In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development.

Spike protein sequences in SARS-CoV-2 have been employed for vaccine epitopes, but many short constituent sequences (SCSs) in the spike protein are present in the human proteome, suggesting that some anti-spike antibodies induced by infection or vaccination may be autoantibodies against human proteins. To evaluate this possibility of "molecular mimicry" in silico and in vitro, we exhaustively identified common SCSs (cSCSs) found both in spike and human proteins bioinformatically. The commonality of SCSs between the two systems seemed to be coincidental, and only some cSCSs were likely to be relevant to potential self-epitopes based on three-dimensional information. Among three antibodies raised against cSCS-containing spike peptides, only the antibody against EPLDVL showed high affinity for the spike protein and reacted with an EPLDVL-containing peptide from the human unc-80 homolog protein. Western blot analysis revealed that this antibody also reacted with several human proteins expressed mainly in the small intestine, ovary, and stomach. Taken together, these results showed that most cSCSs are likely incapable of inducing autoantibodies but that at least EPLDVL functions as a self-epitope, suggesting a serious possibility of infection-induced or vaccine-induced autoantibodies in humans. High-risk cSCSs, including EPLDVL, should be excluded from vaccine epitopes to prevent potential autoimmune disorders.

Immune response to vaccination in people with psychotic disorders relative to healthy controls: prospective study of SARS-CoV-2 vaccination.

This prospective study examines the immune response to SARS-CoV-2 vaccination in patients with psychotic disorders compared with healthy volunteers. Participants were recruited naturalistically as part of the UK's COVID-19 vaccination programme. Prior to receiving their first COVID-19 vaccine, blood samples were provided by participants to examine anti-SARS-CoV-2 immunoglobulins (IgG) at baseline, followed by a repeat assay 1 month after receiving their first vaccine to assess vaccine response. The increase of IgG levels from baseline to 1 month post-vaccination was significantly lower in patients compared with controls, supporting evidence of impaired vaccine response in people with psychotic disorders. When excluding patients treated with clozapine from the analysis, this difference was no longer significant, suggesting that effects may be particularly marked in people taking clozapine.

Dopamine in major depressive disorder: A systematic review and meta-analysis of in vivo imaging studies.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the magnitude and consistency of the findings are unknown. We address this by systematically reviewing in vivo imaging evidence for dopamine measures in MDD and meta-analysing these where there are sufficient studies. METHODS: Studies investigating the dopaminergic system using positron emission tomography or single photon emission computed tomography in MDD and a control group were included. Demographic, clinical and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted. RESULTS: We identified 43 studies including 662 patients and 801 controls. Meta-analysis of 38 studies showed no difference in mean or mean variability of striatal D2/3 receptor availability (g = 0.06, p = 0.620), or combined dopamine synthesis and release capacity (g = 0.19, p = 0.309). Dopamine transporter (DAT) availability was lower in the MDD group in studies using DAT selective tracers (g = -0.56, p = 0.006), but not when tracers with an affinity for serotonin transporters were included (g = -0.21, p = 0.420). Subgroup analysis showed greater dopamine release (g = 0.49, p = 0.030), but no difference in dopamine synthesis capacity (g = -0.21, p = 0.434) in the MDD group. Striatal D1 receptor availability was lower in patients with MDD in two studies. CONCLUSIONS: The meta-analysis indicates striatal DAT availability is lower, but D2/3 receptor availability is not altered in people with MDD compared to healthy controls. There may be greater dopamine release and lower striatal D1 receptors in MDD, although further studies are warranted. We discuss factors associated with these findings, discrepancies with preclinical literature and implications for future research.

Changes in telepsychiatry regulations during the COVID-19 pandemic: 17 countries and regions' approaches to an evolving healthcare landscape.

