero, R., Alonso-Lana, S., Ortiz-Gil, J., Segura, B., Barbeito, S., Vega, P., Fernández, M., Ugarte, A., Subirà, M., Cerrillo, E., Custal, N., Menchón, J.M., Saiz-Ruiz, J.,
Cognition as a target in schizophrenia, bipolar disorder and depression Rodao, K.N., Isella, S., Alegría, A., Al-Halabi, S., Bobes, J., Galván, G., Saiz, P.A., Balanzá-Martínez, V., Selva, G., Fuentes-Durá, I., Correa, P., Mayoral, M., Chiclana, G., Merchan-Naranjo, J., Rapado-Castro, M., Salamero, M., Vieta, E., 2013. Efﬁcacy of functional remediation in bipolar disorder: a multicenter randomized controlled study. Am. J. Psychiatry 170, 852–859. Vieta, E., 2009. The inﬂuence of medications on neurocognition in bipolar disorder. Acta Psychiatr. Scand. 120, 414–415. Vieta, E., 2014. The bipolar maze: a roadmap through translational psychopathology. Acta Psychiatr. Scand. 129, 323–327. Volkert, J., Kopf, J., Kazmaier, J., Glaser, F., Zierhut, K.C., Schiele, M.A., Kittel-Schneider, S., Reif, A., 2015. Evidence for cognitive subgroups in bipolar disorder and the inﬂuence of subclinical depression and sleep disturbances. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/j.euroneuro.2014.07.017 (2014 Aug 15. pii: S0924-977X(14)00231-4), this issue. Wingo, A.P., Wingo, T.S., Harvey, P.D., Baldessarini, R.J., 2009. Effects of lithium on cognitive performance: a meta-analysis. J. Clin. Psychiatry 70, 1588–1597. Wykes, T., Huddy, V., Cellard, C., McGurk, S.R., Czobor, P., 2011. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am. J. Psychiatry 168, 472–485.
Yatham, L.N., Torres, I.J., Malhi, G.S., Frangou, S., Glahn, D.C., Bearden, C.E., Burdick, K.E., Martinez-Aran, A., Dittmann, S., Goldberg, J.F., Ozerdem, A., Aydemir, O., Chengappa, K.N., 2010. The International Society for Bipolar Disorders-Battery for Assessment of Neurocognition (ISBD-BANC). Bipolar Disord. 12, 351–363.
Anabel Martinez-Aran Bipolar Disorders Unit, Department of Psychiatry, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Eduard Vietan Bipolar Disorders Unit, Department of Psychiatry, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain E-mail address: [email protected]
10 December 2014; accepted 8 January 2015
Correspondence to: Bipolar Disorder Program. Clinical Institute of Neuroscience. Hospital Clinic of Barcelona, Villarroel, 170. 08036 Barcelona, Spain. Tel.: +34 93 227 54 01; fax: +34 93 227 9228.