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Negative symptoms are core symptoms of schizophrenia associated with poorer clinical outcome (Strauss et al., 2010). They can be clinically subdivided into primary and secondary features, representing different phenomenology and pathophysiological mechanisms (Miller et al., 1994). Secondary negative symptoms phenotypically present as primary symptoms, but are attributed to external causes. Positive symptom severity, depression and antipsychotic side-effects are known sources of secondary negative symptoms (Carpenter et al., 1985). Discriminating whether a negative symptom is primary or secondary is clinically relevant as it might require specific, and often opposite interventions (Miller et al., 1994). Despite the development of new symptom severity rating scales, none have considered this distinction.

Background Schizophrenia is a complex medical entity with a reduced life expectancy, mostly due to an increased prevalence of cardiovascular diseases compared to the general population. An unbalanced immune response and a pro-inflammatory state might underlie this process. In treated patients, abnormal white blood cell (WBC), lymphocyte and neutrophil count suggests atypical immune response related to clinical variables. We aimed to test the hypothesis that newly diagnosed naive patients with non-affective psychosis would show abnormal blood cell count values after controlling for potential confounding factors compared to matched controls. Methods Seventy-five patients were compared with 80 controls matched for age, gender, body mass index and smoking. Analyses were conducted before and after controlling for smoking. Results Patients and controls displayed similar mean values (×103/μL [SD]) for WBC count 7.02 [2.2] vs 6.50 [1.7] (P = .159), neutrophil count 4.25 [1.8] vs 3.84 [1.3] (P = .110) and monocyte count 0.43 [0.2] vs 0.40 [0.1] (P = .326). After controlling for smoking, 38 non-smoking patients showed a higher WBC and neutrophil count compared with 49 matched controls. Respective means of 7.01 [2.2] vs 5.97 [1.4] (P = .011) for WBC and 4.24 [1.9] vs 3.51 [1.2] (P = .028) for neutrophil count. Monocyte count showed an increased mean value 0.43 [0.2] vs 0.36 [0.1] with a trend towards signification (P = .063). Conclusions These results suggest that abnormal immune response is present before the effects of medication and other confounders had taken place. Increased immune parameters might underlie the high ratio of medical co-morbidities described in schizophrenia.

Although an interaction between COMT Val158Met and BDNF Val66Met polymorphisms with cannabis use has been proposed with respect to the risk of psychosis emergence, findings remain inconclusive. The aim of the present study was to evaluate the different possible associations between these polymorphisms and early cannabis use and the age at the first episode of psychosis. The relationship between age at psychosis onset and COMT Val158Met and BDNF Val66Met polymorphisms with early cannabis use as well as those factors associated with early cannabis use were investigated. Among 260 Caucasian first-episode psychosis patients, early cannabis use and the presence of the met-allele from the BDNF Val66Met polymorphism were significantly associated with age at psychosis onset. Furthermore, early cannabis use was significantly associated with male gender in the logistic regression analysis. These findings provide evidence of the important role of early cannabis use and the Val66Met BDNF polymorphism on age at psychosis onset and they point out to sex-specific differences in cannabis use patterns.

Background Patients with schizophrenia display a wide and characteristic array of cognitive deficits. A range of factors has been shown to influence cognition, including cognitive reserve (CR). Amongst antipsychotics only clozapine has shown positive results on cognition to date. Although it is known that delayed initiation of clozapine may be related to poor clinical psychotic response, no previous results have been tested on relation to cognitive improvements. This study aimed to analyze the improvement in cognitive performance after starting clozapine treatment according to the early versus late treatment initiation after diagnosis. Methods 41 patients with schizophrenia were enrolled. All subjects were assessed clinically, neuropsychologically and functionally at baseline and at the 18th week of clozapine treatment. Premorbid IQ was calculated with the vocabulary subtest of the WAIS-III and it was considered a measure of CR. For study purposes, sample was divided into early or late treatment initiation of clozapine (± 3 years after diagnosis). Lineal mixed model analyses were used while confounding from different factors. Results There were no differences between groups in terms of gender, functional, clinical and neuropsychological outcomes at baseline and follow-up. Neither clozapine dose, nor plasma concentration of nor-clozapine, have been found to be different at 18 weeks. Significant difference in age was found (p Discussion There were no differences between groups at baseline, except for age. Patients who started an early treatment of clozapine improved more cognitive domains at 18-week that those who started it later. In both cases, CR is a key factor in predicting cognitive improvement. Reducing clozapine treatment delay might represent immediate prospective improvements on cognitive domains in comparison with delayed start. Time-wise cognitive monitoring and CR enhancement at early stages of the psychotic illness/treatment may be helpful in order to prevent cognitive impairment.

Background Family environment plays a key role in the development of psychotic symptoms (Pitschel-Walz et al., 2001; Tienari et al., 2004) and negative family environmental factors are linked to poor prognosis in psychosis (Geller et al., 2000). By contrast, a positive family environment is associated with greater improvements in negative and disorganized symptoms among individuals at imminent risk of becoming psychotic (O’Brien et al., 2006). Nonetheless, little is known about the implication of family environment on longitudinal functioning in patients that presented a first psychotic episode. Methods This study is part of the “Phenotype-genotype and environmental interaction. Application of a predictive model in first psychotic episodes” (PEPS) study, a multicentric, longitudinal, naturalistic follow-up study (Bernardo et al., 2013). The Functional Assessment Short Test (FAST) was used to assess functional outcome. The Family Environment Scale (FES) evaluated family emotional climate in different categories: COHESION (C) for mutual reliance; EXPRESSIVITY (EX), the extent to which family members express their feelings directly; CONFLICTS (CON) for open expression of anger, aggressiveness and conflict; INDEPENDENCE (IND), the extent to which family members are independent in their decisions; ACHIEVEMENT ORIENTATION (AO) for an achievement-orientated environment; INTELLECTUAL–CULTURAL ORIENTATION (ICO) for political, intellectual, cultural interests; ACTIVE–RECREATIONAL ORIENTATION (ARO) for participation in social activities; MORAL–RELIGIOUS EMPHASIS (MRE) for the importance given to ethical and religious practices and values; ORGANIZATION (ORG) for the organization in activities and responsibilities; and CONTROL (CTL), the extent to which the family considers rules and established procedures. Patients with a first psychotic episode (FEPs) and healthy controls (HCs) have been evaluated baseline and after two years of follow-up. Diagnoses at 2 years have been established according to the Structured Clinical Interview for DSM-IV. Linear regression models have been conducted in order to assess the effect that different family environments exert on functioning at baseline but also at 2 years of follow-up, when the group of FEPs has been divided in patients diagnosed with psychotic disorders (PSYC) versus bipolar disorder (BD). All data were analyzed with the Statistic Package for Social Sciences (SPSS v.23 for Windows). All the analyses were two-tailed with alpha set at p < 0.05. Results At baseline, the total sample included 335 FEPs (mean FAST=27.8±16.1) and 253 HCs (mean FAST 3.5±8.1). At baseline the linear model was not significant neither for FEPs nor for HCs and no family environment was associated with functioning. At 2 years (mean FAST BD=13.8±15.1, mean FAST PSYC =20.98±15.4), in the BD group (F(10,14)=2.6, p=.05) worse functioning was associated with CON (β=.741, p=.004) whilst in the PSYC group (F(10,108)=3.509, p= Discussion At baseline, no specific family environment was associated with functioning. At 2 years, in BD worse functioning was associated with higher rates of open expression of conflict in the family whilst in PSYC it was associated with lower rates of participation in social activities and achievement-orientated family environment as well as with higher rates of religious practices and values. Family environment exerts an important role in the functioning of FEPs mainly in the long-term, with important implications for early interventions for both patients and caregivers.

