COX-2 pathway is upregulated in ultra-high risk individuals for psychosis.

BACKGROUND: The identification of Ultra-High Risk (UHR) individuals is thought to be useful for early intervention to improve psychosis outcomes. However, transition rates vary widely, and there is an effort to make these criteria more specific and accurate. Neuroinflammation has been discussed in the pathophysiology of psychosis. The metabolism of eicosanoids is a key process in inflammatory states. Therefore, we investigated whether the study of the inflammatory COX-2 pathway through the quantification of the eicosanoid levels can be a useful approach for the characterisation of UHR individuals. METHODS: One hundred and twenty-two individuals were included in this study (67 UHR and 55 controls) based on performance on the Prodromal Questionnaire. UHR status was assessed by Structured Interview for Prodromal Syndromes (SIPS). We determined the levels of Prostaglandin F2α (PGF2α), Prostaglandin E2 (PGE2), and Thromboxane B2 (TxB2) in plasma using ELISA assays. RESULTS: Concentrations of PGE2 and TxB2 were increased in UHR compared to controls (p = 0.01 and p < 0.05, respectively). PGE2 and PGF2α levels were correlated to negative symptoms (p < 0.01 and p < 0.05), whereas TxB2 correlated with positive symptoms (p = 0.05) as assessed by the SIPS. CONCLUSIONS: Our findings suggest that overactivation of the COX-2 pathway may be related to an increased risk for psychosis. However, our data do not allow us to draw conclusions related to the cause-effect mechanisms. Future studies should determine whether the levels of the eicosanoids have a predictive value for the transition of UHR to frank psychosis.

Plasmatic endocannabinoids are decreased in subjects with ultra-high risk of psychosis.

The onset of frank psychosis is usually preceded by a prodromal phase characterized by attenuated psychotic symptoms. Currently, research on schizophrenia prodromal phase (ultra-high risk for psychosis [UHR]) has focused on the risk of developing psychosis, on the transition to full blown psychosis and on its prediction. Neurobiological differences between UHR individuals who fully recover (remitters) versus those who show persistent/progressive prodromal symptoms (nonremitters) have been little explored. The endocannabinoid system constitutes a neuromodulatory system that plays a major role in brain development, synaptic plasticity, emotional behaviours and cognition. It comprises two cannabinoid receptors (CB1/CB2), two endocannabinoid ligands, arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2AG) along with their inactivation enzymes. Despite much evidence that the endocannabinoid system is imbalanced during psychosis, very little is known about it in UHR. Therefore, we aimed to quantify the plasma endocannabinoid levels in UHR and healthy controls (HC) and verify if these metabolites could differentiate between remitters and nonremitters. Circulating concentrations of AEA (p = .003) and 2AG (p < .001) were lower in UHR when compared with HC, with no difference between remitters and nonremitters. Regarding clinical evolution, it was observed that out of 91 UHRs initially considered, 16 had psychiatric complaints (3 years of follow-up). Considering those subjects, there were weak correlations between clinical parameters and plasma concentrations of endocannabinoids. Our results suggest that the endocannabinoids are imbalanced before frank psychosis and that changes can be seen in plasma of UHR individuals. These molecules proved to be potential biomarkers to identify individuals in the prodromal phase of psychosis.

Influence of migration on the thought process of individuals at ultra-high risk for psychosis

Objective: To assess the influence of migration on the psychopathological presentation of individuals at ultra-high risk for psychosis (UHR) in São Paulo, Brazil. Methods: This study is part of the Subclinical Symptoms and Prodromal Psychosis (SSAPP) project, a cohort study in São Paulo, Brazil, designed to follow individuals at UHR. After screening with the Prodromal Questionnaire (PQ) and a clinical interview, the Global Assessment of Functioning (GAF) was administered, a neuropsychological assessment was performed, sociodemographic and migration data were obtained. We then analyzed UHR individuals who had migration data to see if migration had any effect on their cognition and psychopathology. Chi-square tests were used for categorical variables, and Student's t test or analysis of variance (ANOVA) were used for nonparametric and parametric distributions, respectively. Results: The sample was composed of 42 at-risk subjects, of whom 5 had a migration history in the past two generations. Those with migration history showed significantly more formal thought disturbances (p = 0.012) and sleeping problems (p = 0.033) compared to those without. Conclusions: Our data reinforce migration as a risk factor for psychosis in developing countries as well, and highlights the importance of studying the specific effect of this factor in UHR psychopathology.