BACKGROUND: During the COVID-19 pandemic, the use of telemedicine as a way to reduce COVID-19 infections was noted and consequently deregulated. However, the degree of telemedicine regulation varies from country to country, which may alter the widespread use of telemedicine. This study aimed to clarify the telepsychiatry regulations for each collaborating country/region before and during the COVID-19 pandemic. METHODS: We used snowball sampling within a global network of international telepsychiatry experts. Thirty collaborators from 17 different countries/regions responded to a questionnaire on barriers to the use and implementation of telepsychiatric care, including policy factors such as regulations and reimbursement at the end of 2019 and as of May 2020. RESULTS: Thirteen of 17 regions reported a relaxation of regulations due to the pandemic; consequently, all regions surveyed stated that telepsychiatry was now possible within their public healthcare systems. In some regions, restrictions on prescription medications allowed via telepsychiatry were eased, but in 11 of the 17 regions, there were still restrictions on prescribing medications via telepsychiatry. Lower insurance reimbursement amounts for telepsychiatry consultations v. in-person consultations were reevaluated in four regions, and consequently, in 15 regions telepsychiatry services were reimbursed at the same rate (or higher) than in-person consultations during the COVID-19 pandemic. CONCLUSIONS: Our results confirm that, due to COVID-19, the majority of countries surveyed are altering telemedicine regulations that had previously restricted the spread of telemedicine. These findings provide information that could guide future policy and regulatory decisions, which facilitate greater scale and spread of telepsychiatry globally.

Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan.

OBJECTIVE: Clozapine is generally recommended to be prescribed in a divided dosing regimen based on its relatively short plasma half-life. However, there has been little evidence to support the superiority of divided dosing of clozapine over once-daily dosing. To our knowledge, there have been no studies examining differences in actual plasma concentrations or adverse effects between the 2 dosing strategies of clozapine. We aimed to compare actual plasma concentrations of clozapine between once-daily and divided dosing regimens, and to examine the relationships of these regimens with psychiatric symptoms and adverse effects of clozapine. METHODS: We analyzed data from 108 participants of a previous study conducted in 2 hospitals in Japan. A population pharmacokinetic model was used to estimate the peak and trough plasma concentrations of clozapine based on actual plasma concentrations. We evaluated psychiatric symptoms with the Brief Evaluation of Psychosis Symptom Domains and adverse effects of clozapine with the Glasgow Antipsychotic Side-effects Scale for Clozapine. RESULTS: The estimated peak and trough plasma concentrations of clozapine did not differ significantly between once-daily and divided dosing regimens. There were no significant differences in psychiatric symptoms except for depression/anxiety or subjective adverse effects of clozapine between the 2 dosing strategies. CONCLUSIONS: Our findings tentatively support the feasibility and clinical utility of once-daily dosing of clozapine in clinical practice. Further studies are needed to replicate these findings and determine causality between dosing strategies and clinical outcomes.

Comprehensive assessment of exposure to clozapine in association with side effects among patients with treatment-resistant schizophrenia: a population pharmacokinetic study.

BACKGROUND: There have been scarce data on the distribution of clozapine concentrations in comparison with the recommended range (350-600 ng/ml) or their relationship with side effects among patients with treatment-resistant schizophrenia. Furthermore, no studies have assessed the association between side effects and overall exposure to the drug by calculating the 24-h area-under-curve (AUC). METHODS: In- and outpatients with schizophrenia or schizoaffective disorder (ICD-10) who were receiving a stable dose of clozapine for ⩾2 weeks were included. Side effects were assessed using the Glasgow antipsychotic side-effects scale for clozapine (GASS-C). Using two collected plasma samples, plasma clozapine and norclozapine concentrations at peak and trough and their 24-h AUC were estimated using population pharmacokinetic models. RESULTS: A total of 108 patients completed the study (mean ± SD age, 43.0 ± 10.1 years; clozapine dose, 357.5 ± 136.9 mg/day); 33 patients (30.6%) showed estimated trough concentrations of clozapine within the recommended range (350-600 ng/ml) whereas the concentrations were higher and lower than this range among 37 (43.5%) and 28 (25.9%) patients (%), respectively. There were no significant correlations between estimated peak or trough concentrations or 24-h AUC of both clozapine or norclozapine, and GASS-C total or individual scores. No significant differences were found between GASS-C total or individual item scores between the patients with estimated trough concentrations of clozapine of >600 ng/ml and the other subjects. CONCLUSION: The results suggest that clozapine or norclozapine concentrations are not linked directly to the extent of side effects experienced in clozapine-treated patients with treatment-resistant schizophrenia while the cross-sectional study design limits the interpretation of any causal relationships. These findings indicate that side effects associated with clozapine may occur at any dose or concentration.

The efficacy and heterogeneity of antipsychotic response in schizophrenia: A meta-analysis.

