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Background Cognitive difficulties have a significant impact on life functioning and overall well-being in patients with psychosis spectrum disorders (PSDs). There are indications that continuous use of benzodiazepines (BZDs) in various patient groups has a detrimental effect on cognition. Our aim was to explore the association between long-term BZD prescription, global functioning, and cognitive functioning in persons with PSD. Methods This exploratory study included 55 PSD patients, recruited from 2 outpatient services in Serbia. Patients were grouped into BZD long-term prescription group and BZD-other group. Brief Psychiatric Rating Scale was used for symptom assessment, functioning was measured by Global Assessment and Functioning Scale, and cognition was assessed by the Global Assessment of Functioning–Cognition in Schizophrenia Scale. Results The sample comprised 52.7% patients who were prescribed with BZD for 6 months or more continually (29/55), with a mean daily dose of 3.16 ± 0.66 mg lorazepam equivalents. There were no differences between study groups in any of the sociodemographic characteristics, duration of illness, or antipsychotic daily dosages. The BZD long-term prescription group had lower global (P < 0.01) and cognitive functioning (P < 0.01), higher Brief Psychiatric Rating Scale scores (1.86 vs 1.58, respectively, P < 0.01), and more psychotropic drugs prescribed on a daily basis than the other group (median: 4 vs 2, respectively, P < 0.01). Conclusions The study explored a topic that continues to be underresearched, especially in the Balkans. Prospective studies and comprehensive cognitive batteries are needed to further elucidate the associations between polypharmacy, long-term BZD use, cognitive functioning, and global functioning during maintenance therapy of individuals with PSD.

Objective The primary objective of this paper is to present a short measure of perceptions on the impact of the COVID-19 pandemic on quality of life, along with analysis of its reliability and validity in non-clinical and clinical samples. Methods The scale was named The COV19 – Impact on Quality of Life (COV19-QoL) and it consists of six items presented in the form of a 5-point Likert scale. The items (i.e. statements) cover main areas of quality of life with regard to mental health. The scale was administered to 1346 participants from the general population in Croatia (the non-clinical sample) and 201 patients with severe mental illness recruited from four European countries (Bosnia and Herzegovina, Montenegro, North Macedonia and Serbia), constituting the clinical sample. The clinical sample was part of the randomised controlled trial IMPULSE funded by the European Commission. Data on age and gender were collected for both samples, along with psychiatric diagnoses collected for the clinical sample. Results Main findings included a high internal consistency of the scale and a moderate to strong positive correlation among participants’ scores on different items. Principal component analysis yielded one latent component. The correlation between participants’ age and their results on COV19-QoL was negligible. Participants’ perceived quality of life was the most impacted domain, whereas mental health, personal safety and levels of depression were the least impacted domains by the pandemic. Discussion The COV19-QoL is a reliable and valid scale which can be used to explore the impact of COVID-19 on quality of life. The scale can be successfully used by researchers and clinicians interested in the impact of the pandemic on people experiencing various pre-existing mental health issues (e.g. anxiety, mood and personality disorders) as well as those without such issues.

Background: Negative symptoms are core features of schizophrenia and very challenging to be treated. Identification of their structure is crucial to provide a better treatment. Increasing evidence supports the superiority of a five-factor model (alogia, blunted affect, anhedonia, avolition, and asociality as defined by the NMIH-MATRICS Consensus); however, previous data primarily used the Brief Negative Symptoms Scale (BNSS). This study, including a calibration and a cross-validation sample (n = 268 and 257, respectively) of participants with schizophrenia, used the Clinical Assessment Interview for Negative Symptoms (CAINS) to explore the latent structure of negative symptoms and to test theoretical and data-driven (from this study) models of negative symptoms. Methods: Exploratory factor analysis (EFA) was carried out to investigate the structure of negative symptoms based on the CAINS. Confirmatory factor analysis (CFA) tested in a cross-validation sample four competing theoretical (one-factor, two-factor, five-factor, and hierarchical factor) models and two EFA-derived models. Result: None of the theoretical models was confirmed with the CFA. A CAINS-rated model from EFA consisting of five factors (expression, motivation for recreational activities, social activities, vocational, and close/intimate relationships) was an excellent fit to the data (comparative fix index = 0.97, Tucker–Lewis index = 0.96, and root mean square error of approximation = 0.07). Conclusions: This study cannot support recent data on the superiority of the five-factor model defined by the NMIH-MATRICS consensus and suggests that an alternative model might be a better fit. More research to confirm the structure of negative symptoms in schizophrenia, and careful methodological consideration, should be warranted before a definitive model can put forward and shape diagnosis and treatment of schizophrenia

