Early growth response 1 (EGR1) is downregulated in peripheral blood from patients with major psychiatric disorders.

OBJECTIVES: To evaluate relative expression of genes with the potential to translate environmental stimuli into long-term alterations in the brain - namely Early Growth Response (EGR)1, EGR3, and Cryptochrome Circadian Regulator 2 (CRY2) - in peripheral blood from patients with Bipolar Disorder (BD), Schizophrenia (SZ), Major Depressive Disorder (MDD) and healthy controls (HC). METHODS: Thirty individuals ranging from 18 to 60 years were recruited for each group (BD, SZ, MDD or HC) from a Brazilian public hospital. Therefore, individuals' peripheral blood was collected and EGR1, EGR3 and CRY2 gene expression analyzed by PCR Real Time. RESULTS: EGR1 mRNA levels are significantly lower in psychiatric patients when compared to HC, but there is no difference for EGR3 and CRY2. Exploring the findings for each diagnosis, there is a significant difference between each diagnosis group only for EGR1, which was lower in BD, MDD and SZ as compared to HC. No significant correlations were found between gene expression and clinical features. CONCLUSIONS: EGR1 is downregulated in psychiatric patients, regardless of the diagnosis and may be a potential common target in major psychiatric disorders. EGR1, as a transcription factor, modulates many other genes and participates in crucial neuronal and synaptic processes, such as plasticity, neurotransmitters metabolism, vesicular transport and signaling pathways. The study of EGR1 and its upstream regulators in psychiatry might lead to potential new therapeutic targets.

Association of daily-life functioning and obesity in individuals with schizophrenia and controls.

Early weight gain following the diagnosis of schizophrenia (SCZ) has been associated with improved daily functioning. However, in the general population and in other psychiatric conditions such as bipolar disorder, increased body mass index (BMI) has been associated with worse functioning. The data on this association in chronic individuals with SCZ is still scarce. To address this gap in knowledge, our objective was to evaluate the association between BMI and psychosocial functioning in chronic outpatients with SCZ and in healthy individuals. Six-hundred individuals (n = 600), 312 with schizophrenia (SCZ) and 288 individuals with no personal or family history of severe mental illness (CTR), underwent weight, height and psychosocial functioning score (FAST) assessment. Linear regression models tested the association between FAST as dependent variable and BMI as independent variable, controlling for age, sex, use of clozapine and years of illness. In the CTR group, the highest BMI could predict a worse result in FAST, explaining about 22% of the variation found (Model: AdjR2 = 0.225 F(3,284) = 28.79 p < .001; BMI main effect: ß = 0.509 t = 9.240 p < .001). In the SCZ group, there was no statistically significant association. Our findings corroborate the perception that increased BMI is associated with worse functioning status in the general population. In chronic SCZ, whatsoever, there is no association. Our findings suggest that patients with higher BMI in the SCZ group may compensate for the possible impairment of functionality due to increased body weight, through improved adherence and responsiveness to prescribed psychopharmacological treatment, leading to better control of psychiatric symptoms.

Country-level gender inequality is associated with structural differences in the brains of women and men.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Immunoinflammatory and oxidative alterations in subjects with schizophrenia under clozapine: A meta-analysis.

Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced by clozapine and its relationship with the drug's clinical response and compare it with other antipsychotics. Our systematic review has selected nineteen studies meeting the inclusion criteria, from which eleven were included in the meta-analysis, totalizing 689 subjects distributed over three different comparisons. The results revealed that clozapine treatment activates the compensatory immune-regulatory system (CIRS) (Hedges's g = +1.049; CI +0.62 - +1.47, p < 0.001) but has no effects on the immune-Inflammatory Response System (IRS) (Hedges's g= -0.27; CI -1.76 - +1.22, p = 0.71), M1 macrophage (Hedges's g= -0.32; CI -1.78 - +1.14, p = 0.65) and Th1 (Hedge's g = 0.86; CI -0.93 - +1.814, p = 0.07) profiles. Comparing clozapine-treated patients with other anti-psychotics-treated, plasma levels of interleukin (IL)-6 were greater in the clozapine group (Hedge's g = 0.75; CI 0.35 - 1.15, p<0.001). In addition, higher IL-6 plasma levels after four weeks of clozapine treatment were related to the development of clozapine-induced fever; however, IL-6 levels recovered to baseline in 6-10 weeks due to an unexplained compensatory mechanism. In conclusion, our results show that clozapine treatment causes a time-dependent mixed immune profile characterized by increased IL-6 levels and CIRS activation, which may contribute to this drug mechanism of action and adverse effects. Future studies must be designed to investigate the relationship between clozapine-induced immune alterations and symptom remission, treatment resistance, and adverse effects, given the importance of this drug for treating resistant schizophrenia.