The response to antipsychotic treatment in schizophrenia appears to vary, and as such it has been proposed that different subtypes of schizophrenia exist, defined by treatment-response. This has not been formally examined using meta-analysis. Randomised controlled trials comparing placebo and antipsychotics in acute treatment of schizophrenia listed in PubMed, EMBASE and PsycINFO from inception until 30 November 2018 were examined. Relative variability of symptomatic improvement in antipsychotic-treated individuals compared to placebo-treated individuals was quantified using coefficient of variation ratio (CVR). Mean difference in symptom change was quantified using Hedges' g. In addition, individual patient data from two clinical trials was examined in terms of both the distribution of total symptom change, and the variability of individual symptoms and symptom factors. In total, 11,006 articles were identified. Sixty six met inclusion criteria, reporting on 17,202 patients. Compared with placebo, antipsychotic-treated patients demonstrated greater total symptom improvement (g = 0.47, p < 0.001) and reduced variability in symptomatic improvement for total (CVR = 0.86, p < 0.001), positive (CVR = 0.89, p < 0.001), and negative symptoms (CVR = 0.86, p = 0.001). Lower variability in antipsychotic-response relative to placebo was associated with studies published earlier (z = 3.98, p < 0.001), younger patients (z = 3.07, p = 0.002), higher dose treatments (z = -2.62, p = 0.009), and greater mean-difference in symptom-change (z = -5.70, p < 0.001). In the individual patient dataset (N = 522 patients), antipsychotic treated patients did not show significantly increased variability for any individual symptom, and there was no evidence of a bimodal distribution of response. Compared to placebo, antipsychotic treatment shows greater improvement and lower variability of change in total, positive and negative symptoms. This is contrary to the hypothesis that there is a subtype of antipsychotic non-responsive schizophrenia. Instead our findings, provide evidence for a relatively homogeneous effect of antipsychotic treatment in improving symptoms of schizophrenia.

The magnitude and heterogeneity of antidepressant response in depression: A meta-analysis of over 45,000 patients.

OBJECTIVE: To determine the relative variability and magnitude of symptomatic improvement in antidepressant-treated individuals compared to placebo-treated individuals, and to investigate moderating factors. METHODS: Multiple databases and previous publications were searched through February 2019 to identify all randomized controlled trials comparing placebo and antidepressants in acute treatment of depression. Primary outcome was relative variability of change in symptom severity in antidepressant-treated individuals compared to placebo-treated patients quantified using the coefficient of variation ratio (CVR). RESULTS: Of 9389 identified records, 134 were found to be eligible (total n = 46,646). Antidepressant-treated patients showed a significantly greater magnitude (g = 0.28, 95% CI 0.25-0.30, p < .0001) and lower variability (CVR = 0.94, 95% CI 0.93-0.95, p < .0001) of change in symptom severity relative to placebo-treated patients. Compared to placebo antidepressant-related improvement was more uniform in older studies (z = 3.01, p = .003) and in studies where antidepressants showed greater efficacy (z = -7.21, p < .0001). | Imipramine, moclobemide, amitriptyline and mirtazapine showed significantly lower CVR than several other antidepressants. However, no difference in CVR exists between multiple and single-neurotransmitter profile antidepressants (z = -0.01, p = .99). CONCLUSION: There is lower variability and greater magnitude of change in symptom severity with antidepressant treatment relative to placebo. This is not consistent with our hypothesis that there are distinct sub-groups of treatment-responsive and treatment-resistant patients with major depression. Our results in-stead suggest that antidepressants show a relatively uniform effect.

Reliability of the Glasgow Antipsychotic Side-effects Scale for Clozapine Japanese version (GASS-C-J).

The purpose of this study was to develop the Glasgow Antipsychotic Side effects Scale for Clozapine Japanese version (GASS-C-J) and examine its reliability to assess clozapine-related side effects. We developed the GASS-C-J using forward and backward translation. Semantic equivalence of the GASS-C-J to the GASS-C was confirmed by the original author. We then administered the GASS-C-J twice to 109 patients on clozapine treatment at two psychiatric hospitals in Japan. We assessed the internal consistency and test-retest reliability of the GASS-C-J using Cronbach's alpha and weighted kappa coefficient, respectively. We also examined if discrepancies in each GASS-C-J item score between the first and second rating were correlated with items of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD). The Cronbach's alpha coefficient of the GASS-C-J at the first and second rating was 0.78 (95% CI: 0.72 to 0.84) and 0.82 (95% CI: 0.76 to 0.88), respectively. The weighted kappa coefficient of individual and total GASS-C-J item scores ranged from 0.45 to 0.88. Some symptom domains were correlated with discrepancies in specific items of the GASS-C-J: psychotic symptoms and nausea/vomiting (rs = 0.27), thirst (rs = 0.31), and appetite/weight gain (rs = 0.27); disorganized thinking and urinary incontinence (rs = 0.26); depression/anxiety and myoclonus (rs = 0.25), hypersalivation (rs = -0.27), and blurred vision (rs = -0.22). These findings demonstrate that the GASS-C-J can be used in clinical and research settings as a reliable scale to assess clozapine-related side effects.

Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis.

BACKGROUND: Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment. METHODS: We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change. FINDINGS: Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m2 (-0·68 to 0·17) for haloperidol to 1·07 kg/m2 (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035). INTERPRETATION: Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians. FUNDING: UK Medical Research Council, Wellcome Trust, National Institute for Health Research Oxford Health Biomedical Research Centre.

Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis.

Two important clinical questions are whether there is a subtype of schizophrenia which responds differently to clozapine relative to other antipsychotics, and whether greater efficacy of clozapine is dependent on the degree of treatment-resistance. The authors address this by examining both variability and magnitude of response in patients treated with clozapine and other antipsychotics for both treatment-resistant schizophrenia (TRS) and non-resistant schizophrenia. Double-blind randomised controlled trials comparing clozapine with other antipsychotics in patients with schizophrenia were identified using five databases. Standard deviations and means of change in total, positive, and negative symptoms were extracted. Variability ratio (VR) and coefficient of variation ratio (CVR) were used to quantify relative variability in symptom change. Hedges' g was used to quantify mean differences. Ten TRS studies (n = 822) and 29 non-TRS studies (n = 2566) were meta-analysed. Relative variability in change of total symptoms did not differ significantly between clozapine and other antipsychotics in TRS studies (VR = 1.84; 95%CI, 0.85-4.02). These findings were similar with CVR, and for positive and negative symptoms. Clozapine was superior to other antipsychotics in improving total symptoms in both TRS (g = 0.34; 95%CI, 0.13-0.56) and non-TRS (g = 0.20; 95%CI, 0.08-0.32) studies. Furthermore, clozapine was superior in improving positive symptoms in both study groups, but not for negative symptoms. Pooled effect sizes showed no significant difference between TRS and non-TRS studies. These findings do not support a subtype of schizophrenia which responds specifically to clozapine. Clozapine is more effective than other antipsychotics irrespective of treatment-resistance, arguing for its use more generally in schizophrenia. PROSPERO CRD42018086507.

Tobacco smoking and dopaminergic function in humans: a meta-analysis of molecular imaging studies.

RATIONALE: About 1.1 billion people smoke tobacco globally and tobacco-related health care costs 1.8% of GDP in many countries. The majority of people are unable to quit smoking despite pharmacological intervention, highlighting the need to understand the pathophysiology associated with tobacco smoking to aid the development of new therapeutics. The reinforcing effects of tobacco smoking are thought to be mediated by the dopamine system. However, the nature of dopamine dysfunction seen in smokers is unclear. OBJECTIVE: To determine the nature and robustness of the evidence for dopaminergic alterations in smokers. METHODS: The entire MEDLINE, EMBASE, and PsycINFO databases were searched for studies from inception date to November 18, 2018. In vivo human molecular imaging studies of dopamine measures (dopamine synthesis or release capacity, transporter levels, receptor levels) in tobacco smokers were selected. Demographic, clinical, and imaging measures were extracted from each study and meta-analyses, and sensitivity analyses were conducted. RESULTS: Fourteen studies met inclusion criteria comprising a total sample of 219 tobacco smokers and 297 controls. The meta-analysis showed a significant reduction in dopamine transporter availability in the smokers relative to controls with an effect size of - 0.72 ([95% CI, - 1.38 to - 0.05], p = 0.03). However, there was no difference in D2/3 receptor availability in smokers relative to controls (d = -0.16 ([95% CI, - 0.42 to 0.1], p = 0.23). There were insufficient studies for meta-analysis of other measures. However, findings from the published studies indicated blunted dopamine release and lower D1 receptor availability, while findings for dopamine synthesis capacity were inconsistent. CONCLUSION: Our data indicate that striatal dopamine transporter availability is lower but D2/3 receptors are unaltered in smokers relative to controls. We discuss the putative mechanisms underlying this and their implications.