The combination of care, medication and psychosocial interventions helps people affected by psychotic disorders to lead productive life and be integrated in society. This approach has been widely recommended and implemented in countries with developed economies, but most of the low and middle income countries (LMIC) are still far from this goal. The reasons for underuse of psychosocial interventions span from financial and organizational issues to insufficient data about the efficacy and safety of non-pharmacological interventions in the local context. In 2018, the European Commission and Global Alliance for Chronic Diseases (GACD) invested 2.4 million Euros in the IMPULSE consortium to deliver a new research study called ‘Implementation of an effective and cost-effective intervention for patients with psychotic disorders in low and middle income countries in South Eastern Europe (IMPULSE). The main goal of the project is to improve treatment of individuals diagnosed with psychotic disorders in five low and middle income countries of Southeast Europe: Bosnia and Herzegovina, Kosovo* UN Resolution, Republic of North Macedonia, Montenegro, and Serbia. The project also focuses on bridging the gap between research and policy, facilitating community-based mental health care, facilitating user-led involvement, and building research capacity in the participating countries. The partners, coordinated by the Queen Mary University of London, conducted a longitudinal trial which involved 468 patients and 81 clinicians from the region to explore effectiveness and implementation of a digital psychosocial intervention called DIALOG+ in healthcare systems of participatingcountries. The DIALOG+ intervention was designed specifically to improve therapeutic effectivenessof routine clinical meetings. The intervention was shown to be effective, cost saving and acceptable to patients and staff in the UK. The IMPULSE study team has created this guide for all who work in the field of mental health care and who have been searching for methods which could improve routine patient-clinician meetings. This Guide offers essential advice on how to understand and to implement a psychosocial approach in order to protect and ameliorate mental health and psychosocial well-being of people with both non-affective and affective psychoses. This publication has been created for clinicians (psychiatrists, psychologists, social workers, andnurses), patients and their caregivers, but also for policy makers and service commissioners and organizers. All of them will find new information which could be used to better integrate people withpsychosis in society.

Background: Cognitive difficulties have a significant impact on life functioning and overall well-being in patients with psychosis spectrum disorders (PSDs). There are indications that continuous use of benzodiazepines (BZDs) in various patient groups has a detrimental effect on cognition. Our aim was to explore the association between long-term BZD prescription, global functioning, and cognitive functioning in persons with PSD. Methods: This exploratory study included 55 PSD patients, recruited from 2 outpatient services in Serbia. Patients were grouped into BZD long-term prescription group and BZD-other group. Brief Psychiatric Rating Scale was used for symptom assessment, functioning was measured by Global Assessment and Functioning Scale, and cognition was assessed by the Global Assessment of Functioning–Cognition in Schizophrenia Scale. Results: The sample comprised 52.7% patients who were prescribed with BZD for 6 months or more continually (29/55), with a mean daily dose of 3.16 ± 0.66 mg lorazepam equivalents. There were no differences between study groups in any of the sociodemographic characteristics, duration of illness, or antipsychotic daily dosages. The BZD long-term prescription group had lower global (P < 0.01) and cognitive functioning (P < 0.01), higher Brief Psychiatric Rating Scale scores (1.86 vs 1.58, respectively, P < 0.01), and more psychotropic drugs prescribed on a daily basis than the other group (median: 4 vs 2, respectively, P < 0.01). Conclusions: The study explored a topic that continues to be under-researched, especially in the Balkans. Prospective studies and comprehensive cognitive batteries are needed to further elucidate the associations between polypharmacy, long-term BZD use, cognitive functioning, and global functioning during maintenance therapy of individuals with PSD.

Face Inversion Effects (FIEs) – differences in response to upside down faces compared to upright faces – occur for both behavioural and electrophysiological responses when people view face stimuli. In EEG, the inversion of a face is often reported to evoke an enhanced amplitude and delayed latency of the N170 event-related potential. This response has historically been attributed to the indexing of specialised face processing mechanisms within the brain. However, inspection of the literature revealed that while the N170 is consistently delayed to photographed, schematic, Mooney and line drawn face stimuli, only naturally photographed faces enhance the amplitude upon inversion. This raises the possibility that the increased N170 amplitudes to inverted faces may have other origins than the inversion of the face’s structural components. In line with previous research establishing the N170 as a prediction error signal, we hypothesise that the unique N170 amplitude response to inverted photographed faces stems from multiple expectation violations, over and above structural inversion. For instance, rotating an image of a face upside down not only violates the expectation that faces appear upright, but also lifelong priors that illumination comes from above and gravity pulls from below. To test this hypothesis, we recorded EEG whilst participants viewed face stimuli (upright versus inverted), where the faces were illuminated from above versus below, and where the models were photographed upright versus hanging upside down. The N170 amplitudes were found to be modulated by a complex interaction between orientation, lighting and gravity factors, with the amplitudes largest when faces consistently violated all three expectations and smallest when all these factors concurred with expectations. These results confirm our hypothesis that FIEs on N170 amplitudes are driven by a violation of the viewer’s expectations across several parameters that characterise faces, rather than a disruption in the configurational disposition of its features.