Background In a unique deeply phenotyped longitudinal dataset consisting of first-episode psychosis (FEP) patients with a wide age at FEP onset (15 to 35 years) and healthy controls, we aimed to determine whether cortical abnormalities are already present at FEP, whether they progress further over the first two years of the illness, and, if so, whether change patterns are associated with age at first episode. Methods Multicenter (four-site) two-year follow-up case-control brain magnetic resonance imaging study; 74 patients with a FEP of less than 12 months’ duration, and 64 healthy controls (matched for age, sex, parental socioeconomic status and handedness) were scanned twice (median time between baseline and follow-up scan 24 months, range [16 – 32]). We computed percentage changes (PC) over follow-up in thickness/area/volume for frontal, temporal, parietal and occipital lobes. We included diagnosis (patient vs. control), age at baseline scan, sex, TBV and site as potential confounders. We conducted post-hoc comparisons for young (≤19y) and adult (>19y) diagnostic pairs (FEP vs healthy controls). Results A significant age-by-diagnosis interaction was only found for temporal lobe cortical thickness (CT)-PC (d = -.54, p = .002). Within this lobe, the largest effects for the age x diagnosis interaction were found in the middle (d = -.43, p = .01) and inferior (d = - .48, p = .007) temporal gyrus CT-PC. The younger the patient group, the greater temporal thinning relative to their age-matched control group. The most extreme patient vs. control PC difference (i.e. the largest effect size) was found at an age cut-off of 19 years (d=0.9, p= .01). Discussion In individuals with psychosis, the two-year cortical changes that follow the FEP are dependent of age at first episode, with those with an earlier onset showing more severe cortical thinning in the temporal lobe.

OBJECTIVE The aim of this study was to identify predisposing factors and clinical features at baseline that might help predict diagnosis of bipolar disorder vs schizophrenia in a first-episode psychosis (FEP) cohort. METHODS In this prospective, naturalistic study, we evaluated a cohort of 335 subjects with FEP recruited from April 2009 to April 2012. Baseline features were compared between subjects with a final DSM-IV diagnosis of bipolar disorder and schizophrenia at 12-month follow-up. A binary logistic regression model was used to assess predictors of diagnosis of bipolar disorder at follow-up. RESULTS At 12-month follow-up, 47 of the 335 subjects included in the study received the diagnosis of bipolar disorder and 105, of schizophrenia. Subjects with a final diagnosis of bipolar disorder had a higher prevalence of family history of mood disorders (38.2% vs 18.0%, P = .02), better baseline premorbid adjustment (Premorbid Adjustment Scale [PAS]: 38.4 vs 50.6, P < .01) and psychosocial functioning (Functional Assessment Short Test [FAST]: 23.6 vs 33.7, P = .001), better cognitive flexibility (number of perseverative errors on the Wisconsin Card Sorting Test [WCST]: 14.2 vs 19.7, P = .01), more manic symptoms (Young Mania Rating Scale [YMRS]: 14.1 vs 7.3, P < .01), lesser negative symptoms (Positive and Negative Syndrome Scale negative scale [PANSS-N]: 15.0 vs 22.3, P < .001), and shorter duration of untreated psychosis (144.2 vs 194.7 days, P < .01) than subjects with a schizophrenia diagnosis. Binary logistic regression model revealed that lower FAST scores (odds ratio [OR] = 0.956; P = .015), lower PANSS-N scores (OR = 0.93; P = .048), and lower number of perseverative errors on the WCST (OR = 0.946; P = .035) were significantly related to diagnosis of bipolar disorder at follow-up. CONCLUSIONS In our FEP cohort, better psychosocial functioning, lesser negative symptoms, and better cognitive flexibility were related to diagnosis of bipolar disorder at 12-month follow-up.

(1) Background: The cognitive reserve (CR) concept has not been precisely defined in severe mental disorders and has been estimated using heterogeneous methods. This study aims to investigate and develop the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH), an instrument designed to measure CR in people with severe mental illness; (2) Methods: 100 patients with severe mental illness (non-affective psychoses and affective disorders) and 66 healthy controls were included. The internal consistency and convergent validity of CRASH were assessed. Spearman’s correlations coefficients were also performed to examine the relationship between CRASH and neuropsychological tests, psychosocial functioning, and clinical course; (3) Results: The internal consistency was high (Cronbach’s alpha coefficient = 0.903). The CRASH global score had a large positive correlation with the Cognitive reserve questionnaire total score (r = 0.838, p < 0.001), demonstrating good convergent validity. The correlation coefficients between the CRASH total scores and clinical, functional, and neuropsychological performance were different between groups. In order to provide clinical interpretation, severity classification based on diagnosis (non-affective psychotic disorders, affective disorders, and healthy controls) have been created; (4) Conclusions: CRASH is the first CR measure developed specifically for patients with severe mental illness, facilitating reliable and valid measurement of this construct. The scale may aid in the stratification of patients and the implementation of personalized interventions.

