Postural changes in different stages of schizophrenia is associated with inflammation and pain: a cross-sectional observational study.

OBJECTIVES: To assess the relationship between posture and inflammatory response markers (C-reactive protein [CRP] and von Willebrand factor [vWF]) in schizophrenics. METHODS: Forty patients with stable schizophrenia were divided into early-stage (<10 years since first episode, n = 15) and late-stage (≥10 years since first episode, n = 25) groups. Both groups were compared to controls (n = 26). All participants underwent postural assessment by biophotogrammetry. Cases alone underwent blood collection. The significance level was set at 5%, and analyses were carried out in SPSS 18.0. RESULTS: In the early-stage group, 15 postural angles were significantly different from their reference ranges, whereas in the late-stage group, only seven angles were significantly different. In comparison with the control group, only six angles were significantly different. There was no difference in inflammation markers between the early- and late-stage groups. However, CRP levels were higher in cases with greater disease severity, and vWF was associated with forward head posture. Pain correlated with five postural angles, and late-stage patients reported more pain than early-stage cases. CONCLUSIONS: CRP was associated with disease severity, while vWF and pain were associated with forward head posture, hyperlordosis and scoliosis, suggesting an association between vascular inflammation and pain, with an influence on posture.

Severity but not comorbidities predicts response to methylphenidate in adults with attention-deficit/hyperactivity disorder: results from a naturalistic study.

Although the identification of reliable predictors of methylphenidate response in adults with attention-deficit/hyperactivity disorder (ADHD) is necessary to guide treatment decisions, very few data exist on this issue. Here, we assessed the predictors of clinical response to immediate-release methylphenidate hydrochloride (IR-MPH) in a naturalistic setting by analyzing the influence of demographic factors, severity, and a wide range of comorbid psychiatric disorders. Two hundred fifty adult patients with ADHD were evaluated and completed a short-term treatment with IR-MPH. Mental health diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria through the use of standard structured interviews. The Swanson, Nolan, and Pelham Rating Scale, version 4, adapted to adults was used to assess the severity of ADHD. In the linear regression model, only higher severity of ADHD was associated to a better IR-MPH response (b = 0.770; P < 0.001). Treatment of comorbidities in a subsample (n = 62) did not modify this pattern. Our findings suggest that in clinical settings, patients with more severe ADHD symptoms have a good response to treatment independently from the presence of mild or stabilized comorbidities and their treatments. For adults with ADHD, differently from other common psychiatric disorders such as depression and anxiety, higher severity is associated with better treatment response.

Could comorbid bipolar disorder account for a significant share of executive function deficits in adults with attention-deficit hyperactivity disorder?

OBJECTIVE: The frequent comorbidity between attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) represents a challenge for disentangling specific impairments of each disorder in adulthood. Their functional impairments seem to be mediated by executive function deficits. However, little is known about the extent to which each executive function deficit might be disorder specific or explained by the comorbidity. The aim of the present study was to determine if comorbid BD could account for a significant share of executive function deficits when measured by the Wisconsin Card Sorting Test (WCST) in adults with ADHD. METHODS: Adult patients with ADHD and healthy subjects were evaluated in the ADHD outpatient Program at the Hospital de Clínicas de Porto Alegre. Psychiatric diagnoses were based on DSM-IV criteria. WCST scores were compared by multivariate analysis of covariance among three groups: ADHD with BD (n = 51), ADHD without BD (n = 278), and healthy subjects (n = 91). RESULTS: When compared to patients without BD and healthy subjects, patients with ADHD and comorbid BD showed lower scores in total correct answers (p = 0.003); higher scores in total errors (p = 0.004) and non-perseverative errors (p = 0.002); and completed fewer categories (p = 0.009). Patients with ADHD without BD did not differ from healthy subjects. CONCLUSIONS: WCST impairments among patients with ADHD seem to be to a large extent attributable to comorbid BD. Although other executive function deficits (e.g., in the inhibitory control domain) have been demonstrated to accompany ADHD, the present findings suggest that set-shifting deficits are strongly related to comorbid BD.

Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults.

The dopamine transporter (SLC6A3/DAT1) plays a key role in the regulation of dopaminergic neurotransmission and is the major site of action for methylphenidate, a first-line medication for attention deficit hyperactivity disorder (ADHD). Most genetic association studies with ADHD have investigated a 40-bp variable number of tandem repeats (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1, but these investigations have reported heterogeneous findings. The few studies focused on the 5' region have reported promising results. Despite rs2652511 not being included, nor having any proxy SNP available in GWAS, the few candidate gene studies that analyzed it suggested an association with ADHD and schizophrenia. Here, we analyzed the -839 C/T (rs2652511) promoter variant and the 3'-UTR and intron 8 (Int8) VNTR polymorphisms in 522 adults with ADHD and 628 blood donor controls. The diagnostic procedures followed the DSM-IV criteria. A significant association was detected (P = 0.002) between the rs2652511 C-allele with ADHD. In addition, the 6-repeat allele of Int8 VNTR was associated with higher inattention scores (P = 0.034). The haplotype analysis including DAT1 3'-UTR and Int8 VNTR polymorphisms did not reveal associations with ADHD susceptibility or severity dimensions. These findings extend to adult samples previous findings from children samples on the role of the rs2652511 polymorphism in the promoter region of DAT1 as a risk factor for ADHD susceptibility.

Discordant transsexualism in male monozygotic twins: neuroanatomical and psychological differences.

One monozygotic male twin pair discordant for transsexualism is described. Both twins were interviewed and tested with the Wechsler Adult Intelligence Scale battery for cognitive functions and they underwent magnetic resonance imaging to measure the volumes of specific cerebral structures. Interviews with the twins and their mother indicated no unusual medical or life history events that could have had a causal role in the emergence of the disorder. Both cognitive function testing and neuroimaging detected differences between the twins that could be related to unexplained epigenetic effects and exogenous hormone usage.

The role of a mineralocorticoid receptor gene functional polymorphism in the symptom dimensions of persistent ADHD.

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 5 % of school-aged children and 2.5 % of adults. Genetic studies in ADHD have pointed to genes in different neurobiological systems, with relatively small individual effects. The mineralocorticoid receptor is the main receptor involved in the initial triggering of stress response. Therefore, its encoding gene (NR3C2) is a candidate for psychiatric disorder studies, including ADHD, and behavioral phenotypes. There is evidence that the Val allele of the MRI180V polymorphism (rs5522) increases the risk of depression, attention and cognitive deficits. We investigated the possible role of the mineralocorticoid receptor gene in the symptom dimensions and susceptibility to persistent ADHD. We compared genotype and allele frequencies in 478 adult patients with ADHD and 597 controls and symptom dimensions in 449 patients and 132 controls. Diagnoses were based on the DSM-IV criteria. ADHD symptom dimensions were investigated with SNAP-IV for ADHD severity and Barkley scales for severity and impairment. Carriers of the Val allele presented higher inattention, hyperactivity/impulsivity and impairment scores, while genotype and allele frequencies did not differ between patients and controls. These results are consistent with a possible link between genetic variations in the HPA axis and inattention and hyperactivity measures.

Aerobic and Postural Strength Exercise Benefits in People with Schizophrenia.

BACKGROUND: This study aimed to evaluate the effect of two different types of physical intervention on sedentary behavior and clinical changes in people with schizophrenia. METHOD: This is a clinical trial including people with schizophrenia in regular outpatient care who realized a 3-month exercise protocol and were separated into two groups: aerobic physical intervention (API) and postural physical intervention (PPI). All participants performed an assessment of (a) functional capacity through a 6 min walk test (6MWT), (b) flexibility using Well's bench, (c) disease severity using the Brief Psychiatric Rating Scale (BPRS), (d) quality of life using the SF-36 Questionnaire and (e) physical activity using the Simple Physical Activity Questionnaire (SIMPAQ). RESULTS: Thirty-eight patients with schizophrenia completed the intervention (24 patients in API and 14 patients in PPI). Regarding sedentary behavior, there was an improvement in the API group in the time exercising and in the PPI group concerning time in bed, time walking and exercising. Regarding quality of life, there was an improvement in the API group (functional capacity) and in the PPI group, there was an improvement in physical limitation, pain and emotional limitations. In the API group, there was an improvement in BMI (body mass index), diastolic blood pressure and systolic blood pressure. Functional capacity was improved only in the PPI group. There was no change in flexibility and disease severity. CONCLUSIONS: The study demonstrated a change response in the physical and mental aspects in people with schizophrenia after a change in sedentary behavior.