The purpose of this study was to evaluate the shear bond strength and adhesive remnant index ARI) of orthodontic brackets following enamel conditioning with acid etching, hydroabrasion, and with both procedures. Thirty extracted human premolars were divided into three groups and received either acid etching, hydroabrasion or both procedures. Orthodontic brackets were bonded with composite resin. Shear bond strength was tested with a tensile machine, then the teeth were observed under a stereomicroscope to evaluate ARI scores. The enamel morphology after each conditioning method was evaluated with scanning electron microscope imaging. A one-way ANOVA and a Kruskal&minus, Wallis H test were used to compare the bond strength and the ARI scores among the three groups. Hydroabrasion alone produced shear bond strength values below clinical acceptability, while the combination of acid etching and hydroabrasion produced the highest values. The ARI scores in the hydroabrasion group were significantly different from the other groups. Hydroabrasion followed by acid etching was effective in increasing the shear bond strength of orthodontic brackets. Further in vivo studies are needed to confirm the cost and benefits of this technique.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1–5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p

BackgroundOur previous work revealed substantial heterogeneity in the cognitive profile of bipolar disorder (BD) due to the presence of three underlying cognitive subgroups characterized as: globally impaired, selectively impaired, or cognitively intact. In an effort to determine whether these subgroups are differentially related to genetic risk for the illness, we investigated whether cognitive deficits were more pronounced in unaffected siblings (UAS) of BD probands within identified clusters.MethodsCluster analysis was used to identify cognitive clusters in BD (N = 60). UAS (N = 49) were classified into groups according to their proband sibling's cluster assignment; comparisons were made across all clusters and healthy controls (HCs; N = 71).ResultsThree cognitive clusters in BD emerged: a globally impaired (36.7%), a selectively impaired (30%), and a cognitively intact cluster (33.3%). UAS showed a qualitatively similar pattern to their BD siblings; UAS of the globally impaired BD cluster showed verbal memory and general cognitive impairments relative to HCs. In contrast, UAS of the other two clusters did not differ from HCs.ConclusionsThis study corroborates findings from prior work regarding the presence of cognitive heterogeneity in BD. UAS of subjects in the globally impaired BD cluster presented with a qualitatively similar cognitive profile to their siblings and performed worse than all other BD clusters and UAS groups. This suggests that inherited risk factors may be contributing to cognitive deficits more notably in one subgroup of patients with BD, pointing toward differential causes of cognitive deficits in discrete subgroups of patients with the disorder.

Background: Verbal memory (VM) impairment is prominent in bipolar disorder (BD) and is linked to functional outcomes. However, the intricacies of VM impairment have not yet been studied in a large sample of BD patients. Moreover, some have proposed VM deficits that may be mediated by organizational strategies, such as semantic or serial clustering. Thus, the exact nature of VM break-down in BD patients is not well understood, limiting remediation efforts. We investigated the intricacies of VM deficits in BD patients versus healthy controls (HCs) and examined whether verbal learning differences were mediated by use of clustering strategies. Methods: The California Verbal Learning Test (CVLT) was administered to 113 affectively stable BD patients and 106 HCs. We compared diagnostic groups on all CVLT indices and investigated whether group differences in verbal learning were mediated by clustering strategies. Results: Although BD patients showed significantly poorer attention, learning, and memory, these indices were only mildly impaired. However, BD patients evidenced poorer use of effective learning strategies and lower recall consistency, with these indices falling in the moderately impaired range. Moreover, relative reliance on semantic clustering fully mediated the relationship between diagnostic category and verbal learning, while reliance on serial clustering partially mediated this relationship. Conclusions: VM deficits in affectively stable bipolar patients were widespread but were generally mildly impaired. However, patients displayed inadequate use of organizational strategies with clear separation from HCs on semantic and serial clustering. Remediation efforts may benefit from education about mnemonic devices or “chunking” techniques to attenuate VM deficits in BD. (JINS, 2017, 23, 358–366)

Social cognition deficits are recognized as key features of psychotic disorders, causing significant disability. Recent evidence supports that oxytocin may be a promising treatment to enhance social cognition. In this chapter, we review the biology of endogenous oxytocin, the mechanisms of action of exogenous oxytocin, and the role of oxytocin in social cognition. We present an overview of the current evidence by summarizing clinical trials of oxytocin across the spectrum of psychotic disorders. We also describe the results of clinical trials combining oxytocin with either psychotherapy or cognitive behavioral interventions. The latest literature has demonstrated that oxytocin may improve social cognition in severe mental disorders. Further studies are needed to clarify the therapeutic potential of oxytocin as a treatment for social cognitive deficits in psychotic disorders, and to develop specific evidence-based clinical guidelines.