The concept of cognitive reserve (CR) suggests that the premorbid intelligence quotient (IQ), years of education and leisure activities provide more efficient cognitive networks and therefore allow a better management of some conditions associated to cognitive impairment. Fifty-two DSM-IV diagnosed FEP subjects were matched with 41 healthy controls by age, gender and parental socio-economic status. All subjects were assessed clinically, neuropsychologically and functionally at baseline and after a two-year follow-up. To assess CR at baseline, three proxies have been integrated: premorbid IQ, years of education-occupation and leisure activities. Higher CR was associated with better cognitive, functional and clinical outcomes at baseline. The CR proxy was able to predict working memory, attention, executive functioning, verbal memory and global composite cognitive score accounting for 48.9%, 19.1%, 16.9%, 10.8% and 14.9% respectively of the variance at two-year follow-up. CR was also significantly predictive of PANSS negative scale score (12.5%), FAST global score (13.4%) and GAF (13%) at two-year follow-up. In addition, CR behaved as a mediator of working memory (B=4.123) and executive function (B=3.298) at baseline and of working memory (B=5.034) at 2-year follow-up. An additional analysis was performed, in order to test whether this mediation could be attributed mainly to the premorbid IQ. We obtained that this measure was not enough by itself to explain this mediation. CR may contribute to neuropsychological and functional outcome. Specific programs addressed to improve cognition and functioning conducted at the early stages of the illness may be helpful in order to prevent cognitive and functional decline.

Objectives: Well-being perception is seldom explored in schizophrenia patients. Recurrent limitations, such as the questionable applicability of gold standard definitions of health and well-being, and fewer tools available to assess well-being, are pronounced in this subpopulation. This cross-sectional study sought to explore potential clinical factors that may predict subjective well-being scores in chronic schizophrenia patients (N = 142) receiving clozapine treatment. Methods: The Short Warwick–Edinburgh Mental Well-being Scale (SWEMWBS) was used to measure well-being. We correlated SWEMWBS scores and 27 clinically recognized factors, spanning socio-demographics, symptom severity scores, physical health diagnosis, clozapine side effects, habits and prescribed medication. Factors with a p

This study investigated whether the risk of presenting antipsychotic (AP)-induced extrapyramidal symptoms (EPS) could be related to single-nucleotide polymorphisms (SNPs) in a naturalistic cohort of first episode psychosis (FEP) patients. Two hundred and two SNPs in 31 candidate genes (involved in dopamine, serotonin and glutamate pathways) were analyzed in the present study. One hundred and thirteen FEP patients (43 presenting EPS and 70 non-presenting EPS) treated with high-potency AP (amisulpride, paliperidone, risperidone and ziprasidone) were included in the analysis. The statistical analysis was adjusted by age, gender, AP dosage, AP combinations and concomitant treatments as covariates. Four SNPs in different genes (DRD2, SLC18A2, HTR2A and GRIK3) contributed significantly to the risk of EPS after correction for multiple testing (P

Background Neural correlates of psychotic disorders encompass multiple brain regions in multiple brain circuits, even at early stages. Previous research has characterized structural brain alterations in first-episode psychosis (FEP), but few studies have focused on the relationship between brain alterations and disease trajectories. First psychotic episodes typically evolve into a chronic course, affecting quality of life of patients and their families, with huge societal costs. Importantly, up to 80% of the patients relapse in the next five years after a first psychotic episode, with a significant risk of developing treatment resistance. Here, we investigated whether disease course may be predicted from brain structural assessments. Specifically, we measured structural covariance, a well-established approach to identify abnormal patterns of volumetric correlation across distant brain regions, which allows to incorporate network-level information to structural assessments. We performed a whole-brain structural covariance assessment of three bilateral regions form to three different cortical networks - dorsolateral prefrontal cortex (dlPFC) for the executive network, posterior cingulate cortex for the default mode network and insulae for the salience network - and subcortical structures (hippocampi, amygdalae and dorsomedial nucleus of the thalamus) that have shown to play a key role in schizophrenia. Methods We assessed a sample of 74 subjects from a multicenter, naturalistic, prospective and longitudinal study designed to evaluate clinical, neuropsychological, neuroimaging, biochemical, environmental and pharmacogenetic variables in first episode psychotic patients (PEPs project). Magnetic resonance imaging (MRI) scans were acquired at baseline and at 2-year follow-up, as well as clinical assessments. Psychotic symptoms were assessed using the Positive and Negative Symptom Scale (PANSS) due its widespread use in clinical studies and its reliability in assessing psychopathology across a range of patient populations. The sample was split in two groups as a function of the clinical improvement at 2-year follow-up: responders (i.e. 40% reduction in PANSS global score from baseline; n=29) and non-responders (n=45). Results Responder patients showed increase structural covariance between the left dlPFC and the left middle frontal gyrus, and between the right dlPFC and the right middle and superior gyrus, the left rectus and inferior frontal gyrus, the right hippocampus, and the vermis of the cerebellum. In addition, they showed increased structural covariance between the left anterior hippocampus and the ipsilateral middle occipital gyrus and the contralateral postcentral gyrus. Likewise, the structural covariance of right anterior hippocampus with right superior occipital gyrus and precentral gyrus was also increased in responder patients. Discussion This study shows, for the first time in the literature, that increased structural covariance at baseline within the executive network and between the hippocampi and posterior brain regions was associated with a superior treatment response at two-year follow-up. These results indicate that the integrity of structural networks should be taken into account to predict treatment outcome in FEP patients.