A five-year follow-up of the verbal memory performance of individuals with bipolar disorder and schizophrenia: evidence of unchanging deficits under treatment.

OBJECTIVE: Bipolar disorder (BD) and schizophrenia (SZ) are chronic and heterogeneous mental disorders that present cognitive and functional impairments. Verbal memory is considered an important predictor of functioning and a domain vulnerable to the aging process. However, only few studies investigate the progression of memory longitudinally in BD and SZ, especially in lower- and middle-income countries. Therefore, we aim to evaluate the course of verbal memory in individuals with BD and SZ. METHODS: We assessed 31 individuals with BD and 27 individuals with SZ under treatment at outpatient clinics at baseline and after five years. They were assessed through a sociodemographic questionnaire, memory and estimated IQ (eIQ) instruments, and clinical scales. RESULTS: Individuals with SZ showed worse verbal memory performance in comparison to BD, however, we did not observe changes over time within patient groups. Individuals with BD with higher eIQ showed a better verbal memory performance, while no effect of eIQ was found for subjects with SZ. CONCLUSION: Patients with SZ and BD showed different levels of verbal memory impairment, although they had similar unchanging trajectories after 5 years under psychiatric treatment. This finding indicates a relative stable cognitive course for both disorders.

The role of semantic clustering in the relationship between verbal memory and psychosocial functioning in schizophrenia and bipolar disorder: Possible distinct cognitive pathway compared to healthy controls.

BACKGROUND: Verbal memory (VM) is impaired in schizophrenia (SZ) and bipolar disorder (BD), and predicts psychosocial functioning. However, there is a lack of research exploring the role of VM component processes, including semantic clustering, in these disorders. Semantic clustering might impact this association, as effective semantic memory strategies may reflect unimpaired executive control, leading to an adequate functioning. We aimed to investigate VM components in SZ and BD, and the role of semantic clustering in the relationship between VM and functioning. METHODS: We included 495 participants (156 SZ, 172 BD, and 167 healthy controls (HC)) that underwent an assessment using the Hopkins Verbal Learning Test - Revised for VM and the Functioning Assessment Short Test for psychosocial functioning. We compared groups through ANOVAs and investigated the effect of semantic clustering in the relationship between VM total immediate free recall and functioning through linear regression models. RESULTS: SZ had worse overall VM performance compared to BD, which performed worse than HCs. HCs used more semantic clustering than SZ and BD, but there were no differences between the two clinical groups. In HCs, semantic clustering impacted the relationship between VM performance and functioning, while no interaction was observed in SZ or BD. LIMITATIONS: Cross-sectional design; no medication effects or other cognitive functions were assessed. CONCLUSIONS: SZ and BD may use an alternative cognitive pathway in which the relationship between VM and functioning is independent of complex cognitive processes such as semantic clustering, supporting the cognitive remediation targeting of VM in these disorders.

Latin American consensus recommendations for the management and treatment of patients with treatment-resistant depression (TRD).

Despite the abundance of literature on treatment-resistant depression (TRD), there is no universally accepted definition of TRD, and available treatment pathways for the management of TRD vary across the Latin American region, highlighting the need for a uniform definition and treatment principles to optimize the management of TRD in Latin America. METHODS: Following a thematic literature review and pre-meeting survey, a Latin America expert panel comprising 14 psychiatrists with clinical experience in managing patients with TRD convened and utilized the RAND/UCLA appropriateness method to develop consensus-based recommendations on the appropriate definition of TRD and principles for its management. RESULTS: The expert panel agreed that 'treatment-resistant depression' (TRD) is defined as 'failure of two drug treatments of adequate doses, for 4-8 weeks duration with adequate adherence, during a major depressive episode'. A stepwise treatment approach should be employed for the management of TRD - treatment strategies can include maximizing dose, switching to a different class, and augmenting or combining treatments. Nonpharmacological treatments, such as electroconvulsive therapy, are also appropriate options for patients with TRD. CONCLUSION: These consensus recommendations on the operational definition of TRD and approved treatments for its management can be adapted to local contexts in the Latin American countries but should not replace clinical judgement. Individual circumstances and benefit-risk balance should be carefully considered while determining the most appropriate treatment option for patients with TRD.