Background Bipolar disorder (BD) patients encounter significant life adversity, which has contributed to bipolar disorder being a leading cause of disability worldwide. Studies suggest BD patients have more maladaptive coping strategies, some of which can impact their illness course. Yet research on which coping strategies most influence disability is lacking. Such research could inform cognitive-behavioral targets to improve functional outcomes. Thus, we sought to identify relations between coping strategies and real-world function in BD. Methods In 92 affectively-stable BD outpatients, we measured coping strategies via the Brief COPE, real-world disability via the World Health Organization Disability Assessment Schedule, current symptoms, illness chronicity, and neurocognitive functioning via the MATRICS. Multiple regression analysis served to identify the neurocognitive domains predictive of disability for entry into subsequent analyses. Multiple regressions assessed how adaptive and maladaptive coping strategies influenced disability. Results Only one neurocognitive domain, verbal learning, significantly predicted disability and was included in subsequent analyses. Maladaptive coping significantly predicted disability while adaptive coping did not. Behavioral disengagement (giving up) and self-blame were the only remaining predictors of disability, after controlling for age, sex, illness chronicity, current symptoms, and neurocognitive functioning. Limitations The study was limited by the use of a self-report disability measure and a brief-form coping scale. Conclusions Results suggest that giving up and self-blame are significant predictors of real-world functioning beyond sub-threshold depressive symptoms. Our results in BD expand upon recent schizophrenia studies suggesting that defeatist beliefs negatively influence functional outcomes across the range of major psychiatric disorders.

Background The need for mental health care services is particularly high in low and middle income countries (LMICs) where socio-economic factors have a deep impact on treatment and management of psychosis. Lack of funds and qualified professional represent the main challenge to treatment gap leaving between 36% and 45% of people with psychosis without care for their condition thus having a huge impact at individual and societal level. Although data from epidemiological research show that prevalence of psychosis is equal between sexes, some differences in terms of needs for care might be relevant, particularly in a context that has been affected by dramatic socio-economic and cultural changes. In this study we explore in a representative sample of people with psychosis from Kosovo*, as part of a large multi-country study (EU-funded IMPULSE project), whether demographic, socio-economic and clinical differences exist between male and female patients. Methods Data on demographic, socio-economic characteristics, use of psychosocial treatment and medication was collected; general level of psychopathology and negative symptoms were assessed through the Brief Psychiatric Rating Scale, Brief Symptom Inventory and Clinical Assessment Interview for Negative Symptoms. Male and female patients were compared in terms of demographic, socio-economic and clinical characteristics using Chi-square and independent sample t- test as appropriate. Results The sample (n=103) was composed by 33 female and 70 male patients with psychosis. The two groups did not show any statistically significant difference in age, employment, level of education; however, marital status seems to differ with higher proportion of women being separated (p=0.009). No differences emerged in monthly income, while a trend of significance (p=0.079) suggested that female patients had slightly higher financial benefits than their male counterpart. While there was no difference in terms of psychiatric diagnosis, higher depressive (p=0.017) and paranoid symptoms (at trend level, p=0.054) were reported by females patients. There were no differences on antipsychotic medication. Attendance of a psychosocial treatment was higher in male than in female patients (80% vs 57.6%; p=0.017) without any difference though in the type of approach. Overall, patients who attended a psychosocial treatment had lower negative symptoms (p Discussion Female patients with psychosis were found to have a worse clinical presentation compared to male patients, and to have a lower attendance to psychosocial treatment. Regardless of sex, psychosocial treatment seems to be associated to less negative symptomatology. More research is needed to better characterise clinical presentation of people with psychosis in LMICs and to understand whether access to mental health service, particularly psychosocial intervention, is accountable to clinical characteristics or to contextual factors, social and/or economic in nature. Offering psychosocial intervention to this clinical population could alleviate burden of the illness in this clinical population.

Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p < 1 × 10− 10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of > 10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia. We are grateful for the support of all study staff and participants. Acknowledgements for each sample are provided in the Supplementary Materials. Data processing and analyses (of the legacy data) at the central site was supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) grant number R01MH092380 to T.L.P. supporting the Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium, and NIMH grant R21MH109819 to E.D.R. Appendix A

Aim Several studies have suggested that lifetime cannabis consumption and childhood abuse synergistically contribute to the risk for psychotic disorders. This study aimed to extend existing findings regarding an additive interaction between childhood abuse and lifetime cannabis use by investigating the moderating role of type and frequency of cannabis use. Methods Up to 231 individuals presenting for the first time to mental health services with psychotic disorders and 214 unaffected population controls from South London, United Kingdom, were recruited as part of the Genetics and Psychosis study. Information about history of cannabis use was collected using the Cannabis Experiences Questionnaire. Childhood physical and sexual abuse was assessed using the Childhood Experience of Care and Abuse Questionnaire. Results Neither lifetime cannabis use nor reported exposure to childhood abuse was associated with psychotic disorder when the other environmental variable was taken into account. Although the combination of the two risk factors raised the odds for psychosis by nearly three times (adjusted OR = 2.94, 95% CI: 1.44–6.02, P = 0.003), no evidence of interaction was found (adjusted OR = 1.46, 95% CI: −0.54 to 3.46, P = 0.152). Furthermore, the association of high-potency cannabis and daily consumption with psychosis was at least partially independent of the effect of childhood abuse. Conclusions The heavy use of high-potency cannabis increases the risk of psychosis but, in addition, smoking of traditional resin (hash) and less than daily cannabis use may increase the risk for psychosis when combined with exposure to severe childhood abuse.

