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We conducted a randomized controlled trial to assess the effectiveness of social skills training (SST) in improving negative symptoms in patients with treatment-resistant schizophrenia with predominantly negative symptoms. Patients were randomized to receive SST (n = 29) or to a control group (n = 33), in a 20-week program with weekly group sessions. Patients were assessed at baseline, post-treatment (20 weeks) and 6-month follow-up with the Positive and Negative Syndrome Scale. There was no significant improvement in the negative symptoms in either group, at any timepoint. Caution is warranted to interpret the results due to small sample size., Competing Interests: Declaration of Competing Interest Helio Elkis has received research grants from FAPESP, Janssen, and Roche and honoraria for travel support, advisory board participation, or speaking from Aché, Daiichi-Sankyo, Cristalia, Janssen, Roche and Teva. Ary Gadelha was speaker of Daiichi-Sankyo, Janssen, Aché, Cristália and Lundbeck and member of advisory boards of Daiichi-Sankyo and Janssen. Rodrigo Affonseca Bressan reports grants, personal fees and non-financial support from Janssen, and personal fees from Pfizer and Aché outside the scope of this study. Monica Kayo has acted as a consultant for pharmaceutical companies in other therapeutic areas, non-related to this study: Bayer, Gilead, Moksha 8, Takeda, Teva, Ultragenyx, União Química and Zambon. The other authors declared that did not have any potential conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: The treatment of schizophrenia with antipsychotics is still unsatisfactory. Therefore, the search for new treatments and prevention is crucial, and animal models are fundamental tools for this objective. Preclinical and clinical data evidence the antipsychotic profile of sodium nitroprusside (SNP), a nitric oxide (NO) donor. We aimed to investigate SNP in treating and/or preventing the schizophrenia-related behaviors presented by the spontaneously hypertensive rats (SHR) strain., Methods: Wistar rats (WR) and SHRs were submitted to two schemes of treatment: (i) a single injection of SNP or vehicle in adulthood; (ii) a long-term early treatment from 30 to 60 postnatal day with SNP or vehicle. The following behaviors were evaluated 24 hours after the acute treatment or 30 days after the long-term treatment: locomotion, social interaction, and contextual fear conditioning., Results: Spontaneously hypertensive rats presented hyperlocomotion, decreased social interaction, and impaired contextual fear conditioning. Single injection of SNP decreased social interaction in both strains and induced a deficit in contextual fear conditioning in WR. Oppositely, early treatment with SNP prevented the behavioral abnormalities in adult SHRs without promoting any effects in WR., Conclusion: Our preclinical data point to SNP as a preventive and safe strategy with a broad range of effectiveness to the positive, negative, and cognitive symptoms of schizophrenia., (© 2018 John Wiley & Sons Ltd.)

Objective: Work is considered one of the main forms of social organization; however, few individuals with schizophrenia find work opportunities. The purpose of this study was to evaluate the relationship between schizophrenia symptoms and job acquisition., Method: Fifty-three individuals diagnosed with schizophrenia from an outpatient treatment facility were included in an 18-month follow-up study. After enrollment, they participated in a prevocational training group. At the end of training (baseline) and 18 months later, sociodemographic, clinical data and occupational history were collected. Positive and negative symptoms (Positive and Negative Syndrome Scale - PANSS), depression (Calgary Depression Scale), disease severity (Clinical Global Impression - CGI), functionality (Global Assessment of Functioning - GAF), personal and social performance (Personal and Social Performance - PSP) and cognitive functions (Measurement and Treatment Research to Improve Cognition in Schizophrenia - MATRICS battery) were applied at baseline and at the end of the study., Results: Those with some previous work experience (n=19) presented lower scores on the PANSS, Calgary, GAF, CGI and PSP scales (p < 0.05) than those who did not work. Among those who worked, there was a slight worsening in positive symptoms (positive PANSS)., Conclusions: Individuals with less severe symptoms were more able to find employment. Positive symptom changes do not seem to affect participation at work; however, this calls for discussion about the importance of employment support.