Clozapine prescription trends in Brazil in the last decade

Objective: Clozapine is a second-generation antipsychotic indicated for treatment-resistant schizophrenia. Studies in several countries have shown a low rate of clozapine use despite the fact that approximately 30% of schizophrenia cases are treatment-resistant. In Brazil, few studies have addressed the frequency and variety of antipsychotic use in individuals diagnosed with schizophrenia (ICD F20). The objective of this study was to measure the rates of clozapine use in this population in the last decade using Brazilian Ministry of Health data. Methods: Prescriptions made between 2010 and 2020 in all 26 states and the Federal District registered at the Outpatient Information System Database from the Brazilian Health System (SIASUS) were evaluated. Results: A total of 25,143,524 prescriptions were recorded in this period, with clozapine representing 8.86% of all antipsychotics. The most frequently prescribed antipsychotic for patients with schizophrenia was olanzapine (35.8%), followed by quetiapine (27.5%). From 2010 to 2020, the rate of clozapine prescriptions in Brazil increased from 7.2% to 10.9%. Conclusions: Despite a slight increase in prescriptions in the last decade, clozapine is still underutilized in Brazil.

Clozapine prescription trends in Brazil in the last decade.

OBJECTIVE: Clozapine is a second-generation antipsychotic indicated for treatment-resistant schizophrenia. Studies in several countries have shown a low rate of clozapine use despite the fact that approximately 30% of schizophrenia cases are treatment-resistant. In Brazil, few studies have addressed the frequency and variety of antipsychotic use in individuals diagnosed with schizophrenia (ICD F20). The objective of this study was to measure the rates of clozapine use in this population in the last decade using Brazilian Ministry of Health data. METHODS: Prescriptions made between 2010 and 2020 in all 26 states and the Federal District registered at the Outpatient Information System Database from the Brazilian Health System (SIASUS) were evaluated. RESULTS: A total of 25,143,524 prescriptions were recorded in this period, with clozapine representing 8.86% of all antipsychotics. The most frequently prescribed antipsychotic for patients with schizophrenia was olanzapine (35.8%), followed by quetiapine (27.5%). From 2010 to 2020, the rate of clozapine prescriptions in Brazil increased from 7.2% to 10.9%. CONCLUSIONS: Despite a slight increase in prescriptions in the last decade, clozapine is still underutilized in Brazil.

Obstetric complications and cognition in schizophrenia: a systematic review and meta-analysis.

BACKGROUND: Schizophrenia (SZ) is a complex brain disorder linked to cognitive and neurostructural abnormalities that involves genetic and environmental factors with obstetric complications (OCs) at birth conferring a high risk for the disease. Indeed, current research in the general population describes the deleterious effect of OCs on cognitive performance in adulthood. With this rationale, we aim to review the relationship between OCs and cognition in SZ and related psychotic disorders. METHODS: A systematic review and meta-analysis describing cognitive function and OCs in patients with SZ and related disorders were conducted. PubMed, EmBase, SCOPUS, and the Cochrane Library were systematically searched to identify eligible studies up to January 2022. We calculated the effect sizes (Hedges' g) of cognitive domains within each study and quantified the proportion of between-study variability using the I2 statistic. Homogeneity was assessed using the Q-statistic (X2). The study was registered on PROSPERO (CRD42018094238). RESULTS: A total of 4124 studies were retrieved, with 10 studies meeting inclusion criteria for the systematic review and eight for meta-analysis. SZ subjects with OCs showed poor verbal memory [Hedges' g = -0.89 (95% CI -1.41 to -0.37), p < 0.001] and working memory performance [Hedges' g = -1.47 (95% CI -2.89 to -0.06), p = 0.01] in a random-effect model compared to those without OCs. CONCLUSIONS: OCs appear to have a moderate impact on specific cognitive such as working memory and verbal memory. Our findings suggest that OCs are associated with brain development and might underlie the cognitive abnormalities described at onset of psychosis.

The enduring gap in educational attainment in schizophrenia according to the past 50 years of published research: a systematic review and meta-analysis.