A controlled open clinical trial of the positive effect of a physical intervention on quality of life in schizophrenia.

Justification: Schizophrenia is a severe mental disorder associated with important physical (obesity and low motor functional capacity) and metabolic (diabetes and cardiovascular diseases) changes that contribute to a more sedentary lifestyle and a low quality of life. Objective: The study aimed to measure the effect of two different protocols of physical exercise [aerobic intervention (AI) versus functional intervention ([FI)] on lifestyle in schizophrenia compared with healthy sedentary subjects. Methodology: A controlled clinical trial involving patients diagnosed with schizophrenia from two different locations [Hospital de Clinicas de Porto Alegre (HCPA) and Centro de Atenção Psicosocial (CAPS) in the city of Camaquã] was carried out. The patients undertook two different exercise protocols (IA: 5-min warm-up of comfortable intensity; 45 min of aerobic exercise of increasing intensity using any of the three modalities-a stationary bicycle, a treadmill, or an elliptical trainer; and 10 min of global stretching of large muscle groups; and FI: a 5 min warm-up with a stationary walk; 15 min of muscle and joint mobility exercises; 25 min of global muscle resistance exercises; and 15 min of breathing body awareness work) twice a week for 12 weeks and were compared with physically inactive healthy controls. Clinical symptoms (BPRS), life quality (SF-36), and physical activity levels (SIMPAQ) were evaluated. The significance level was p ≤ 0.05. Results: The trial involved 38 individuals, of which 24 from each group performed the AI, and 14 from each group underwent the FI. This division of interventions was not randomized but was instead decided upon for convenience. The cases showed significant improvements in quality of life and lifestyle, but these differences were greater in the healthy controls. Both interventions were very beneficial, with the functional intervention tending to be more effective in the cases and the aerobic intervention more effective in the controls. Conclusion: Supervised physical activity improved life quality and reduced sedentary lifestyle in adults with schizophrenia.

Inflammatory markers in outpatients with schizophrenia diagnosis in regular use of clozapine: a cross-sectional study.

It is known that inflammation worsen the course of schizophrenia and induce high clozapine serum levels. However, no study evaluated this change in function of clozapine daily dose in schizophrenia. We assessed the correlation between inflammation and severity symptoms in patients with schizophrenia that take and do not take clozapine. We also assessed the correlation between clozapine daily dose and inflammatory markers to patients who take this drug. Patients were recruited from Schizophrenia Ambulatory and Psychosocial Care Center of Clinical Hospital of Porto Alegre and from an association of relatives of patients with schizophrenia. Exam results, and other important clinical exam were assessed in patients record or patients were asked to show their exam in the case of outpatients. We included 104 patients, 90 clozapine users and 14 non-clozapine users. We calculate the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and the psychopathology severity by the Brief Psychiatric Rating Scaled anchored (BPRS-a)]. These variables were compared between clozapine users and non-clozapine users. It was used mean/median test according to data distributing, with study factor (SII, MLR, and PLR), the clinical outcome: severity of symptomatology (BPRS score), and clozapine daily dose as adjustment factor. Clozapine users exhibited a significantly higher neutrophil count (mean ± SD: 5.03 ± 2.07) compared to non-clozapine users (mean ± SD: 3.48 ± 1.27; p = 0.031). After controlling for comorbidity, other parameters also showed significant differences. These findings are consistent with previous studies that have demonstrated an inflammatory response following the administration of clozapine.