Backgrounds Sleep and circadian rhythm disruptions are prominent, trait-like features of bipolar disorder (BD) which precede the onset of mood episodes. Neurocognitive impairments also characterize BD not only during acute phases of the illness but also during remission. Although the relationship between these two debilitating aspects of the illness might seem intuitive, very little is known about their relationship. We examined the association between sleep dysfunction and neurocognition in BD. Methods In a sample of 117 BD patients (mean age=45.0±10.7; 59.0% ( n =69) male), neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Sleep quality data were collected using the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). Partial Pearson correlations tested for a relationship between sleep and neurocognition. Path analyses were conducted to examine the hypothesized direct influence of sleep disruption on neurocognition. Results Higher levels of sleep disruptions were associated with a more severe clinical presentation and poorer performance in social cognition, visual learning and working memory. Social cognition and working memory were directly (negatively) predicted by sleep disruptions. Limitations The study was limited by a relatively small sample size and the lack of behavioral and biological objectives measure of activity/rest cycles. Conclusions Our study suggests that in patients with BD, sleep disruptions have a detrimental effect on general level of psychopathology and contribute directly to impaired cognitive functioning in the domains of social cognition and working memory. More research using objective measurement of sleep should be pursued to support these data and to further investigate the causal relationship between these disabling aspects of the illness.

Many patients with bipolar disorder (BD) have difficulties in facial emotion recognition, which may also be impaired in maltreated children and in subjects who have a positive history of childhood traumatic experiences. Childhood trauma is reported with a high prevalence in BD and it is considered a risk factor for the disorder. As the relationship between facial emotion recognition and childhood trauma in BD has not yet been directly investigated, in this study we examined whether the presence of a childhood trauma in affectively stable BD patients was associated with poorer performance in emotion recognition. Seventy-five BD I and II participants completed the Childhood Trauma Questionnaire retrospectively assessing five types of childhood trauma (emotional, physical and sexual abuse, and emotional and physical neglect) and the Emotion Recognition Task evaluating the ability to correctly identify six basic facial emotions (happiness, sadness, anger, disgust, fear and surprise). Our results suggest that the presence of childhood trauma in participants with BD is associated with a more severe clinical presentation (earlier onset, longer duration of illness, and higher depressive symptom ratings) and that BD patients with a positive childhood history of emotional neglect perform worse than those without such a history in recognizing anger.

Bipolar disorder is a heterogeneous, complex, multidimensional neuropsychiatric condition characterized by episodes of (hypo)mania and depression. The neurobiology of bipolar disorder is undoubtedly complicated, and much remains to be discovered regarding the neural and genetic correlates of this disorder. In the present work, we present an update on what is currently known regarding the neurobiology of bipolar disorder with a focus on data from neuroimaging and genetic studies. Magnetic resonance imaging studies suggest alterations in both the structure and function of prefrontal and cortical regions implicated in emotion regulation and cognition. Genetic studies have identified several risk variants for the disorder, yet the functional relevance of these variants remains to be clarified. Future studies that take into account the phenotypic heterogeneity of bipolar disorder are likely to advance our understanding of the neurobiology of this complicated neuropsychiatric illness.

Background: There is evidence that patients with bipolar disorder (BD) score higher on affective temperament ratings compared to healthy controls (HCs). Moreover, unaffected relatives demonstrate similar patterns as BD patients suggesting that such temperaments are related to the genetic risk for BD and may serve as endophenotypes for the disorder. It is unknown whether affective temperaments are associated with other core features of BD, such as impairments in neurocognition. This study examined the relationship between affective temperaments and neurocognition in patients with BD and in HCs. Methods: Temperaments were evaluated using the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego, Auto-questionnaire version (TEMPS-A) in 64 patients with BD and 109 HCs. Neurocognitive functioning was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). Correlational analyses between temperaments and cognition were conducted in BD and HC subjects. Results: Data suggest that affective temperaments and neurocognition are correlated. In BD higher ratings of cyclothymia and irritability were associated with better processing speed, working memory, reasoning and problem-solving. In the HC group, increased irritability was related to worse performance on measures of attention and social cognition. Limitations: Lack of functional outcome measures to evaluate the impact of temperaments and cognition on psychosocial functioning. It would be useful to test these findings on unaffected relatives of BD patients. Conclusions: Cyclothymic and irritable temperaments are correlated with specific aspects of neurocognition in BD. This study is among the few exploring the dimensional relationship between temperaments and cognition in BD, and provides preliminary evidence for future studies investigating the neural and genetic mechanisms underlying the association between these variables.

Neurocognitive deficits are acknowledged as integral features of bipolar disorder (BD) and are known to contribute to the compromised level of functioning in individuals with BD. This chapter provides an overview of the current state of cognitive enhancement in BD. Few pharmacological agents have been investigated with regard to their potential for pro-cognitive effects in BD. Dopaminergic agents (pramipexole) and stimulants (modafinil, armodafinil, and amphetamine) as adjunctive treatment in BD appear to be promising cognitive enhancers, and there are few ongoing randomized clinical trials targeting both cognitive dysfunctions and clinical symptomatology in BD. Glutamatergic agents (d-cycloserine) may hold promise as potential cognitive enhancing agents in BD; however, as for dopaminergic agents and stimulants, no conclusive data exist. Larger samples and longer follow-up are needed to obtain a deep understanding of the efficacy and safety of these compounds and their role in the neurobiological mechanisms underpinning cognition in BD.

