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Impaired insight into illness is a common element of schizophrenia that contributes to treatment nonadherence and negative clinical outcomes. Previous studies suggest that impaired insight may arise from brain abnormalities. However, interpretations of these findings are limited due to small sample sizes and inclusion of patients with a narrow range of illness severity and insight deficits. In a large sample of patients with schizophrenia, the majority of which were designated as treatment-resistant, we investigated the associations between impaired insight and cortical thickness and subcortical volumes. A total of 94 adult participants with a schizophrenia spectrum disorder were included. Fifty-six patients (60%) had treatment-resistant schizophrenia. The core domains of insight were assessed with the VAGUS insight into psychosis scale. We obtained 3T MRI T1-weighted images, which were analysed using CIVET and MAGeT-Brain. Whole-brain vertex-wise analyses revealed impaired insight, as measured by VAGUS average scores, was related to cortical thinning in left frontotemporoparietal regions. The same analysis in treatment-resistant patients showed thinning in the same regions, even after controlling for age, sex, illness severity, and chlorpromazine antipsychotic dose equivalents. No association was found in non-treatment-resistant patients. Region-of-interest analyses revealed impaired general illness awareness was associated with cortical thinning in the left supramarginal gyrus when controlling for covariates. Reduced right and left thalamic volumes were associated with VAGUS symptom attribution and awareness of negative consequences subscale scores, respectively, but not after correction for multiple testing. Our results suggest impaired insight into illness is related to cortical thinning in left frontotemporoparietal regions in patients with schizophrenia, particularly those with treatment resistance where insight deficits may be more chronic., (© 2023. The Author(s).)

Introduction: Governments and public health authorities across many jurisdictions implemented social (physical) distancing measures to contain the spread of the 2019 novel coronavirus disease (COVID-19). Adherence to these measures is variable and likely influenced by various factors. This study aimed to 1) identify the individual sociodemographic, COVID-19 and social distancing related, and psychological determinants of social distancing adherence, and 2) explore regional differences in social distancing adherence in the United States (U.S.) and English-speaking Canada based on each region's discrepant response to social distancing restrictions., Methods: A web-based repeated cross-sectional survey was conducted in 4,942 English-speaking participants from the four most populous U.S. states, specifically New York, California, Texas, and Florida, and Canada (www.covid19-database.com). The study was conducted at two timepoints, from May 1 to 5, 2020 ( n = 1,019, Canadian participants only) and from July 6 to 10, 2020 ( n = 3,923). Separate univariate models were computed for individual sociodemographic, COVID-19 and social distancing related, and psychological determinants of social distancing adherence. To determine the total variance explained, a univariate analysis including all of the determinants was performed. Regional differences in social distancing were compared between the four U.S. states and Canada, and between the U.S. as a whole and Canada., Results: Adherence to social distancing was higher in May (mean = 4.4/5.0±0.7) compared to July (mean = 4.3/5.0±0.7) [ t (4940) = 6.96, p < 0.001], likely a reflection of relaxing restrictions. There were no regional differences in adherence. Sociodemographic, COVID-19 and social distancing related, and psychological determinants explained 10, 36, and 23% of the variance of social distancing adherence, respectively. Higher perceived seriousness of COVID-19 [β (SE) = 0.39 (0.01), p < 0.001, partial η 2 = 0.22], lower risk propensity [β (SE) = -0.15 (0.01), p < 0.001, partial η 2 = 0.06], germ aversion [β (SE) = 0.12 (0.01), p < 0.001, partial η 2 = 0.03], age [β (SE) = 0.01 (0.00), p < 0.001, partial η 2 = 0.02], and greater social support [β (SE) = 0.03 (0.00), p < 0.001, partial η 2 = 0.02] had the largest effects on social distancing adherence., Conclusion: Public service initiatives to emphasize the serious consequences of infection and targeted interventions toward certain sociodemographic groups, such as younger adults and vulnerable individuals in greater need of social support, may help enhance the public's adherence to social distancing measures during subsequent waves of COVID-19 and future pandemics., Competing Interests: PG reports receiving research support from the Canadian Institute of Health Research (CIHR), Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and the Center for Addiction and Mental Health (CAMH). FC has received funding from the CIHR Post-doctoral Fellowship Award and the CAMH Foundation. AG-G has received support from the United States National Institute of Health, CIHR, OMHF, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain & Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gerretsen, Kim, Brown, Quilty, Wells, Caravaggio, Song, Sanches, Agic, Pollock and Graff-Guerrero.)