Impact of subjective vs. objective remission status on subjective cognitive impairments in depression.

OBJECTIVE: The impact of subjective vs. objective illness severity on subjective cognitive impairment in patients with depression has not been addressed. METHODS: This study is a post-hoc analysis of our cross-sectional study in Japanese outpatients with depressive disorder (ICD-10) (Ozawa et al., 2017). The participants received assessments with the Japanese version of the Perceived Deficits Questionnaire (J-PDQ), Quick Inventory of Depressive Symptomatology (QIDS), and Montgomery-Asberg Depression Rating Scale (MADRS). First, multiple regression analysis was conducted to examine the effects of demographic and clinical characteristics, including illness severity and medications (e.g., antidepressants and benzodiazepines), on the PDQ total score. Next, we categorized the participants into 4 groups based on the presence/absence of subjective and objective symptom remission (i.e., QIDS total score of ≤5 and MADRS total score of ≤9, respectively), and compared the differences in PDQ total scores between the QIDS- and MADRS-remitted group and the QIDS-non-remitted but MADRS-remitted group. RESULTS: 102 participants were included (45 men; mean ±â€¯SD age, 50.5 ±â€¯14.7 years). Higher QIDS and MADRS total scores were significantly associated with a greater PDQ total score (both p's < 0.001), while other factors did not exhibit any associations. The QIDS-non-remitted but MADRS-remitted group showed a significantly higher PDQ total score than that of the QIDS- and MADRS-remitted group (median 10.0 [8.0-12.0] vs. 3.0 [range: 2.0-4.0], p < 0.001). CONCLUSIONS: These findings suggest that objective remission in the absence of subjective remission may not be adequate to improve subjective cognitive functioning.

Quality of life in stabilized outpatients with bipolar I disorder: Associations with resilience, internalized stigma, and residual symptoms.

OBJECTIVES: Improving Quality of Life (QoL) is an important objective in the treatment of bipolar disorder. The aim of the current study was to examine to which extent resilience, internalized stigma, and psychopathology are correlated to QoL. METHODS: We recruited 60 outpatients diagnosed with bipolar I disorder according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, symptoms were quantified by the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) and internalized stigma by the Internalized Stigma of Mental Illness (ISMI) scale. In order to assess QoL and resilience, the Berliner Lebensqualitätsprofil (BELP) and the Resilience Scale (RS-25) were used in both patients and control subjects. RESULTS: Despite presenting with a very mild symptom level and relatively low internalized stigma, patients with bipolar I disorder indicated significantly lower QoL and resilience as compared to healthy control subjects. In patients, QoL correlated significantly with resilience, internalized stigma, and residual symptoms of depression. No significant correlations were observed between QoL and residual manic symptoms. LIMITATIONS: The cross-sectional design and the relatively small sample size limit the generalizability of our results. Furthermore, levels of resilience and internalized stigma may change over the course of the illness and have different impacts on the long-term outcome of patients with bipolar disorder. CONCLUSION: Our results show that QoL of patients suffering from bipolar I disorder, even when only mildly ill, is strongly associated with the degree of resilience and internalized stigma, and that particularly residual depressive symptoms have a negative impact on QoL. In addition to drug treatment, psychotherapeutic approaches should be applied to strengthen resilience, to reduce internalized stigma, and, ultimately, to improve quality of life.

Effects of chair yoga therapy on physical fitness in patients with psychiatric disorders: A 12-week single-blind randomized controlled trial.