Stigma toward individuals with mental disorders among Brazilian psychiatrists: a latent class analysis

Objective: The stigma toward individuals with mental disorders is highly prevalent, not only in the general population but among health care providers as well. The aim of this study was to identify subgroups based on stigmatizing beliefs related to psychiatric disorders among Brazilian psychiatrists, as well as to investigate their association with clinical and personality characteristics. Methods: Latent cluster analysis was used to find subgroups of cases in multivariate data according to a psychotic (schizophrenia) and a nonpsychotic disorder (attention-deficit hyperactivity disorder). The clusters for each psychiatric disorder were compared according to sociodemographic, emotional traits, and personality characteristics. Results: A total of 779 psychiatrists answered the questionnaire. Three different subgroups of stigma levels were identified regarding schizophrenia: the highest (n=202 [51.7%]), intermediate (108 [27.6%]), and the lowest (81 [20.7%]). Participants from the highest stigma group had a significantly longer time since graduation, higher anxiety-state scores, and lower positive affect. Two subgroups were identified with respect to attention-deficit hyperactivity disorder, although there were no differences between them in sociodemographic or clinical variables. Conclusion: There were more subgroups of stigmatizing beliefs regarding psychotic disorders. Individual characteristics, such as those related to trait anxiety and affect, can be associated with high stigma toward schizophrenia.

Increased PLA2 activity in individuals at ultra-high risk for psychosis.

Phospholipase A2 is the main enzyme in the metabolism of membrane phospholipids. It comprises a family of enzymes divided into iPLA2, cPLA2 and sPLA2. Studies have reported increased PLA2 activity in psychotic patients, which suggests an accelerated breakdown of membrane phospholipids. In the present study we investigated whether increased PLA2 activity is also present in individuals at ultra-high risk (UHR) for psychosis. One-hundred fifty adults were included in this study (85 UHR and 65 controls). UHR was assessed using the "structured interview for prodromal syndromes". PLA2 activity was determined in platelets by a radio-enzymatic assay. We found in UHR individuals increased activities of iPLA2 (p < 0.001) and cPLA2 (p = 0.012) as compared to controls. No correlations were found between socio-demographic and clinical parameters and PLA2 activity. Our findings suggest that increased PLA2 activities may be useful as a biological risk-marker for psychotic disorders.

Stigma toward individuals with mental disorders among Brazilian psychiatrists: a latent class analysis.

OBJECTIVE: The stigma toward individuals with mental disorders is highly prevalent, not only in the general population but among health care providers as well. The aim of this study was to identify subgroups based on stigmatizing beliefs related to psychiatric disorders among Brazilian psychiatrists, as well as to investigate their association with clinical and personality characteristics. METHODS: Latent cluster analysis was used to find subgroups of cases in multivariate data according to a psychotic (schizophrenia) and a nonpsychotic disorder (attention-deficit hyperactivity disorder). The clusters for each psychiatric disorder were compared according to sociodemographic, emotional traits, and personality characteristics. RESULTS: A total of 779 psychiatrists answered the questionnaire. Three different subgroups of stigma levels were identified regarding schizophrenia: the highest (n=202 [51.7%]), intermediate (108 [27.6%]), and the lowest (81 [20.7%]). Participants from the highest stigma group had a significantly longer time since graduation, higher anxiety-state scores, and lower positive affect. Two subgroups were identified with respect to attention-deficit hyperactivity disorder, although there were no differences between them in sociodemographic or clinical variables. CONCLUSION: There were more subgroups of stigmatizing beliefs regarding psychotic disorders. Individual characteristics, such as those related to trait anxiety and affect, can be associated with high stigma toward schizophrenia.

Influence of migration on the thought process of individuals at ultra-high risk for psychosis.