Background The Brain-derived Neurotrophic Factor (BDNF) modulates cognitive processes and is associated with increased risk of schizophrenia. Childhood trauma (CT) is frequent in patients with psychosis and severely affects course and outcome. Aims We investigated the hypothesis that BDNF is associated with both CT and cognitive deficits in a sample of first-episode psychosis (FEP) cases and unaffected controls. Method Participants with FEP and healthy controls were recruited between August 2008 and July 2011 from South London, UK. Childhood traumatic events were detected using the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Neuropsychological data were also collected. BDNF plasma levels were measured from fasting blood samples. Results Data were available on 87 FEP patients and 152 controls. Our results showed a significant effect of separation (F = 5.5; df = 1,115; p = .02), physical (F = 4.7; df = 1, 118; p = .03) and sexual abuse (F = 5.4; df = 1,117; p = .02) on BDNF levels with lower levels among those who experienced the traumatic event compared to those who did not. Physical abuse predicted lower plasma levels of BDNF (β = − .30; p = .03) whereas sexual and/or physical abuse showed a trend (β = − .26; p = .06) in FEP patients but not in unaffected controls. No association between BDNF plasma levels and cognitive functions was found among patients with FEP and controls. Conclusion Our findings suggest the possible involvement of BDNF in the onset of first-episode psychosis in individuals exposed to early trauma and propose BDNF as a potential clinical biomarker to detect the detrimental effects of CT on human brain plasticity.

PurposeThis study investigates the effect of sex and childhood trauma on affective processing in bipolar disorder (BPD) patients.MethodsIn a sample of fifty-six BPD patients, we administered the Childhood Trauma Questionnaire (CTQ), and the Iowa Gambling Task (IGT) and the Affective Go/No-Go (AGNG) to measure affective processing. Analysis of Variance (ANOVA) was used to evaluate the effect of sex and childhood trauma on IGT; Repeated-Measures ANOVAs to measure accuracy and bias measures across conditions on the AGNG.ResultsIn the context of childhood abuse, females evidenced a more conservative cognitive style than males by selecting fewer cards from the disadvantageous decks [F(1, 49) = 14.218;P< 0.001] and showed an improvement throughout the task, as noted in a normal learning curve [F(1.49) = 4.385;P= 0.041)]. For the AGNG, an interaction specific to the negative valence stimuli on response bias measures was found. Abused females scored higher (mean = 8.38; SD = 6.39) than abused males (mean = 0.69; SD = 1.19) [F(1.46) = 6.348;P= 0.015].ConclusionSeverity of childhood trauma was significantly different between sexes. In the context of a history of emotional abuse, male bipolar patients tended toward a more risk-taking behavior compared to female. Further investigations are needed to elucidate potential pathophysiological mechanisms underlying this interaction.

Background Psychotic disorders are characterized by large heterogeneity in clinical presentation, response to treatment and cognitive functioning. Indeed, there is evidence of the presence of cognitive subgroups of patients across affective and non-affective psychosis. However, very little is known about these subgroups in first episode psychosis (FEP) and whether they can be informative about course of illness, particularly response to treatment. The aim of this study is to investigate the number and the pattern of cognitive clusters in FEP, their external validity and association with treatment response at 12-week and 1-year follow up. Methods The sample was composed by a total of 212 participants including 105 FEP patients from the South London and Maudsley Foundation Trust and 107 Healthy Controls (HC). All participants underwent a comprehensive clinical and neurocognitive battery. Z-score [mean=0, and standard deviation (SD)=1] were created for the whole sample based on the neurocognitive performance of the HCs. Treatment response at 12-week and 1-year follow-up was used to explore potential utility of subtypes in predicting response to treatment. Hierarchical cluster analysis was carried out to determine the number of cognitive clusters in FEP patients. A series of analyses of variance were carried out to determine if FEP clusters differed among each other in relation to demographic and clinical characteristics, level of functioning and from the HC sample in term of cognitive performance. Logistic regression was used to explore whether cognitive clustering was predictive of treatment response at 12-week and 1-year FU. Results Four cognitive clusters emerged: one with near normal cognition (42.9% of the FEP patients) with a general cognitive score of z=-0.20, one with selected cognitive deficits (14.3%) in the domains of verbal memory, processing speed and executive functions (general cognitive score of z=-0.55); and two severe deficit clusters consisting in one cluster with severe deficits (33.3%; general score of z=-1.48) and the other with a deeply compromised cognitive ability (9.55%; general cognitive score of z=-2.34). There were no significant differences between clusters in terms of clinical features at baseline (including diagnosis, positive and negative symptoms, medication), apart from the level of functioning that was significantly lower in the severely compromised cluster compared to the near normal cognition cluster. It emerged that majority (about 68%) of the patients from the near normal cognition cluster were responsive to treatment, whilst the majority of the selective and severely impaired clusters did not respond to treatment at 12-week follow-up. There were no significant results with regard to treatment response at 1-year FU. Discussion Distinct patterns of cognitive impairments exist within FEP that might be characterized by different response to treatment. Clinical presentation at the onset of the illness is not useful in predicting response to treatment later on in the course of the illness, while cognitive functioning might be a more valid indicator. Cognitive stratification could represent a promising way forward to elucidate pathophysiology of psychosis and to provide tailored interventions.