INTRODUCTION: Since falls may lead to fractures and have serious, potentially fatal outcomes, prevention of falls is an urgent public health issue. We examined the effects of chair yoga therapy on physical fitness among psychiatric patients in order to reduce the risk of falls, which has not been previously reported in the literature. METHODS: In this 12-week single-blind randomized controlled trial with a 6-week follow-up, inpatients with mixed psychiatric diagnoses were randomly assigned to either chair yoga therapy in addition to ongoing treatment, or treatment-as-usual. Chair yoga therapy was conducted as twice-weekly 20-min sessions over 12 weeks. Assessments included anteflexion in sitting, degree of muscle strength, and Modified Falls Efficacy Scale (MFES) as well as QOL, psychopathology and functioning. RESULTS: Fifty-six inpatients participated in this study (36 men; mean ± SD age, 55.3 ± 13.7 years; schizophrenia 87.5%). In the chair yoga group, significant improvements were observed in flexibility, hand-grip, lower limb muscle endurance, and MFES at week 12 (mean ± SD: 55.1 ± 16.6 to 67.2 ± 14.0 cm, 23.6 ± 10.6 to 26.8 ± 9.7 kg, 4.9 ± 4.0 to 7.0 ± 3.9 kg, and 114.9 ± 29.2 to 134.1 ± 11.6, respectively). Additionally, these improvements were observable six weeks after the intervention was over. The QOL-VAS improved in the intervention group while no differences were noted in psychopathology and functioning between the groups. The intervention appeared to be highly tolerable without any notable adverse effects. CONCLUSIONS: The results indicated sustainable effects of 20-min, 12-week, 24-session chair yoga therapy on physical fitness. Chair yoga therapy may contribute to reduce the risk of falls and their unwanted consequences in psychiatric patients.

Resilience and spirituality in patients with depression and their family members: A cross-sectional study.

OBJECTIVE: The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. METHODS: This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery-Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). RESULTS: One hundred outpatients with depression (mean±SD age, 50.8±14.5years; 44 men; MADRS total score 9.8±9.0) and 36 healthy family members (mean±SD age, 56.5±15.0years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean±SD, 112.3±17.1 vs. 84.8±27.7, p<0.001). No correlation was found in RS total scores between patients and their family members (p=0.265), regardless of patients' remission status. CONCLUSIONS: Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self-esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression.

Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-analysis.

Importance: Stimulant use disorder is common, affecting between 0.3% and 1.1% of the population, and costs more than $85 billion per year globally. There are no licensed treatments to date. Several lines of evidence implicate the dopamine system in the pathogenesis of substance use disorder. Therefore, understanding the nature of dopamine dysfunction seen in stimulant users has the potential to aid the development of new therapeutics. Objective: To comprehensively review the in vivo imaging evidence for dopaminergic alterations in stimulant (cocaine, amphetamine, or methamphetamine) abuse or dependence. Data Sources: The entire PubMed, EMBASE, and PsycINFO databases were searched for studies from inception date to May 14, 2016. Study Selection: Case-control studies were identified that compared dopaminergic measures between stimulant users and healthy controls using positron emission tomography or single-photon emission computed tomography to measure striatal dopamine synthesis or release or to assess dopamine transporter availability or dopamine receptor availability. Data Extraction and Synthesis: Demographic, clinical, and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted for stimulants combined, as well as for cocaine and for amphetamine and methamphetamine separately if there were sufficient studies. Main Outcomes and Measures: Differences were measured in dopamine release (assessed using change in the D2/D3 receptor availability after administration of amphetamine or methylphenidate), dopamine transporter availability, and dopamine receptor availability in cocaine users, amphetamine and methamphetamine users, and healthy controls. Results: A total of 31 studies that compared dopaminergic measures between 519 stimulant users and 512 healthy controls were included in the final analysis. In most of the studies, the duration of abstinence varied from 5 days to 3 weeks. There was a significant decrease in striatal dopamine release in stimulant users compared with healthy controls: the effect size was -0.84 (95% CI, -1.08 to -0.60; P < .001) for stimulants combined and -0.87 (95% CI, -1.15 to -0.60; P < .001) for cocaine. In addition, there was a significant decrease in dopamine transporter availability: the effect size was -0.91 (95% CI, -1.50 to -0.32; P < .01) for stimulants combined and -1.47 (95% CI, -1.83 to -1.10; P < .001) for amphetamine and methamphetamine. There was also a significant decrease in D2/D3 receptor availability: the effect size was -0.76 (95% CI, -0.92 to -0.60; P < .001) for stimulants combined, -0.73 (95% CI, -0.94 to -0.53; P < .001) for cocaine, and -0.81 (95% CI, -1.12 to -0.49; P < .001) for amphetamine and methamphetamine. Consistent alterations were not found in vesicular monoamine transporter, dopamine synthesis, or D1 receptor studies. Conclusions and Relevance: Data suggest that both presynaptic and postsynaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users. The commonality and differences between these findings and the discrepancies with the preclinical literature and models of drug addiction are discussed, as well as their implications for future drug development.