Background The cognitive reserve (CR) refers to the brain’s capacity to cope with pathology in order to minimize the symptoms. In the field of first episode psychosis (FEP), the CR was able to predict functional and neurocognitive performance. Nevertheless, CR has been estimated using heterogeneous methods, which, in term, difficult to compare studies. Therefore, there is a need to create a specific scale for the assessment of this relevant construct. The Cognitive Reserve Assessment Scale in Health (CRASH) is the first measure developed specifically for patients with severe mental illness with optimal psychometric properties, facilitating reliable and valid measurement of CR. The study of the internal structure of the CRASH determined a four-factor structure (Education, Occupation, Leisure activities and Sociability) that can be analyzed separately to know what kind of relationship they might have with other variables. The aim of this study was to analyze the effects of CR measured with CRASH scale on functioning and neurocognitive performance and to explore the relationship of each factor with the outcome in an adult sample of subjects with FEP. Methods The sample of this study came from a multicentre, naturalistic and longitudinal research project financed by a catalan grant (“Pla Estratègic de Recerca i Innovació en Salut” - PERIS 2016–2018). Expedient Nº: SLT006/17/00345; entitled “Identificación y caracterización del valor predictivo de la reserva cognitiva en el curso evolutivo y respuesta en terapéutica en personas con un primer episodio psicótico”. 23 FEP patients and 72 healthy control (HC) were enrolled. The premorbid IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS-IV) vocabulary subtest. To assess processing speed, Trail Making Test-part A was used. Sustained attention was tested with the Continuous Performance Test–II. The working memory was assessed with the Letters and Numbers Subtest of the WAIS-IV. Finally, the executive functions tested set shifting, planning and cognitive flexibility using the Tower of London task and the Trail Making Test (TMT) part B. Results Significant differences between the total CRASH score of patients and HC groups have been found. The patient group obtained lower scores compared to the HC group (36.66±16.01 vs 49.83±11.08, p In FEP patients, the CRASH score was associated with premorbid IQ (p Discussion FEP patients were shown to have lower CR than HC, and CRASH correctly classified 83.2% of the sample. Each CRASH factor was associated with different outcome, which is why it can be interesting to analyze the total CRASH score and each factor separately. Patients with higher CR showed a better cognitive performance. Therefore, enhancing each factor involved in cognitive reserve may improve outcomes in FEP.

Schizophrenia is a complex mental disorder with genetic and environmental components. Obstetric complications (OCs) are one of the most common environmental risk factors described. However, despite being different in timing and outcome, OCs are usually described as a homogeneous entity. In the present study, we evaluate the presence of different patterns of OCs evaluated with the Lewis-Murray Scale in chronic schizophrenia patients (n = 101) and their association with a crude marker of the intrauterine environment such as weight at birth.OCs related with abnormal fetal growth (p < 0.001) and OCs during gestation (p = 0.003) were associated with lower birth weight. However, difficulties in delivery, complications in pregnancy, and OCs all together (as a set) were not associated with weight at birth.Our results infer that OCs cannot be taken as a homogeneous group. Different patterns of OCs result in different birth weights, which is associated with specific metabolic, cognitive, and brain structure outcomes.

OBJECTIVE: Cognitive reserve (CR) refers to the brain's capacity to cope with pathology in order to minimize the symptoms. CR is associated with different outcomes in severe mental illness. This study aimed to analyze the impact of CR according to the diagnosis of first-episode affective or non-affective psychosis (FEP). METHOD: A total of 247 FEP patients (211 non-affective and 36 affective) and 205 healthy controls were enrolled. To assess CR, common proxies have been integrated (premorbid IQ; education-occupation; leisure activities). The groups were divided into high and low CR. RESULTS: In non-affective patients, those with high CR were older, had higher socioeconomic status (SES), shorter duration of untreated psychosis, and a later age of onset. They also showed greater performance in most cognitive domains. In affective patients, those with a greater CR showed a higher SES, better functioning, and greater verbal memory performance. CONCLUSION: CR plays a differential role in the outcome of psychoses according to the diagnosis. Specifically, in order to address the needs of non-affective patients with low CR, cognitive rehabilitation treatments will need to be 'enriched' by adding pro-cognitive pharmacological agents or using more sophisticated approaches. However, a functional remediation therapy may be of choice for those with an affective psychosis and low CR.

Background We investigated whether negative symptoms, such as poor motivation or anhedonia, were associated with higher body mass index (BMI) in stable patients with schizophrenia chronically treated with antipsychotic medication. Methods 62 olanzapine- or clozapine-treated patients with illness duration of at least four years were selected from an international multicenter study on the characterization of negative symptoms. All participants completed the Brief Negative Symptom Scale (BNSS) and the Positive and Negative Syndrome Scale (PANSS). Bivariate correlations between BMI and negative symptoms (BNSS) were explored, as well as multiple regression analyses. We further explored the association of two principal component factors of the BNSS and BMI. Subsidiary analyses re-modeled the above using the negative symptoms subscale of the PANSS and the EMSLEY factor for negative symptoms for convergent validity. Results Lower negative symptoms (BNSS score) were associated with higher BMI ( r = − 0.31; p = 0.015). A multiple regression analysis showed that negative symptoms (BNSS score) and age were significant predictors of BMI ( p = 0.037). This was mostly driven by the motivation/pleasure factor of the BNSS. Within this second factor, BMI was negatively associated with anhedonia ( r = − 0.254; p = 0.046) and asociality ( r = − 0.253; p = 0.048), but not avolition ( r = − 0.169; p = 0.188). EMSLEY score was positively associated with BNSS ( r = 0.873, p r = − 0.308; p = 0.015). The association between PANSS and BMI did not reach significance ( r = − 224, p = 0.080). Conclusions We conclude that lower negative symptoms were associated with higher BMI (assessed using both the BNSS and EMSLEY) in chronic stable schizophrenia patients, mostly due to lower anhedonia and asociality levels.

BackgroundCognitive deficits are a core feature of early stages in schizophrenia. However, the extent to which antipsychotic (AP) have a deleterious effect on cognitive performance remains under debate. We aim to investigate whether anticholinergic loadings and dose of AP drugs in first episode of psychosis (FEP) in advanced phase of remission are associated with cognitive impairment and the differences between premorbid intellectual quotient (IQ) subgroups.MethodsTwo hundred and sixty-six patients participated. The primary outcomes were cognitive dimensions, dopaminergic/anticholinergic load of AP [in chlorpromazine equivalents (Eq-CPZ) and the Anticholinergic Risk Scale (ARS), respectively].ResultsImpairments in processing speed, verbal memory and global cognition were significantly associated with high Eq-CPZ and verbal impairment with high ARS score. Moreover, this effect was higher in the low IQ subgroup.ConclusionsClinicians should be aware of the potential cognitive impairment associated with AP in advanced remission FEP, particularly in lower premorbid IQ patients.