Objective: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines., Method: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus., Results: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients., Conclusions: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Psychotic disorders affect ~3% of the general population and are among the most severe forms of mental diseases. In early stages of psychosis, clinical aspects may be difficult to distinguish from one another. Undifferentiated psychopathology at the first-episode of psychosis (FEP) highlights the need for biomarkers that can improve and refine differential diagnosis. We investigated gene expression differences between patients with FEP-schizophrenia spectrum (SCZ; N=53) or FEP-Mania (BD; N=16) and healthy controls (N=73). We also verified whether gene expression was correlated to severity of psychotic, manic, depressive symptoms and/or functional impairment. All participants were antipsychotic-naive. After the psychiatric interview, blood samples were collected and the expression of 12 psychotic-disorder-related genes was evaluated by quantitative PCR. AKT1 and DICER1 expression levels were higher in BD patients compared with that in SCZ patients and healthy controls, suggesting that expression of these genes is associated more specifically to manic features. Furthermore, MBP and NDEL1 expression levels were higher in SCZ and BD patients than in healthy controls, indicating that these genes are psychosis related (independent of diagnosis). No correlation was found between gene expression and severity of symptoms or functional impairment. Our findings suggest that genes related to neurodevelopment are altered in psychotic disorders, and some might support the differential diagnosis between schizophrenia and bipolar disorder, with a potential impact on the treatment of these disorders.

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Although several studies have pointed to a possible role of interleukin 2 (IL-2) in schizophrenia (SZ), association between IL-2 and the different groups of symptoms has not been explored. The objective of this study was to investigate a possible correlation of peripheral IL-2 levels with symptoms and cognitive performance in patients with SZ. In addition, we compared the plasma levels of IL-2 between patients with SZ and healthy controls. Twenty-nine chronically medicated outpatients with SZ according to DSM-IV were compared with twenty-six healthy controls. The patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF). All the participants had blood collected into EDTA tubes by venipuncture between 9:00 and 10:00AM. Plasma concentrations of IL-2 were determined by cytometric bead array. A computerized neuropsychological battery assessed verbal learning, verbal fluency, working memory, set shifting, executive function, inhibition and intelligence. Patients with SZ had lower levels of IL-2 than healthy controls (p<0.001). In the SZ group, IL-2 levels were positively correlated with scores in the digit span test (rho=0.416, P=0.025) and intelligence (rho=0.464, P=0.011). We also found a negative correlation between IL-2 and total score in the negative subscale of PANSS (rho=-0.447, p=0.015). Our findings suggest that IL-2 may be involved in the mechanisms related to cognitive deterioration and negative symptomatology in schizophrenia., (Copyright © 2014. Published by Elsevier Inc.)

Background: Memory impairments in patients with schizophrenia have been associated with various cognitive and clinical factors. Hallucinations have been more specifically associated with errors stemming from source monitoring failure., Methods: We conducted a broad investigation of verbal memory and visual memory as well as source memory functioning in a sample of patients with schizophrenia. Various memory measures were tallied, and we studied their associations with processing speed, working memory span, and positive, negative, and depressive symptoms., Results: Superficial and deep memory processes were differentially associated with processing speed, working memory span, avolition, depression, and attention disorders. Auditory/verbal and visual hallucinations were differentially associated with specific types of source memory error., Conclusions: We integrated all the results into a revised version of a previously published model of memory functioning in schizophrenia. The model describes the factors that affect memory efficiency, as well as the cognitive underpinnings of hallucinations within the source monitoring framework., (© 2013.)