BACKGROUND: Educational attainment is associated with wellbeing and health, but patients with schizophrenia achieve lower levels of education than people without. Several effective interventions can ameliorate this situation. However, the magnitude of the education gap in schizophrenia and its change over time are unclear. We aimed to reconstruct the trajectories of educational attainment in patients with schizophrenia and, if reported, their healthy comparator controls. METHODS: We did a systematic review and meta-analysis including all studies reporting on patients with schizophrenia (of mean age ≥18 years) and describing the number of years of education of the participants, with or without healthy controls. There were no other design constraints on studies. We excluded studies that included only patients with other schizophrenia spectrum disorders and studies that did not specify the number of years of education of the participants. 22 reviewers participated in retrieving data from a search in PubMed and PsycINFO (Jan 1, 1970, to Nov 24, 2020). We estimated the birth date of participants from their mean age and publication date, and meta-analysed these data using random-effects models, focusing on educational attainment, the education gap, and changes over time. The primary outcome was years of education. The protocol was registered on PROSPERO (CRD42020220546). FINDINGS: From 32 593 initial references, we included 3321 studies reporting on 318 632 patients alongside 138 675 healthy controls (170 941 women and 275 821 men from studies describing sex or gender; data on ethnicity were not collected). Patients' educational attainment increased over time, mirroring that of controls. However, patients with schizophrenia in high-income countries had 19 months less education than controls (-1·59 years, 95% CI -1·66 to -1·53; p<0·0001), which is equivalent to a Cohen's d of -0·56 (95% CI -0·58 to -0·54) and implies an odds ratio of 2·58 for not completing 12 years of education (ie, not completing secondary education) for patients compared with controls. This gap remained stable throughout the decades; the rate of change in number of total years of education in time was not significant (annual change: 0·0047 years, 95% CI -0·0005 to 0·0099; p=0·078). For patients in low-income and middle-income countries, the education gap was significantly smaller than in high-income countries (smaller by 0·72 years, 0·85 to 0·59; p<0·0001), yet there was evidence that this gap was widening over the years, approaching that of high-income countries (annual change: -0·024 years, -0·037 to -0·011; p=0·0002). INTERPRETATION: Patients with schizophrenia have faced persistent inequality in educational attainment in the last century, despite advances in psychosocial and pharmacological treatment. Reducing this gap should become a priority to improve their functional outcomes. FUNDING: Ciencia y Tecnología para el Desarrollo (CYTED) to the Latin American Network for the Study of Early Psychosis (ANDES).

Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls

Objective: To test the hypothesis that genetic variations of cannabinoid receptors contribute to the pathophysiology of cognitive deficits in schizophrenia. Methods: In this genetic association case-control study, cannabinoid receptor polymorphisms CNR1 rs12720071 and CNR2 rs2229579 were tested for association with neurocognitive performance in 69 patients with schizophrenia and 45 healthy controls. Neurocognition was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS). Results: We found a consistent association between CNR1 rs12720071 polymorphism and the cognitive performance of patients in several cognitive domains. Patients with C/C polymorphism presented significantly worse performance in motor speed, verbal fluency, attention/processing speed and reasoning/problem solving. Conclusion: Although limited, our data support the hypothesis that CNR1 variations may be associated with the pathogenesis of cognitive deficits of schizophrenia.

Heterogeneous trajectories in schizophrenia: insights from neurodevelopment and neuroprogression models

The notion that schizophrenia is a neuroprogressive disorder is based on clinical perception of cumulative impairments over time and is supported by neuroimaging and biomarker research. Nevertheless, increasing evidence has indicated that schizophrenia first emerges as a neurodevelopmental disorder that could follow various pathways, some of them neuroprogressive. The objective of this review is to revisit basic research on cognitive processes and neuroimaging findings in a search for candidate keys to the intricate connections between neurodevelopment and neuroprogression in schizophrenia. In the complete panorama, schizophrenia is a neurodevelopmental disorder, possibly associated with an additional burden over the course of the disease through pathologically accelerated aging, and cognitive heterogeneity may explain the different trajectories of each patient.

Risk of neutropenia among clozapine users and non-users: results from 5,847 patients

Objective: Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those on continuous treatment for > 1 year who have never had an absolute neutrophil count (ANC) < 2,000/µL has been proposed as a monitoring strategy; however, there are no South American data to support this recommendation. This study sought to investigate whether clozapine use and other variables could explain the occurrence of ANC < 1,000/µL in patients with severe mental disorders. Methods: A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox regression considering the outcome as ANC < 1,000/µL at any time point. Predictors were sex, age, ethnicity, clozapine use, ANC > 2,000/µL during the first year of blood monitoring, and presence of a severe medical condition. Results: In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99, p < 0.05) and ANC > 2,000/µL (HR 0.04; 95%CI 0.01-0.10, p < 0.001) were protective factors, while presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p < 0.001) was a risk factor for ANC < 1,000/µL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI 0.74-2.39, p > 0.05). Conclusions: These findings suggest that clozapine does not increase the risk of neutropenia in subjects with ANC > 2,000/µL during the first year of use and in the absence of a severe medical condition. These results could help guide clinical and public-health decisions regarding clozapine blood monitoring guidelines.