The search for biomarkers in cognition has been the focus of a large part of the research on patients suffering from schizophrenia. The scientific literature is heterogeneous, and few studies establishing an integrative model of pathogenesis and therapeutic response are available in this field. In this review, we aimed to summarize three essential aspects correlated with cognitive performance: 1) the relationship between inflammation and cognition in schizophrenia, 2) the role of prolactin in cognition, and 3) the association between cognition and neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF).Several studies support the association of inflammatory markers with cognitive status in schizophrenia. In recent decades, the development of effective therapies for cognitive impairment in schizophrenia has focused on the search for anti-inflammatory and immunomodulatory medications. Conversely, the implications of prolactin and its functions in cognition, the transition to psychosis and the diagnosis and prognosis of schizophrenia have been established independent of antipsychotic treatment. With regard to neurotrophic factors, a recent study has correlated BDNF levels with cognitive recovery in schizophrenic patients treated with cognitive remediation.We conclude that although there is a diversity of biomarkers focused on cognitive function in schizophrenia, BDNF is the biomarker that has accumulated the vast majority of evidence in the current literature.

Background The extent to which socio-demographic, clinical, and premorbid adjustment variables contribute to cognitive deficits in first-episode schizophrenia spectrum disorders remains to be ascertained. Aims To examine the pattern and magnitude of cognitive impairment in first-episode psychosis patients, the profile of impairment across psychosis subtypes and the associations with premorbid adjustment. Methods 226 first-episode psychosis patients and 225 healthy controls were assessed in the PEPsCog study, as part of the PEPs study. Results Patients showed slight to moderate cognitive impairment, verbal memory being the domain most impaired compared to controls. Broad affective spectrum patients had better premorbid IQ and outperformed the schizophrenia and other psychosis groups in executive function, and had better global cognitive function than the schizophrenia group. Adolescent premorbid adjustment together with age, gender, parental socio-economic status, and mean daily antipsychotic doses were the factors that best explained patients' cognitive performance. General and adolescent premorbid adjustment, age and parental socio-economic status were the best predictors of cognitive performance in controls. Conclusions Poorer premorbid adjustment together with socio-demographic factors and higher daily antipsychotic doses were related to a generalized cognitive impairment and to a lower premorbid intellectual reserve, suggesting that neurodevelopmental impairment was present before illness onset.

Background Many studies having shown significant improvements in non-social and social cognitive performance in smoking FEP patients compared to non-smoking FEP patients. The findings are controversial. This study analyzed the effects of tobacco use on non-social and social cognitive function in a large group of FEP patients and a matched healthy control group. Methods A sample of 335 patients with FEP and 253 healthy controls was divided into four subgroups: control tobacco users (CTU), control non-tobacco users (CNTU), patient tobacco users (PTU) and patient non-tobacco users (PNTU). Demographic variables, tobacco use variables (presence or absence, frequency and duration of tobacco use), neurocognitive (non-social) performance and social cognition were assessed. Results Comparison of 4 subgroups in non-social cognitive function revealed significant differences after controlling for covariables in executive functions (F = 13.45; p ≤0.001) and working memory domains (F = 4.30; p = 0.005). CTU and CNTU subgroups scored higher in all the domains compared to the PTU and the PNTU subgroups respectively. Social cognitive function was also significantly different within the four subgroups, with control subgroups showing better social cognition than patient subgroups. Significant differences in the executive functions domain were observed when comparing PTU and CTU groups (F = 19.60; p ≤0.001). No significant differences were revealed in the comparison between the patient groups. Conclusions This large study suggests that tobacco use in FEP patients is not related to better non-social or social cognitive performance.

Background Brain-derived neurotrophic factor (BDNF) is considered to be a putative biomarker for cognitive recovery in schizophrenia. However, current evidence is still scarce for pharmacological treatments, and the use of BDNF as a biomarker has only been tested once with cognitive remediation treatment (CRT). Methods A randomized and controlled trial (NCT02341131) with 70 schizophrenia outpatients and 15 healthy volunteers was conducted. The participants with schizophrenia were randomly assigned to either CRT or the control group. All the participants were assessed in terms of cognition, quality of life, and their serum BDNF levels at both baseline and after the intervention. Additionally, comparisons of the effects of the different genotypes of the Val66Met polymorphism at the BDNF gene on the outcome variables were also performed. Results The patients in the CRT group presented with improvements in both cognition and quality of life. However, no significant changes were detected in the serum levels of BDNF. Interestingly, we found a significant positive interaction effect between the serum BDNF levels and the different BDNF genotypes. The Val/Val group showed significantly higher serum levels after the CRT treatment. However, the interaction among the serum BDNF levels, the BDNF genotypes and the treatment condition was not statistically significant. Conclusions The replication of the previous finding of increased serum BDNF levels after cognitive remediation in clinically stable individuals with schizophrenia was not achieved. However, our data indicated that genetic variability may be mediating serum BDNF activity in the context of CRT.

Individual changes over time in cognition in patients with psychotic disorders have been studied very little, especially in the case of first episode psychosis (FEP). We aimed to establish whether change in individual trajectories in cognition over 2 years of a sample of 159 FEP patients was reliable and clinically significant, using the reliable change index (RCI) and clinically significant change (CSC) methods. We also studied a sample of 151 matched healthy controls. Patients and controls were assessed with a set of neuropsychological tests, as well as premorbid, clinical and functionality measures. We analysed the course of cognitive measures over time, using analysis of variance, and the individual trajectories in the cognitive measures with the regression-based RCI (RCI(SRB)) and the CSC. The RCI(SRB) showed that between 5.4 and 31.2% of the patients showed deterioration patterns, and between 0.6 and 8.8% showed improvement patterns in these tests over time. Patients showing better cognitive profiles according to RCI(SRB) (worsening in zero to two cognitive measures) showed better premorbid, clinical and functional profiles than patients showing deterioration patterns in more than three tests. When combining RCI(SRB) and CSC values, we found that less than 10% of patients showed improvement or deterioration patterns in executive function and attention measures. These results support the view that cognitive impairments are stable over the first 2 years of illness, but also that the analysis of individual trajectories could help to identify a subgroup of patients with particular phenotypes, who may require specific interventions.