Ketamine study: Protocol for naturalistic prospective multicenter study on subcutaneous ketamine infusion in depressed patients with active suicidal ideation.

Background: Psychiatric disorders are associated with more than 90% of reported suicide attempts worldwide, but few treatments have demonstrated a direct effect in reducing suicide risk. Ketamine, originally an anesthetic, has been shown anti-suicide effects in clinical trials designed to treat depression. However, changes at the biochemical level were assessed only in protocols of ketamine with very limited sample sizes, particularly when the subcutaneous route was considered. In addition, the inflammatory changes associated with ketamine effects and their correlation with response to treatment, dose-effect, and suicide risk warrant further investigation. Therefore, we aimed to assess whether ketamine results in better control of suicidal ideation and/or behavior in patients with depressive episodes and whether ketamine affects psychopathology and inflammatory biomarkers. Materials and methods: We report here the design of a naturalistic prospective multicenter study protocol of ketamine in depressive episodes carried out at Hospital de Clínicas de Porto Alegre (HCPA) and Hospital Moinhos de Vento (HMV). The study was planned to recruit adult patients with Major depressive disorder (MDD) or Bipolar disorder (BD) types 1 or 2, who are currently in a depressive episode and show symptoms of suicidal ideation and/or behavior according to the Columbia-Suicide Severity Rating Scale (C-SSRS) and have been prescribed ketamine by their assistant psychiatrist. Patients receive ketamine subcutaneously (SC) twice a week for 1 month, but the frequency can be changed or the dose decreased according to the assistant physician's decision. After the last ketamine session, patients are followed-up via telephone once a month for up to 6 months. The data will be analyzed using repeated measures statistics to evaluate the reduction in suicide risk as a primary outcome, as per C-SSRS. Discussion: We discuss the need for studies with longer follow-ups designed to measure a direct impact on suicide risk and that additional information about the safety and tolerability of ketamine in particular subset of patients such as those with depression and ideation suicide. In line, the mechanism behind the immunomodulatory effects of ketamine is still poorly understood. Trial registration: https://clinicaltrials.gov/, identifier NCT05249309.

No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD.

Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with ADHD are still inconsistent, especially among adults. This study investigates the role of genetic variants (SLC6A4, HTR1B, TPH2, DBH, DRD4, COMT, and SNAP25) in the response to MPH in a sample of 164 adults. Genes were chosen owing to previous evidence for an influence in ADHD susceptibility. No significant differences in allele or genotype frequencies between MPH responders and nonresponders were detected. In conclusion, our findings do not support an effect of these genes in the pharmacogenetics of MPH among adults with ADHD.

The role of a lifetime history of oppositional defiant and conduct disorders in adults with ADHD: implications for clinical practice.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are frequently co-occurring disorders in children and adolescents. However, their clinical status among adults is still under discussion. This study analyzes how the current clinical presentation of adult ADHD might be influenced by a lifetime history of CD and ODD. METHODS: We compared three groups of patients: ADHD without history of CD/ODD (n = 178), ADHD + history of ODD (n = 184), and ADHD + history of CD (n = 96). RESULTS: A history of CD (and to a lower extent ODD) is associated with a more severe and externalizing profile. CONCLUSION: Past CD and ODD entail a significant negative mental health impact on persistent ADHD, reinforcing the importance of actively assessing the developmental history of adult ADHD patients.

Allergic reaction induced by subcutaneous administration of ketamine: a case report.

Ketamine can be used for depression and suicidal ideation due to its effectiveness and low complication rates; moreover, allergic reactions are rare. Immediately after subcutaneous (SC) ketamine administration, a 22-year-old man rapidly developed hives on the trunk and face without oxygen desaturation. Symptoms disappeared after treatment with prednisolone. This case presents an allergic reaction to ketamine compatible with mast cell activation and release of preformed mediators, without being able to prove whether the event was mediated by immunoglobulin E. This is the only case reported to date of an allergic reaction to SC ketamine for psychiatric treatment.

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.

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.

A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine.

Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50-70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging (FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings.

ADRA2A polymorphisms and ADHD in adults: possible mediating effect of personality.

Several studies have tested for the association between polymorphisms in the ADRA2A gene and childhood ADHD. A meta-analysis of these results, however, has pointed towards a significant heterogeneity, raising the need for explanatory studies. As the effect of other relevant clinical characteristics could be a possible source, we studied three polymorphisms in the ADRA2A gene (-1291 C>G-MspI or rs1800544; -262 G>A-HhaI or rs1800544; 1780 C>T-DraI or rs553668) in 403 adult patients with ADHD assessed in relation to comorbidity and personality characteristics, as well as in 232 controls. The diagnosis followed DSM-IV criteria, and personality dimensions were evaluated with the Temperament and Character Inventory (TCI). There were no significant differences in allele and genotype frequencies between cases and controls. Patients carrying the G allele of rs1800544 presented lower scores in harm avoidance, and carriers of the T allele of rs553668 had more novelty seeking and less harm avoidance and persistence. Additionally, the haplotype carrying the G-G-T alleles (rs1800544-rs1800545-rs553668) was associated with lower scores in harm avoidance and persistence, and higher scores in novelty seeking compared to other haplotypes. These findings suggest that the conflicting findings obtained in association studies between ADRA2A polymorphisms and ADHD might be related to temperament profiles, and support additional studies addressing these effects in larger samples.

Adrenergic α2A receptor gene is not associated with methylphenidate response in adults with ADHD.

Adrenergic α2A receptor gene (ADRA2A) is one of the most promising candidate genes for ADHD pharmacogenetics. Thus far, three studies have investigated the association between the ADRA2A -1291 C>G polymorphism and the therapeutic response to methylphenidate (MPH) in children with ADHD, all of them with positive results. The aim of this study is to investigate, for the first time, the association between three ADRA2A polymorphisms (-1291 C>G, -262 G>A, and 1780 C>T) and the response to MPH in adults with ADHD. The sample comprises 165 Brazilians of European descent evaluated in the adult ADHD outpatient clinic of the Hospital de Clínicas de Porto Alegre. The diagnostic procedures followed the DSM-IV criteria. Drug response was assessed by both categorical and dimensional approaches, through the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. We found no evidence of association between the three ADRA2A polymorphisms and the therapeutic response to MPH treatment. Our findings do not support a significant role for the ADRA2A gene in ADHD pharmacogenetics, at least among adult patients.

Shortage and underutilization of psychiatric beds in southern Brazil: independent data of Brazilian mental health reform.

BACKGROUND: Mental health policies throughout the world are being subjected to several changes due to increased pressure from the public and from health administrators. Mental health policies in the developing world experienced changes following advice and consultation from the World Health Organization (WHO). This was the case with Brazil, which enacted several laws and policies affecting community care and the closure of beds in psychiatric hospitals (the deinstitutionalization movement). Rio Grande do Sul, the southeast state in Brazil, adopted this policy in 1992, but still suffers from a shortage of psychiatric beds in both general hospitals (GHs) and psychiatric hospitals (PHs), despite advances in the provision of community care. As a result, Rio Grande do Sul (RS) can be studied as an example of "what actually happens" in mental health care in the developing world. METHODS: The study analyzed online administrative data from 2000 to 2007 for three main parameters of mental health care (i.e. hospital use rate, length of stay, and hospital bed capacity). These were used to evaluate differences in psychiatric care among GHs and PHs. The number of existing and required psychiatric beds in RS was also calculated. RESULTS: GHs had very low hospital use rates, while PHs had a very high length of stay (200% higher than GH). The number of admissions to GHs grew by 170% over the 8 year period, and psychiatric bed availability was 1.5 per 10,000 inhabitants. CONCLUSIONS: The study provided evidence for the need of 30-50% more psychiatric beds in GHs. Also, additional staff training is needed to increase use rates in GHs and decrease the length of stay in PHs. Additional studies covering national data must be carried out to assess the extent of these problem in other Brazilian mental health care services.