Objective: To investigate possible differences in peripheral levels of chemokines, BDNF and oxidative markers between patients with Schizophrenia (SZ) and matched healthy controls, and investigate the correlation of these biomarkers with cognitive performance., Methods: Thirty individuals with SZ and 27 healthy controls were included and the following plasmatic biomarkers' levels were determined according to manufacturers' instructions: BDNF, TBARS, protein carbonyl content (PCC) and the chemokines CXCL-10/IP-10, CXCL-8/IL-8, CCL-11, CCL-24/Eotaxin-2, CCL-2/MCP-1, CCL-3/MIP-1. Selected neuropsychological tasks were administered to assess verbal learning (Hopkins Verbal Learning Test), verbal fluency (FAS test), working memory (Visual Working Memory Task, Keep Track Task, Letter Memory Task), set shifting (Plus-minus task, Number-letter task), inhibition (Computerized Stroop Task, Semantic Generation Task) and complex executive function tasks (Tower of London and the shortened version of the WCST-64)., Results: Compared with the healthy control group, individuals with SZ presented significantly higher levels of BDNF and the chemokine CCL-11, and lower levels of TBARS and the chemokine CXCL-10/IP-10. When we examined only the SZ group, BDNF levels were positively correlated with semantic generation tasks. Working memory ability was negatively correlated with PCC. Regarding chemokines, CCL-11 was negatively correlated to performance in working memory test, and positively correlated with cognitive flexibility task. CXCL-8/IL-8 was positively correlated with verbal fluency. CCL-24/Eotaxin-2 was positively correlated with semantic generation ability and letter memory task., Conclusions: Our results indicate that cognitive performance in SZ is associated with mediators of neuroplasticity that can be measured peripherally., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Previous research has shown associations between source memory errors and hallucinations in patients with schizophrenia. We bring together here findings from a broad memory investigation to specify better the type of source memory failure that is associated with auditory and visual hallucinations., Method: Forty-one patients with schizophrenia and 43 healthy participants underwent a memory task involving recall and recognition of lists of words, recognition of pictures, memory for temporal and spatial context of presentation of the stimuli, and remembering whether target items were presented as words or pictures., Results: False recognition of words and pictures was associated with hallucination scores. The extra-list intrusions in free recall were associated with verbal hallucinations whereas the intra-list intrusions were associated with a global hallucination score. Errors in discriminating the temporal context of word presentation and the spatial context of picture presentation were associated with auditory hallucinations. The tendency to remember verbal labels of items as pictures of these items was associated with visual hallucinations. Several memory errors were also inversely associated with affective flattening and anhedonia., Conclusions: Verbal and visual hallucinations are associated with confusion between internal verbal thoughts or internal visual images and perception. In addition, auditory hallucinations are associated with failure to process or remember the context of presentation of the events. Certain negative symptoms have an opposite effect on memory errors.

Previous work has suggested that decrement in both processing speed and working memory span plays a role in the memory impairment observed in patients with schizophrenia. We undertook a study to examine simultaneously the effect of these two factors. A sample of 49 patients with schizophrenia and 43 healthy controls underwent a battery of verbal and visual memory tasks. Superficial and deep encoding memory measures were tallied. We conducted regression analyses on the various memory measures, using processing speed and working memory span as independent variables. In the patient group, processing speed was a significant predictor of superficial and deep memory measures in verbal and visual memory. Working memory span was an additional significant predictor of the deep memory measures only. Regression analyses involving all participants revealed that the effect of diagnosis on all the deep encoding memory measures was reduced to non-significance when processing speed was entered in the regression. Decreased processing speed is involved in verbal and visual memory deficit in patients, whether the task require superficial or deep encoding. Working memory is involved only insofar as the task requires a certain amount of effort.

Previous studies have revealed semantic memory impairments in patients with schizophrenia, and suggested that certain of these impairments were related to thought disorganization. One explanation offered for this is a broadening of the boundaries of semantic categories in schizophrenia. We selected 16 semantic categories, and required a sample of 41 schizophrenia patients and 43 healthy control subjects to produce one exemplar from each category. The typicality of the subjects' responses was rated. The exemplars produced by the patients were on average less typical than those produced by the healthy controls. No significant association between typicality of the response and thought disorganization was revealed in the patient sample. Affective flattening, alogia, and anhedonia were significantly and inversely associated with the typicality score, that is, higher ratings of these symptoms were associated with more typical responses. Our results suggest that a broadening of semantic category boundaries is observed in patients with schizophrenia, but is unrelated to thought disorganization. This semantic abnormality is not a feature of the patients with high ratings of certain negative symptoms.