Aim: Validating the vulnerabilities and pathologies underlying treatment-resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS., Methods: We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first-line antipsychotics (FL-Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ-Resp) and 22 FL- and clozapine-resistant patients (patients with ultratreatment-resistant schizophrenia [URS]). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis., Results: Both CLZ-Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [g H ] = 0.75; P = 0.013, g H  = 0.96) and FL-Resp (P = 0.007, g H  = 1.00; P = 0.002, g H  = 1.31) in the left medial parietal cortex (Lt-MPC). In addition, both CLZ-Resp and URS had lower SA in the Lt-MPC than FL-Resp (P < 0.001, g H  = 1.22; P < 0.001, g H  = 1.75). LGI and SA were positively correlated in non-TRS (FL-Resp) (ρ = 0.64, P = 0.008) and TRS (CLZ-Resp + URS) (ρ = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non-TRS versus TRS with LGI and SA in the Lt-MPC were 0.79 and 0.85, respectively. SA in the Lt-MPC was inversely correlated with negative symptoms (ρ = -0.40, P = 0.018) and clozapine plasma levels (ρ = -0.35, P = 0.042) in TRS., Conclusion: LGI and SA in the Lt-MPC, a functional hub in the default-mode network, were abnormally reduced in TRS compared with non-TRS. Thus, altered LGI and SA in the Lt-MPC might be structural features associated with genetic vulnerability to TRS., (© 2022 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Online anti-vaccination rhetoric has produced far reaching negative health consequences. Persons who endorse anti-vaccination attitudes may employ less analytical reasoning when problem solving. Considering limitations in previous research, we used an online web-based survey (n = 760; mean age = 47.69; 388 males, 372 females) to address this question. Analytical reasoning was negatively correlated with anti-vaccination attitudes ( r = -.18, p < .0001). This relationship remained significant after statistically controlling for potential confounders, including age, sex, education, and religiosity ( r = -.16, p < .0001). We hope that elucidating the cognitive, non-information-based aspects of anti-vaccination attitudes will help to guide effective educational interventions aimed at improving public health in the future.

Three patients with Achilles tendon partial injury were treated with local injection of peripheral blood mononuclear cells (PB-MNCs). All subjects were evaluated both clinically (American Orthopedic Foot and Ankle Society - AOFAS scale) and radiologically (MRI examination) at 2 months, and a clinical reassessment with the AOFAS scale was performed at 6 months. Functional and radiological signs of tendon healing processes were detected as early as 2 months after the procedure and the AOFAS scale rose from an initial average value of 37.0 to 82.7. Even though this study only involved a limited number of participants, our preliminary results indicate that regenerative therapies with PB-MNCs may be a valid alternative to surgical options for Achilles tendon partial injuries, especially in patients with contraindications to surgery, when other conservative approaches (exercises, physical therapies, sclerosing treatment) have failed. Further investigations on the subject seem rationally supported and advisable.

Background: Impaired insight into illness is a common feature of schizophrenia. Improved insight is associated with better treatment adherence and clinical outcomes. At the same time, improving insight has been suggested to increase depressive symptoms and diminish quality of life. The aim of this study was to examine the associations between impaired insight and degree of subjective happiness, perceived level of success, and life satisfaction in patients with schizophrenia spectrum disorders., Methods: A total of 108 participants with schizophrenia or schizoaffective disorder were included. Data for this study were obtained from our group's previous investigation that examined the relationship between impaired insight and visuospatial attention. Insight into illness was measured by the VAGUS scale, which assesses general illness awareness, accurate symptom attribution, awareness of the need for treatment, and awareness of the negative consequences attributable to the illness., Results: Our results revealed no association among the VAGUS average and subscale scores and degree of subjective happiness, perceived level of success, and life satisfaction., Conclusions: Our study suggests that insight into illness is not related to subjective happiness, life satisfaction, or perceived level of success in patients with schizophrenia, which is in contrast to previous reports that demonstrate an association between insight into illness and depression.