Patients with a first episode of psychosis (FEP) display a broad range of metabolic risk factors related to the development of diverse medical comorbidities. Initial stages of these disorders are essential in understanding the increased vulnerability of developing cardiometabolic disturbances, associated with a reduced life expectancy. This study aimed to evaluate the metabolic profile of a cohort of patients with a FEP and its evolution during a two year follow-up, as well as the factors that influence the changes in their metabolic status. 16 participating centers from the PEPs Project recruited 335 subjects with a FEP and 253 matched healthy controls, aged 9–35 years. We investigated a set of anthropometric measures, vital signs and laboratory data obtained from each participant over two years in a prospective, naturalistic study. From the beginning of the study the FEP group showed differences in the metabolic profile compared to the control group, together with a progressive worsening in the major part of the analyzed variables during the follow-up period, with higher rates of obesity and metabolic syndrome. Certain risk factors were related to determinate clinical variables such as male gender, the presence of affective symptoms or an early onset or to treatment variables such as the use of antipsychotic polypharmacy, antidepressants or mood stabilizers. Our results highlight the extremely high risk of patients at early phases of schizophrenia and other psychotic disorders of developing cardiovascular comorbidity and the fast worsening of the metabolic profile during the first two years.

Introduction: Recent research demonstrates the heterogeneous etiology of psychotic disorders, where gen-environment (GxE) interaction plays a key role. Large genetic studies have linked many genetic variants with schizophrenia, but each variant is only associated with a small effect and the GxE interaction contribution has not been evaluated. Methods: The PEPs Project was designed to carefully collect a large amount of genetic and environmental exposure data of 335 FEP patients and 253 matched healthy controls. 780 single-nucleotide polymorphisms (from 159 candidate genes) and 16 environmental variables previously reported as the main psychosis non-genetic risk factors were analyzed together using entropy-based measures of information gain. Results: Our analyses identified an interaction between nine SNPs and the exposition to the environmental risk factors of psychosis, showing a clear enrichment of genes linked to serotonin neurotransmission and neurodevelopmental processes. Conclusions: This study has allowed the identification of several GxE-environment interactions involved in the risk of presenting a FEP. Our results highlight the importance of serotonin neurotransmission interacting with certain environmental stimuli. The serotoninergic system may be playing a key role in the regulatory network of stress and other systems implicated in the emergence and development of psychotic disorders. (C) 2017 Elsevier B.V. All rights reserved.

Background Cognitive impairment is considered a central feature of psychotic disorders, with an important impact on prognosis and functional outcome (Nuechterlein et al., 2011). Among the etiological explanations on psychosis, several hypotheses involving alterations in the immune / inflammatory system have been proposed and recent research links these inflammatory processes with cognitive function, suggesting that the presence of inflammation is associated with poorer cognitive performance (Ribeiro-Santos et al., 2014, Cabrera et al., 2016). The study of the influence of gender on the possible association between inflammatory biomarkers and cognitive performance may favor the implementation of personalized treatments. The aim of the study is to investigate the association between inflammatory biomarkers and gender-based cognition in a sample of first psychotic episode (FEP). A total of 92 patients with a FEP, 62 men and 30 women, recruited in five clinical centers were included. A neurocognitive assessment was performed and the expression of pro and anti-inflammatory mediators in peripheral blood mononuclear cells (PBMC) and plasma was measured. Methods In the neurocognitive evaluation the domains of attention, verbal and working memory and executive function were included. Other and clinical variables included the assessment of psychotic and affective symptoms, age, sex, educational level and socio-economic level. The expression of the proinflammatory mediators (NFκB, iNOS, COX-2, PGE2, NO-2 and TBARS) and anti-inflammatory (15d-PGJ2, PPARγ and IκBα) of the main intracellular inflammatory pathway was measured in PBMC and plasma. Results A correlation was made between inflammatory biomarkers and neurocognitive performance according to gender, and significant associations were selected to perform a subsequent hierarchical regression analysis. In the final model, only the expression of COX2 was associated with better performance in executive function in males (B = 0.504, p =

Background This study aims to explore the gene-environment interaction hypothesis applied to pre-symptomatic neurodevelopmental phenotypes of first episode psychosis (FEP), that is, genetic factors might increase vulnerability to the effects of environmental adverse conditions occurring at later stages of development. Methods We constructed a schematic ‘two-hit’ model, with Val/Val homozygosity for the catechol- O -methyltransferase ( COMT ) Val158Met polymorphism as the ‘first hit’ and history of obstetric complications and parental socioeconomic status as ‘second hits’. Early adjustment, measured using the Premorbid Adjustment Scale, was considered the main outcome. The study population comprised 221 adolescents and adults with FEP and 191 sex- and age-matched controls. Results The interaction between the Val/Val COMT genotype and a positive history of obstetric complications plus low parental socioeconomic status was significantly associated with poorer early adjustment. These results were observed both in FEP individuals and in controls, and remained significant after controlling for age, sex, and diagnosis. Conclusions Individuals carrying Val/Val seem to be more sensitive to the synergistic effect of environmental factors acting early in neurodevelopment, which leads to vulnerability phenotypes such as impaired early adjustment.

Aims: This study aimed to investigate the course of negative symptoms and its stability over a two-year period following a first-episode schizophrenia (FES) and the possible predictors of higher severity in this symptomatology after this period. Methods: In this longitudinal two-year prospective follow-up study we included 268 patients with a FES, according to DSM-IV. Analysis of variance was conducted in patients who completed the full follow-up to study changes in negative symptoms over three visits. Regression analyses were conducted to show correlates and potential predictors of negative symptoms at two-year follow-up. Results: There was a significant effect for time in negative symptomatology, which was less severe at one-year follow-up after a FES and remained stable up to two years (Time 1 > Time 2 > Time 3); F(2,151) = 20.45, p < 0.001. Poorer premorbid adjustment (p = 0.01) and higher negative symptoms at baseline (p < 0.001) made a significant contribution to the changes in the negative symptoms severity at two-years after a FES (R-2 = 0.21, p < 0.001). Conclusions: We found a reduction in the negative symptomatology at one-year after a FES. This change remained stable at two-year. Our results suggested that the presence of this symptomatology early in the course of the illness, together with a poorer premorbid adjustment, predict more severe negative symptoms at mid-term outcome. (C) 2017 Elsevier B.V. All rights reserved.