Background: The insight into psychosis can be assessed reliably by clinicians from interviews with patients. However, patients may retain implicit awareness of illness while lacking explicit awareness. Sampling and Methods: In a sample of first-episode psychosis patients, we used a test of processing of mental illness-related and other negative words as a measure of implicit awareness to see how this varied in relation to insight. An emotional-counting Stroop task tested reaction times to words of three types: psychosis-related (e.g. ‘crazy'), general negative (e.g. ‘cancer') and neutral (e.g. ‘oyster'). Data were available from 43 patients and 23 healthy controls. Patients' insight was assessed using the Schedule for the Assessment of Insight (SAI-E). Results: Patients reacted slower than controls to words across all conditions, and both patients and controls reacted slower to salient and negative words than neutral words. There was a near significant interaction between word type and group (Wilks' lambda = 0.53, p = 0.055); patients experienced greater interference from negative rather than psychosis-related words (p = 0.003), and controls experienced greater interference from salient rather than negative words (p = 0.01). Within the patient group, there was a correlation between insight and interference on salient words (r = 0.33, p = 0.05), such that those with less insight experienced less interference on psychosis-related words. Conclusions: Psychosis-related words were less threatening and less self-relevant to psychosis patients with less insight. This suggests that the lack of awareness such patients have of their illness is genuine and more likely to be mediated by lower-level information processing mechanisms than strategies such as conscious, motivated denial.

Objectives Several studies have documented the prevalence and effects of cigarette smoking on cognition in psychotic disorders; fewer have focused on bipolar disorder (BD). Cognitive and social dysfunction are common in BD, and the severity of these deficits may be related both to illness features (e.g., current symptoms, psychosis history) and health-related behaviors (e.g., smoking, alcohol use). The current study assessed the influence of cigarette smoking on general and social cognition in a BD cohort, accounting for illness features with a focus on psychosis history. Methods We assessed smoking status in 105 euthymic patients with BD, who completed a comprehensive battery including social (facial affect recognition, emotional problem-solving, and theory of mind) and general (the MATRICS Consensus Cognitive Battery and executive functioning) cognitive measures. We compared smokers vs nonsmokers on cognitive performance and tested for the effects of psychosis history, premorbid intellectual functioning, substance use, and current affective symptoms. Results Within the nonpsychotic subgroup with BD (n=45), smokers generally outperformed nonsmokers; by contrast, for subjects with BD with a history of psychosis (n=41), nonsmokers outperformed smokers. This pattern was noted more globally using a general composite cognitive score and on social/affective measures assessing patients’ ability to identify emotions of facial stimuli and solve emotional problems. Conclusions Cigarette smoking differentially affects performance on both general and social cognition in patients with BD as a function of psychosis history. These results suggest that there may be at least partially divergent underlying neurobiological causes for cognitive dysfunction in patients with BD with and without psychosis.

BACKGROUND: An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis. METHOD: We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed. RESULTS: Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long-standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact. CONCLUSIONS: Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood.

Background - Associations between symptom dimensions and cognition have been mainly studied in non-affective psychosis. The present study investigated whether previously reported associations between cognition and four symptom dimensions (reality distortion, negative symptoms, disorganisation and depression) in non-affective psychosis generalise to a wider spectrum of psychoses. It also extended the research focus to mania, a less studied symptom dimension. Methods - Linear and non-linear (quadratic, curvilinear or inverted-U-shaped) associations between cognition and the above five symptom dimensions were examined in a population-based cohort of 166 patients with first-onset psychosis using regression analyses. Results - Negative symptoms showed statistically significant linear associations with IQ and processing speed, and a significant curvilinear association with verbal memory/learning. Significant quadratic associations emerged between mania and processing speed and mania and executive function. The contributions of mania and negative symptoms to processing speed were independent of each other. The findings did not differ between affective and non-affective psychoses, and survived correction for multiple testing. Conclusions - Mania and negative symptoms are associated with distinct patterns of cerebral dysfunction in first-onset psychosis. A novel finding is that mania relates to cognitive performance by a complex response function (inverted-U-shaped relationship). The associations of negative symptoms with cognition include both linear and quadratic elements, suggesting that this dimension is not a unitary concept. These findings cut across affective and non-affective psychoses, suggesting that different diagnostic entities within the psychosis spectrum lie on a neurobiological continuum.