Introduction: Schizophrenic patients have a higher prevalence of obesity than the general population. There are several factors implicated in weight gain, including poor dietary conditions, sedentary lifestyle and antipsychotic drugs use. Obesity is also associated with metabolic disturbances such as diabetes mellitus. Weight gain interventions are necessary in this population, especially non-pharmacological interventions., Objective: To review the non-pharmacological interventions for weight gain management in patients with schizophrenia., Methods: Eight clinical trials and four open-label studies using these interventions were found. The methodology, strength and limitations of the studies were reviewed., Conclusions: Non-pharmacological interventions seem to have an important effect on weight gain prevention and control, and should be encouraged and adapted to patients and in mental health institution's reality.

Background: Previous research has demonstrated that various types of verbal source memory error are associated with positive symptoms in patients with schizophrenia. Notably, intrusions in free recall have been associated with hallucinations and delusions. We tested the hypothesis that extra-list intrusions, assumed to arise from poor monitoring of internally generated words, are associated with verbal hallucinations and that intra-list intrusions are associated with global hallucination scores., Method: A sample of 41 patients with schizophrenia was administered four lists of words, followed by free recall. The number of correctly recalled words and the number of extra- and intra-list intrusions were tallied., Results: The verbal hallucination score was significantly correlated with the number of extra-list intrusions, whereas it was unrelated to the number of correctly recalled words. The number of intra-list intrusions was significantly correlated with the global, but not with the verbal, hallucination score in the subsample of hallucinating patients. It was marginally significantly correlated with the delusion score in delusional patients., Conclusions: The data corroborate the view that verbal hallucinations are linked to defective monitoring of internal speech, and that errors in context processing are involved in hallucinations and delusions.

Previous research had shown that processing speed and premorbid IQ are predictors of verbal-memory efficiency in patients with schizophrenia. We investigated whether the same factors are involved in visual memory. A total of 49 patients with schizophrenia and 43 healthy controls were administered a picture recognition task. Half of the pictures were black and white, and half were in color, in order to vary the depth of encoding. Processing speed was measured by three standard tasks, and premorbid IQ was measured by the National Adult Reading Test (NART). Patients were significantly impaired in picture recognition. Regression analyses revealed that NART score was a significant predictor of the recognition of both types of picture in patients. Processing speed was a significant predictor of the recognition of the colored pictures. The effect of diagnosis on the recognition of colored pictures was reduced to nonsignificance when processing speed was entered in the regression. These data suggest that premorbid IQ is involved in visual-recognition efficiency. However, the deficit observed in patients is accounted for by decreased processing speed.

The authors undertook a study of the clinical correlates of verbal memory deficits in schizophrenia. The first purpose was to replicate the finding of a significant association between depression and impairment in the deep encoding memory processes. The second purpose was to test the hypothesis that certain clinical symptoms--avolition, disorders of attention--also play a role in verbal memory impairment, distinct from a global negative symptomatology score. Forty-one patients with schizophrenia underwent a memory task including forward digit span and learning lists of words with different levels of semantic organization. Regression analyses revealed that the depression score was associated with the total number of recalled words, whereas the global negative symptom score was not. Depression score was not associated with the forward digit span, a measure of superficial serial encoding processes. An analysis of individual symptoms from the Scale for the Assessment of Negative Symptoms (SANS) indicated that avolition was associated with several memory scores, suggesting a pervasive effect of this symptom. Attention disorders were associated with impaired efficiency in serial learning, but not with word recall efficiency. It is suggested that more consideration should be given to depression and motivation in the investigation of cognitive impairment in schizophrenia, as well as in cognitive remediation strategies.

The adaptive behavior of human beings is usually supported by rapid monitoring of outstanding events in the environment. Some investigators have suggested that a primary attention deficit might trigger symptoms of schizophrenia. In addition, researchers have long discussed the relationship between schizophrenia and the schizophrenia-like psychosis of epilepsy (SLPE). On the basis of these considerations, the objective of the present study was to investigate attention performance of patients with both disorders. Patient age was 18 to 60 years, and all patients had received formal schooling for at least four years. Patients were excluded if they had any systemic disease with neurologic or psychiatric comorbidity, or a history of brain surgery. The computer-assisted TAVIS-2R test was applied to all patients and to a control group to evaluate and discriminate between selective, alternating and sustained attention. The TAVIS-2R test is divided into three parts: one for selective attention (5 min), the second for alternating attention (5 min), and the third for the evaluation of vigilance or sustained attention (10 min). The same computer software was used for statistical analysis of reaction time, omission errors, and commission errors. The sample consisted of 36 patients with schizophrenia, 28 with interictal SLPE, and 47 healthy controls. The results of the selective attention tests for both patient groups were significantly lower than that for controls. The patients with schizophrenia and SLPE performed differently in the alternating and sustained attention tests: patients with SLPE had alternating attention deficits, whereas patients with schizophrenia showed deficits in sustained attention. These quantitative results confirmed the qualitative clinical observations for both patient groups, that is, that patients with schizophrenia had difficulties in focusing attention, whereas those with epilepsy showed perseveration in attention focus.