OBJECTIVE To characterize the early cognitive and social functioning characteristics of a sample of first-episode psychosis patients with and without persistent negative symptoms (PNS) and to examine the prevalence and cognitive and functional correlates of PNS in patients with early-onset versus adult-onset first-episode psychosis. METHODS Participants were 235 patients with first-episode psychosis (51 early-onset, 184 adult-onset) and 240 healthy controls from a multicenter longitudinal study (recruited between 2009 and 2011). Standard instruments were used to evaluate symptoms, cognition, and social functioning. Diagnoses were determined according to DSM-IV criteria. PNS proxy was derived from clinical assessments (Positive and Negative Syndrome Scale and Montgomery-Asberg Depression Scale) at 2-, 6-, and 12-month follow-up. Association tests were used to compare the prevalence of PNS in the early-onset versus adult-onset groups. Multivariate analysis of variance was used to examine differences in early cognitive and social functioning (at the 2-month assessment) between patients with and without PNS and between early-onset and adult-onset patients with PNS. RESULTS Thirty-eight patients (16.2%) met criteria for PNS during the first year. This PNS group showed a selective deficit in executive functions and in global, community, and occupational functioning (P < .05). Having PNS was associated with a diagnosis of a schizophrenia spectrum disorder at the 12-month follow-up. The prevalence of PNS was almost double for those patients with an early-onset (0.25 vs 0.14; OR = 2.18; 95% CI, 1.02-4.64), and this was associated with greater cognitive (P < .05) but not social deficits. CONCLUSIONS There was an early, detectable, social and executive dysfunction associated with PNS in first-episode psychosis and a high risk of having PNS in early-onset first-episode psychosis, which in turn was associated with more widespread cognitive impairment. Specific therapeutic interventions for PNS in early-onset first-episode psychosis might be needed.

Patients with schizophrenia exhibit a reduced life expectancy. Although unhealthy lifestyle or suicide risk plays a role, the main causes are diverse medical conditions such as cardiovascular diseases, type 2 diabetes mellitus and metabolic syndrome. Albeit pharmacological secondary side effects might also trigger previous conditions, studies in naïve patients reflect diverse anomalies at the onset. Patients with a first episode of psychosis, display a wide scope of metabolic abnormalities, ranging from normality till pathological values depending on the parameters studied. We attempted to evaluate the metabolic syndrome and glycemic homeostasis in a subset of antipsychotic-naïve patients with a first episode of non-affective psychosis. Patients (n = 84) showed a similar prevalence of metabolic syndrome compared with a matched control sample (n = 98) (6% vs 4%, P = 0.562), while glucose homeostasis values differed significantly (14% vs. 5%, P = 0.034). Our results suggest that metabolic syndrome is not a useful clinical condition to be evaluated in patients before pharmacological treatment. Abnormal glycemic homeostasis at the onset of the disease requires specific diagnostic tools and preventive measures in order to avoid future cardiovascular events. New strategies must be implemented in order to evaluate the cardiovascular risk and subsequent morbidity in patients at the onset of the disease.

ObjectiveA functional polymorphism of the brain-derived neurotrophic factor gene (BDNF) Val66Met has been associated with cognitive function and symptom severity in patients with schizophrenia. It has been suggested that the Val66Met polymorphism has a role as a modulator in a range of clinical features of the illness, including symptoms severity, therapeutic responsiveness, age of onset, brain morphology and cognitive function. However, little work has been done in first-episode schizophrenia (FES) spectrum disorders. The objective of this study is to investigate the association of the BDNF Val66Met polymorphism on cognitive function and clinical symptomatology in FES patients.MethodsUsing a cross-sectional design in a cohort of 204 patients with FES or a schizophrenia spectrum disorder and 204 healthy matched controls, we performed BDNF Val66Met genotyping and tested its relationship with cognitive testing (attention, working memory, learning/verbal memory and reasoning/problem-solving) and assessment of clinical symptom severity.ResultsThere was no significant influence of the BDNF allele frequency on cognitive factor scores in either patients or controls. An augmented severity of negative symptoms was found in FES patients that carried the Met allele.ConclusionsThe results of this study suggest that in patients with a first-episode of schizophrenia or a schizophrenia spectrum disorder, the BDNF Val66Met polymorphism does not exert an influence on cognitive functioning, but is associated with negative symptoms severity. BDNF may serve as suitable marker of negative symptomatology severity in FES patients within the schizophrenia spectrum.

Background Cognitive dysfunction is as a hallmark feature of schizophrenia. Antipsychotic medication is effective for treating the positive symptoms of psychosis, but their potential for therapeutic effects on cognition continues to divide researchers. Improvements in clinical symptoms can occur independently of cognitive functioning, whereby typical antipsychotics improve different clinical domains, but have little or no efficacy for improving primary cognitive functions. However, it has been suggested that the second-generation antipsychotic clozapine can improve cognition in schizophrenia. Unusual cases, such as remitted patients who decide to stop taking clozapine, thus represent a unique opportunity to understand the effect of antipsychotic medication on cognition, as described in the case study below. Methods A 38-year old man suffered severe psychotic episodes at age 19, leading to a diagnosis of treatment-resistant schizophrenia. Clozapine was initiated at age 21, with excellent treatment response and complete remission of positive, negative and depressive symptoms. For the following 16 years, he had a full-time paid job, lived independently and had an ample social circle. For the last five years, he was stable and compliant taking 175 mg of clozapine, with clozapine levels in sub-therapeutic range (between 0.17 and 0.26 mg/L). He had no metabolic syndrome and no oversedation, but complained of hypersalivation and persistent memory problems. He decided, against advice, that medication was no longer needed and requested support for waning off clozapine. A five-month program was subsequently implemented, with 25 mg reductions of clozapine every six weeks. Four enhanced assessments were scheduled after two weeks on stable doses of 125, 75, 25 and 0 mg, respectively, which included the Brief Assessment of Cognition in Schizophrenia (BACS) and the Clinical Global Impression-Schizophrenia scale (CGI-SCH). Results At each level of clozapine dose, the patient continued to be stable. However, the patient showed impaired cognitive performance at the highest dose of clozapine titration (see T-scores from Table and figure), with improvements then shown at each level of dose reduction (75 and 25 mg). The final assessment was done after 6 weeks of not taking medication. At this time, he was admitted to hospital for psychotic relapse. Unfortunately, the patient refused to re-initiate clozapine and has remained floridly psychotic for 18 months. Our case suggests that cognitive impairment is dose-dependent with clozapine. As presented, the t-score of the patient at 125 mg was worse than normative data reported for healthy controls (z-score=0.50) and patients with schizophrenia treated with other first-or second generation antipsychotics (z-score=-1.42). However, cognitive performance of the patient was most notably impaired when medication-free. Discussion The longterm effects of high-dose antipsychotic medication on cognition in patients with schizophrenia are largely unknown. It is also possible that changes in cognitive states are either domain-specific with clozapine. Nonetheless, daily antipsychotic dose and polypharmacy have been shown to predict poor cognitive functioning. The present case is also a reminder that the appropriate long-term maintenance dose of clozapine is poorly understood. As this case suggests, the current recommended therapeutic levels of clozapine (0.35 to 0.50 mg/L) might be unnecessarily high for patients in full remission. Controlled studies are therefore needed to evaluate the potential for cognitive improvements in schizophrenia as a function of reduced clozapine dose, to ensure the optimal delivery needed not just for good clinical but also good cognitive outcome.