OBJECTIVE: To assess the influence of migration on the psychopathological presentation of individuals at ultra-high risk for psychosis (UHR) in São Paulo, Brazil. METHODS: This study is part of the Subclinical Symptoms and Prodromal Psychosis (SSAPP) project, a cohort study in São Paulo, Brazil, designed to follow individuals at UHR. After screening with the Prodromal Questionnaire (PQ) and a clinical interview, the Global Assessment of Functioning (GAF) was administered, a neuropsychological assessment was performed, sociodemographic and migration data were obtained. We then analyzed UHR individuals who had migration data to see if migration had any effect on their cognition and psychopathology. Chi-square tests were used for categorical variables, and Student's t test or analysis of variance (ANOVA) were used for nonparametric and parametric distributions, respectively. RESULTS: The sample was composed of 42 at-risk subjects, of whom 5 had a migration history in the past two generations. Those with migration history showed significantly more formal thought disturbances (p = 0.012) and sleeping problems (p = 0.033) compared to those without. CONCLUSIONS: Our data reinforce migration as a risk factor for psychosis in developing countries as well, and highlights the importance of studying the specific effect of this factor in UHR psychopathology.

Patterns of religiosity and spirituality of psychiatrists in Brazil and the implications for clinical practice: a latent profile analysis.

BACKGROUND: Although there is consensus, in psychiatry, over the inclusion of religious and spiritual aspects when evaluating and treating the patient, investigation of these dimensions is rare. There is evidence as to the relationship between psychiatrists' religious/spiritual beliefs and their willingness to discuss a patient's religion and spirituality (R/S). Due to the lack of information about how psychiatrists in Brazil deal with R/S in patient care, the aim of the present study is to analyze the religious/spiritual profile of these professionals and to ascertain its influence on attitudes and behavior in clinical practice. METHODS: Five hundred and ninety-two psychiatrists from Brazil answered a questionnaire about R/S in clinical practice. The latent profile analysis was used to search for differences of religious/spiritual profiles. The ANOVA and Pearson's chi-square tests were employed to identify any correlation between clinical opinion and behaviors according to the different profiles. RESULTS: Two religious/spiritual profiles were identified (entropy value > 0,96): the so called "less religious" group (n = 245), comprised predominantly by men, professionally more experienced, with a higher level of academic education (Master or PhD degrees) and were the ones who least enquired about their patients' R/S; and the "more religious" psychiatrists (n = 347) those who had higher consideration for R/S on health, and who more often addressed R/S with their patients and therefore usually ascribed importance to include R/S in their professional training. CONCLUSION: The latent profile analysis produced two distinct classes between the Brazilian psychiatrists according to their R/S views: the more religious professionals, who investigate the patient's R/S in a more detailed manner, and the less religious, who tend to disregard this aspect.

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders.

Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment-resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre- and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate-related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors.

Home-Based Psychiatric Outpatient Care Through Videoconferencing for Depression: A Randomized Controlled Follow-Up Trial.

BACKGROUND: There is a tremendous opportunity for innovative mental health care solutions such as psychiatric care through videoconferencing to increase the number of people who have access to quality care. However, studies are needed to generate empirical evidence on the use of psychiatric outpatient care via videoconferencing, particularly in low- and middle-income countries and clinically unsupervised settings. OBJECTIVE: The objective of this study was to evaluate the effectiveness and feasibility of home-based treatment for mild depression through psychiatric consultations via videoconferencing. METHODS: A randomized controlled trial with a 6- and 12-month follow-up including adults with mild depression treated in an ambulatory setting was conducted. In total, 107 participants were randomly allocated to the videoconferencing intervention group (n=53) or the face-to-face group (F2F; n=54). The groups did not differ with respect to demographic characteristics at baseline. The F2F group completed monthly follow-up consultations in person. The videoconferencing group received monthly follow-up consultations with a psychiatrist through videoconferencing at home. At baseline and after 6 and 12 months, in-person assessments were conducted with all participants. Clinical outcomes (severity of depression, mental health status, medication course, and relapses), satisfaction with treatment, therapeutic relationship, treatment adherence (appointment compliance and dropouts), and medication adherence were assessed. RESULTS: The severity of depression decreased significantly over the 12-month follow-up in both the groups. There was a significant difference between groups regarding treatment outcomes throughout the follow-up period, with better results in the videoconferencing group. There were 4 relapses in the F2F group and only 1 in the videoconferencing group. No significant differences between groups regarding mental health status, satisfaction with treatment, therapeutic relationship, treatment adherence, or medication compliance were found. However, after 6 months, the rate of dropouts was significantly higher in the F2F group (18.5% vs 5.7% in the videoconferencing group, P<.05). CONCLUSIONS: Psychiatric treatment through videoconferencing in clinically unsupervised settings can be considered feasible and as effective as standard care (in-person treatment) for depressed outpatients with respect to clinical outcomes, patient satisfaction, therapeutic relationship, treatment adherence, and medication compliance. These results indicate the potential of telepsychiatry to extend access to psychiatric care to remote and underserved populations. CLINICALTRIAL: Clinicaltrials.gov NCT01901315; https://clinicaltrials.gov/ct2/show/NCT01901315 (Archived by WebCite at http://www.webcitation.org/6jBTrIVwg).

Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission.

OBJECTIVE: To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val158Met and dopamine receptor 3 (DRD3) Ser9Gly. METHODS: Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance. RESULTS: For executive functioning, COMT Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT Met allele frequency increased, executive functioning worsened. COMT Met/Met patients carrying the DRD3 Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3 combination significantly differed from all DRD3 Gly/Gly combinations (p < 0.05), from COMT Val/Met DRD3 Ser/Gly (p = 0.02), and from COMT Val/Val DRD3 Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001). CONCLUSION: Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.

Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission

Objective:To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val158Met and dopamine receptor 3 (DRD3) Ser9Gly.Methods:Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance.Results:For executive functioning, COMT Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT Met allele frequency increased, executive functioning worsened. COMT Met/Met patients carrying the DRD3 Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3 combination significantly differed from all DRD3 Gly/Gly combinations (p < 0.05), from COMT Val/Met DRD3 Ser/Gly (p = 0.02), and from COMT Val/Val DRD3 Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001).Conclusion:Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.

Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium.

BACKGROUND: Bipolar disorder (BD) has been associated with diverse abnormalities in neural plasticity and cellular resilience. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) support synaptic neuronal survival and differentiation. NT-3 and NT-4/5 levels were found to be altered in BD, potentially representing a physiological response against cellular stress. However, the use of psychopharmacological agents and heterogeneous mood states may constitute important biases in such studies. Thus, we aimed to assess NT-3 and NT-4/5 levels in medication-free BD type I or II individuals in a current depressive episode, before and after 6 weeks of lithium monotherapy and matched with healthy controls. METHODS: Twenty-three patients with BD type I or II during a depressive episode and 28 healthy controls were studied. Patients were required to have a 21-item Hamilton Depression Rating Scale score ≥18 and had not undergone any psychopharmacological treatment for at least 6 weeks prior to study entry. Patients were treated with lithium for 6 weeks and plasma NT-3 and NT-4/5 levels were determined at baseline and endpoint using ELISA method. RESULTS: Baseline plasma levels of both NT-3 and NT-4/5 were significantly increased in acutely depressed BD subjects in comparison to healthy controls (p=0.040 and 0.039, respectively). The NT-3 and NT-4/5 levels did not significantly change after lithium treatment. NT-3 and NT-4/5 levels were positively correlated to illness duration in BD (p=0.032 and 0.034, respectively). CONCLUSION: Our findings suggest that NT-3 and NT-4/5 levels are increased in the depressive phase of BD, which seems directly associated with illness duration. The increased levels of NT-3 and NT-4/5 may underlie a biological response to cellular stress associated with the course of BD.

Patterns of stigma toward schizophrenia among the general population: a latent profile analysis.

OBJECTIVE: Our purpose was to assess stigma toward schizophrenia in a representative sample of the Brazilian general population. METHODS: The sample consisted of 1015 individuals interviewed by telephone. A vignette describing someone with schizophrenia was read, and four stigma aspects regarding this hypothetical individual were assessed: stereotypes, restrictions, perceived prejudice and social distance. Latent profile analysis searched for stigma profiles among the sample. Multinomial logistic regression was used to find correlates of each class. RESULTS: Four stigma profiles were found; 'no stigma' individuals (n = 251) mostly displayed positive opinions. 'Labelers' (n = 222) scored high on social distance; they more often had familial contact with mental illness and more often labeled the vignette's disorder as schizophrenia. 'Discriminators', the group with the majority of individuals (n = 302), showed high levels of stigmatizing beliefs in all dimensions; discriminators were significantly older. 'Unobtrusive stigma' individuals (n = 240) seemed to demonstrate uncertainty or low commitment since they mostly answered items with the middle/impartial option. CONCLUSION: Some findings from the international literature were replicated; however, familial contact increased stigma, possibly denoting a locally modulated determinant. Hereby, our study also adds important cross-cultural data by showing that stigma toward schizophrenia is high in a Latin-American setting. We highlight the importance of analyzing the general population as a heterogeneous group, aiming to better elaborate anti-stigma campaigns.