Background: Word frequency paradigms have been used repeatedly in healthy populations to help understand the functioning of verbal memory. We investigated the word frequency effects in a sample of patients with schizophrenia, assuming these data may shed light on certain encoding processes., Methods: Two mixed lists of high- and low-frequency words were presented to 46 patients with schizophrenia and 43 healthy control subjects. List learning was followed by free recall and recognition in immediate and delayed conditions., Results: Overall the high-frequency words were better recalled, whereas the low-frequency words were better recognised. The lack of interaction with diagnosis indicates that these effects were equivalent in both groups. In immediate recognition, the discrimination deficit for the high-frequency words in patients tended to be increased relative to that for the low-frequency words, suggesting greater impairment in the encoding of those words., Conclusion: It is argued that the encoding of the distinct low-frequency words is less efficient in patients, but qualitatively unimpaired. By contrast, the familiar words might be more difficult for patients to encode, as they are more easily confused with other common words stored in long-term memory.

We tested the hypothesis that the degree of striatal dopamine D(2) receptor blockade induced by typical antipsychotic treatment directly correlates with the presence and severity of depressive symptoms in schizophrenia. Clinical and [(123)I]-IBZM single-photon emission tomography (SPET) scan data obtained from 18 typical antipsychotic treated schizophrenic patients was analysed to evaluate the relationship between striatal D(2) receptor occupancy and the depressive subscale of the Brief Psychiatric Rating Scale (BPRS-D). Striatal D(2) receptor occupancy by typical antipsychotic drugs was significantly positively correlated with BPRS-D scores (r=0.52, p=0.025). This study suggests that high striatal dopamine D(2) blockade by typical antipsychotic drugs may contribute to the emergence of depressive symptoms in typical antipsychotic treated schizophrenic patients.

Introduction: Although depression is a well-established feature of schizophrenia, it is difficult to measure, because it overlaps with negative symptoms and extrapyramidal symptoms (EPS). Routinely adopted depression scales were not designed to be used in--cases of schizophrenia, and are known to perform poorly when trying to distinguish depression from other symptoms., Objective: The aim of this study was to evaluate the validity of the Brazilian version of the Calgary Depression Rating Scale for Schizophrenia (CDSS)., Method: Outpatients from four mental health units in the city of São Paulo, diagnosed as having schizophrenia by DSM-IV criteria, were evaluated by two independent raters who applied the DSM-IV depression criteria. All patients were assessed by means of the CDSS, the Positive and Negative Syndrome Scale (PANSS), and the Extrapyramidal Symptom Rating Scale (ESRS)., Results: Eighty patients were recruited for the study. The analysis was carried out by comparing the DSM-IV criteria of depression with the CDSS scores, by means of the receiver operating characteristic (ROC) curves. The area under the ROC curve for major depression was 0.95 (SD = 0.02), and at a cut-off point of 6/7 the validity coefficients were as follows: sensibility 77%, specificity 92%, positive predictive value 67% and negative predictive value 95%. The area under the ROC curve for minor depression was 0.95 (SD = 0.02), and at a cut-off point of 4/5 the validity coefficients were as follows: sensibility 95%, specificity 88%, positive predictive value 75% and negative predictive value 98%. The correlation coefficients between the CDSS scores, the PANSS negative and positive subscale scores, and the ESRS scores were all below 0.50., Conclusion: It can be concluded that the Brazilian version of the CDSS is a valid research tool to assess depressive episodes for stabilized patients with schizophrenia.