Background The cognitive reserve (CR) refers to the capacity of an adult brain to cope with pathology in order to minimize the symptoms (Stern, 2002). Recent studies have shown that CR is associated with clinical, functional and cognitive outcomes in patients with severe mental illness (de la Serna et al., 2013; Forcada et al., 2015; Anaya et al., 2016; Amoretti et al. ., 2016; Grande et al., 2017). Higher CR has been related to a later onset of psychosis, greater adherence and fewer psychotic symptoms (Barnett et al., 2006). However, there are no studies that evaluate longitudinally the role of CR depending on the diagnosis. The objective is to analyze the impact of CR according to the diagnosis and to study whether having a high CR may be associated with better clinical, functional and cognitive outcomes. Methods We gathered all the relevant clinical and sociodemographic data. All subjects were assessed clinically, neuropsychologically and functionally at baseline and after a two-year follow-up. To assess CR, three proxies have been integrated: premorbid IQ, years of education-occupation and leisure activities. To determine whether the level of CR was associated with clinical, functional and neuropsychological outcomes and whether it was different between diagnoses, a multivariate analysis of variance was used. Results 285 DSM-IV patients with first episode of psychosis (FEP) were enrolled. The sample was divided into affective and non-affective groups. In the non-affective group, those with high CR are older and had a better socioeconomic status, better functioning and cognitive performance and lower symptoms, as well as a shorter duration of untreated psychosis (DUP) and a later age of onset. After 2 years of follow-up, they showed significant differences in all the cognitive domains evaluated, except for the executive functions. In the affective group, the patients with high and low CR showed differences in positive and manic symptoms, as well as in verbal memory at baseline. At 2 years of follow-up the differences were observed in functionality, positive and negative symptoms and in verbal memory. There were no significant differences in terms of age, gender, DUP, or age of onset, although significant differences were found in socioeconomic level (p = 0.038). Discussion Higher CR can result in better recovery and functioning and in higher cognitive performance in patients with a FEP. Therefore, we propose that early interventions focused on the promotion of neuropsychological abilities and CR could reduce the harmful impact of this disease. However, it is necessary that these interventions should be personalized taking into account that CR plays a differential role according to the diagnosis.

Negative symptoms are a core feature of schizophrenia and their reliable and valid assessment is a prerequisite for developing effective therapeutic interventions. This study examined the psychometric properties and validity of the Spanish version of a new rating instrument, the Clinical Assessment Interview for Negative Symptoms (CAINS). Outpatients and inpatients (N = 100) with DSM-IV schizophrenia were administered the translated CAINS, the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), and the Calgary Depression Scale for Schizophrenia (CDSS). A subsample (N = 46) was rated for Parkinsonism using the Extrapyramidal Symptoms Rating Scale (ESRS). The scale showed good inter-rater and intra-rater reliability. Both the CAINS overall and the subscales for motivation/pleasure (CAINS-Map) and expression (CAINS-Exp) scores correlated significantly with the SANS and PANSS negative symptom scale. Significant correlations with positive symptoms and general psychopathology were also found, but these reduced and mostly became insignificant when overall severity of illness was controlled for. Significant correlations with depression also disappeared when severity was controlled for. There was a trend-level correlation between the CAINS total score and Parkinsonism, which reflected an association with the CAINS-Exp subscale only. Factor analysis revealed a two-dimensional structure that explained the 67.44% of the variance. Overall, the Spanish version of the CAINS appears to be a valid tool for measuring negative symptoms in schizophrenia.

Resumen La busqueda de biomarcadores en la cognicion ha centrado una gran parte de las investigaciones en pacientes con esquizofrenia. La literatura cientifica es heterogenea y son escasos los estudios disponibles que permitan establecer un modelo integrador de la etiopatogenia y respuesta terapeutica basada en estos marcadores. En el presente trabajo nos proponemos revisar tres aspectos fundamentales correlacionados con el rendimiento cognitivo: 1) la relacion entre cognicion e inflamacion en esquizofrenia, 2) el papel de la prolactina en la cognicion, y 3) la asociacion entre cognicion y factores neurotroficos, en particular el BDNF. Numerosos estudios apoyan la asociacion de diversos marcadores inflamatorios con el estado cognitivo en esquizofrenia. El desarrollo de terapias eficaces en el rendimiento cognitivo se ha centrado en las ultimas decadas en la busqueda de farmacos inmunomoduladores o antiinflamatorios. Por otro lado, se ha demostrado la implicacion de la prolactina y su funcion en la cognicion y transicion a la psicosis, asi como en el pronostico y diagnostico de la esquizofrenia con independencia del tratamiento antipsicotico. En cuanto a factores neurotroficos, un estudio reciente correlaciona los niveles de BDNF con la mejoria cognitiva en pacientes diagnosticados de esquizofrenia tratados con rehabilitacion cognitiva. Concluimos que, a pesar de la diversidad de biomarcadores asociados con el estado cognitivo en esquizofrenia, el BDNF es el biomarcador que acumula mayor evidencia en la literatura cientifica actual.