Insight in psychosis is a multi-dimensional phenomenon, and has been hypothesised to have some sort of neuropsychological basis. It is unclear to what extent specific neuropsychological abilities are able to predict insight beyond the effect of generalised cognitive ability. We aimed to test this, alongside the relationship of insight with illness duration and diagnosis, in a sample of first episode psychosis patients. We recruited 102 patients experiencing their first episode of psychosis and assessed their insight, symptoms, diagnosis as well as administering a full neuropsychological battery. Low insight was related to worse performance in a variety of neuropsychological tasks. Regression analysis tested whether any specific tasks were related to insight (or dimensions of insight) beyond the effect of IQ. Verbal memory had an effect on total insight and all dimensions of insight (except compliance) beyond the effect of IQ. Insight appeared to vary with diagnosis, with those diagnosed with depressive affective psychoses having better insight than those with manic affective psychoses. There was no relationship between insight and DUP, but there was a relationship between time spent in treatment before assessment and insight, even after controlling for severity of symptoms. The results taken together suggest a model of insight in early psychosis with a significant neuropsychological component, particularly with verbal memory but also with generalised cognitive ability. There is likely to be a social component to insight affected by initial time spent in contact with treatment, helping patients to understand and come to terms with their illness.

Background Cognitive impairment, particularly in memory and executive function, is a core feature of psychosis. Moreover, psychosis is characterized by a more prominent history of stress exposure, and by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In turn, stress exposure and abnormal levels of the main HPA axis hormone cortisol are associated with cognitive impairments in a variety of clinical and experimental samples; however, this association has never been examined in first-episode psychosis (FEP).Method In this study, 30 FEP patients and 26 controls completed assessment of the HPA axis (cortisol awakening response and cortisol levels during the day), perceived stress, recent life events, history of childhood trauma, and cognitive function. The neuropsychological battery comprised general cognitive function, verbal and non-verbal memory, executive function, perception, visuospatial abilities, processing speed, and general knowledge.Results Patients performed significantly worse on all cognitive domains compared to controls. In patients only, a more blunted cortisol awakening response (that is, more abnormal) was associated with a more severe deficit in verbal memory and processing speed. In controls only, higher levels of perceived stress and more recent life events were associated with a worse performance in executive function and perception and visuospatial abilities.Conclusions These data support a role for the HPA axis, as measured by cortisol awakening response, in modulating cognitive function in patients with psychosis; however, this association does not seem to be related to the increased exposure to psychosocial stressors described in these patients. © 2010 Cambridge University Press., link_to_OA_fulltext

Background: Prognostic biomarkers for psychosis are still unknown and there is a substantial proportion of patients that fails to respond to antipsychotic medications. Neurocognitive functioning, as an intermediate phenotype of psychosis, might have a prognostic role in identifying subgroups of patients with different pathophysiological profiles accountable for treatment response. This study explored whether neurocognitive performance in first-episode psychosis (FEP) patients can predict clinical response after 12 weeks of treatment with antipsychotics.

Summary Background The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders. Methods We applied adjusted logistic regression models to data from patients aged 18–65 years presenting to South London and Maudsley NHS Foundation Trust with first-episode psychosis and population controls recruited from the same area of south London (UK) to estimate the effect of the frequency of use, and type of cannabis used on the risk of psychotic disorders. We then calculated the proportion of new cases of psychosis attributable to different types of cannabis use in south London. Findings Between May 1, 2005, and May 31, 2011, we obtained data from 410 patients with first-episode psychosis and 370 population controls. The risk of individuals having a psychotic disorder showed a roughly three-times increase in users of skunk-like cannabis compared with those who never used cannabis (adjusted odds ratio [OR] 2·92, 95% CI 1·52–3·45, p=0·001). Use of skunk-like cannabis every day conferred the highest risk of psychotic disorders compared with no use of cannabis (adjusted OR 5·4, 95% CI 2·81–11·31, p=0·002). The population attributable fraction of first-episode psychosis for skunk use for our geographical area was 24% (95% CI 17–31), possibly because of the high prevalence of use of high-potency cannabis (218 [53%] of 410 patients) in our study. Interpretation The ready availability of high potency cannabis in south London might have resulted in a greater proportion of first onset psychosis cases being attributed to cannabis use than in previous studies. Funding UK National Institute of Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health, SLaM and the Institute of Psychiatry at King's College London, Psychiatry Research Trust, Maudsley Charity Research Fund, and th European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909 [Project EU-GEI]).

Impairments in social cognition are now recognized as core illness features in psychotic and affective disorders. Despite the significant disability caused by social cognitive abnormalities, treatments for this symptom dimension are lacking. Here, we describe the evidence demonstrating abnormalities in social cognition in schizophrenia, major depressive disorder, and bipolar disorder, as well as the neurobiology of social cognition including the role of oxytocin. We then review clinical trials of oxytocin administration in psychotic and affective disorders and the impact of this agent on social cognition. To date, several studies have demonstrated that oxytocin may improve social cognition in schizophrenia; too few studies have been conducted in affective disorders to determine the effect of oxytocin on social cognition in these disorders. Future work is needed to clarify which aspects of social cognition may be improved with oxytocin treatment in psychotic and affective disorders.