Gender, age and geographical representation over the past 50 years of schizophrenia research.

Previous studies have suggested that subjects participating in schizophrenia research are not representative of the demographics of the global population of people with schizophrenia, particularly in terms of gender and geographical location. We here explored if this has evolved throughout the decades, examining changes in geographical location, gender and age of participants in studies of schizophrenia published in the last 50 years. We examined this using a meta-analytical approach on an existing database including over 3,000 studies collated for another project. We found that the proportion of studies and participants from low-and-middle income countries has significantly increased over time, with considerable input from studies from China. However, it is still low when compared to the global population they represent. Women have been historically under-represented in studies, and still are in high-income countries. However, a significantly higher proportion of female participants have been included in studies over time. The age of participants included has not changed significantly over time. Overall, there have been improvements in the geographical and gender representation of people with schizophrenia. However, there is still a long way to go so research can be representative of the global population of people with schizophrenia, particularly in geographical terms.

Bipolar disorder: an association between body mass index and cingulate gyrus fractional anisotropy not mediated by systemic inflammation.

OBJECTIVE: To investigate associations between body mass index (BMI), white matter fractional anisotropy (FA), and C-reactive protein (CRP) in a group of individuals with bipolar disorder (BD) during euthymia and compare them with a control group of healthy subjects (CTR). METHODS: The sample consisted of 101 individuals (BD n = 35 and CTR n = 66). Regions of interest (ROI) were defined using a machine learning approach. For each ROI, a regression model tested the association between FA and BMI, controlling for covariates. Peripheral CRP levels were assayed, correlated with BMI, and included in a mediation analysis. RESULTS: BMI predicted the FA of the right cingulate gyrus in BD (AdjR2 = 0.312 F(3) = 5.537 p = 0.004; ß = -0.340 p = 0.034), while there was no association in CTR. There was an interaction effect between BMI and BD diagnosis (F(5) = 3.5857 p = 0.012; Fchange = 0.227 AdjR2 = 0.093; ß = -1.093, p = 0.048). Furthermore, there was a positive correlation between BMI and CRP in both groups (AdjR2 = 0.170 F(3) = 7.337 p < 0.001; ß = 0.364 p = 0.001), but it did not act as a mediator of the effect on FA. CONCLUSION: Higher BMI is associated with right cingulate microstructure in BD, but not in CTR, and this effect could not be explained by inflammatory mediation alone.

Heterogeneous trajectories in schizophrenia: insights from neurodevelopment and neuroprogression models.

OBJECTIVES: The notion that schizophrenia is a neuroprogressive disorder is based on clinical perception of cumulative impairments over time and is supported by neuroimaging and biomarker research. Nevertheless, increasing evidence has indicated that schizophrenia first emerges as a neurodevelopmental disorder that could follow various pathways, some of them neuroprogressive. The objective of this review is to revisit basic research on cognitive processes and neuroimaging findings in a search for candidate keys to the intricate connections between neurodevelopment and neuroprogression in schizophrenia. In the complete panorama, schizophrenia is a neurodevelopmental disorder, possibly associated with an additional burden over the course of the disease through pathologically accelerated aging, and cognitive heterogeneity may explain the different trajectories of each patient.

Effects of socioeconomic status in cognition of people with schizophrenia: results from a Latin American collaboration network with 1175 subjects.

BACKGROUND: Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. METHODS: We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. RESULTS: Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. CONCLUSIONS: Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low- and middle-income countries.

Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls.

OBJECTIVE: To test the hypothesis that genetic variations of cannabinoid receptors contribute to the pathophysiology of cognitive deficits in schizophrenia. METHODS: In this genetic association case-control study, cannabinoid receptor polymorphisms CNR1 rs12720071 and CNR2 rs2229579 were tested for association with neurocognitive performance in 69 patients with schizophrenia and 45 healthy controls. Neurocognition was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS). RESULTS: We found a consistent association between CNR1 rs12720071 polymorphism and the cognitive performance of patients in several cognitive domains. Patients with C/C polymorphism presented significantly worse performance in motor speed, verbal fluency, attention/processing speed and reasoning/problem solving. CONCLUSION: Although limited, our data support the hypothesis that CNR1 variations may be associated with the pathogenesis of cognitive deficits of schizophrenia.