Impaired subjective awareness of problem gambling may act as a barrier to help-seeking and treatment adherence. However, the impact of impaired problem gambling awareness on clinical and social outcomes has received little empirical study. The aim of this study was to develop and investigate the psychometric properties of a novel scale that measures impaired illness awareness in individuals with problem gambling. We developed the Gambling Awareness and Insight Scale (GAS), a self-report measure that assesses the core theoretical constructs of illness awareness in problem gambling, namely General Disorder or Problem Awareness, Accurate Symptom Attribution, Awareness of Need for Treatment and the Negative Consequences attributable to problem gambling ( www.illnessawarenessscales.com ). Data were acquired from an online survey platform, Dynata, to evaluate the psychometric properties of the GAS. A total of 100 participants aged 18 years or older with problem gambling defined by a score of 4 or more on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Pathological Gambling Diagnostic Form were included. The GAS demonstrated good convergent (r = 0.57, p < 0.001) and discriminant validity (r = - 0.18, p = 0.080). It also demonstrated good internal consistency (Cronbach's α = 0.80) and one-month test-retest reliability (intra-class correlation = 0.86). An exploratory factor analysis suggested retention of two components. The GAS is a novel psychometric tool designed to evaluate impaired subjective illness awareness in problem gambling. Initial evidence suggests that the GAS can be used in research and clinical settings to evaluate the impact of impaired problem gambling awareness on adherence to treatment programs, clinical and psychosocial outcomes. Replication in applied settings is needed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: Develop a robust and user-friendly software tool for the prediction of dopamine D 2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone, in order to facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements., Methods: Previously developed population pharmacokinetic models for olanzapine and risperidone were combined with a pharmacodynamic model for D2 RO and implemented in the R programming language. Maximum a posteriori Bayesian estimation was used to provide predictions of plasma concentration and RO based on sparse concentration sampling. These predictions were then compared to observed plasma concentration and RO., Results: The average (standard deviation) response times of the tools, defined as the time required for the application to predict parameter values and display the output, were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (95% confidence interval) of predicted vs. observed concentrations were 3.73 ng/mL (-2.42-9.87) and 10.816 ng/mL (6.71-14.93) for olanzapine, and 0.46 ng/mL (-4.56-5.47) and 6.68 ng/mL (3.57-9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and root mean squared error of RO were -1.47% (-4.65-1.69) and 5.80% (3.89-7.72) for olanzapine and -0.91% (-7.68-5.85) and 8.87% (4.56-13.17) for risperidone., Conclusion: Our monitoring software predicts concentration-time profiles and the corresponding D 2 RO from sparsely sampled concentration measurements in an accessible and accurate form., (© 2022 British Pharmacological Society.)

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p<.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48-1.90; p<.0001-0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p<.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed., Competing Interests: Declaration of Competing Interest The authors declare no financial conflicts of interest related to the study., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

Introduction: Impaired illness awareness or the inability to recognize that one has a dependence on nicotine may be a major barrier to seeking cessation treatment. To better understand the role of impaired illness awareness on treatment-seeking behavior and clinical outcomes, we developed and examined the psychometric properties of a novel scale measuring illness awareness in individuals with dependence on nicotine., Aims and Methods: We developed the Nicotine Use Awareness and Insight Scale (NAS), a 7-item self-report measure to assess the theoretical construct of illness awareness in individuals with dependence on nicotine (www.illnessawarenessscales.com). Data from participants 18 years of age or older were collected via a web-based survey company, Dynata. Participants with moderate dependence on nicotine were included, defined by a score of four or more on the Fagerström Test for Cigarette Dependence (FTCD) or the FTCD adapted for electronic cigarettes (eFTCD)., Results: A total of 100 participants (mean [SD] age = 49.1 [16.1] years, 52% women) that met the inclusion criteria for either FTCD (n = 50) or eFTCD (n = 50) were included. The NAS demonstrated good convergent (r = .74, p < .001) and discriminant validity (r = .03, p = .786). It also demonstrated good internal consistency (Cronbach's alpha = 0.78) and one-month test-retest reliability (intra-class correlation = 0.86). An exploratory factor analysis yielded the retention of two components., Conclusions: The NAS is a novel scale to asses illness awareness in individuals with dependence on nicotine. This study provides initial support for the psychometric validity and reliability of NAS., Implications: The NAS may be used in research and clinical practice to evaluate the impact of impaired illness awareness on treatment-seeking behavior and clinical outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Impaired illness awareness or inability to recognize that one has a substance use disorder can be a barrier to treatment seeking and rehabilitation. A validated scale is needed to better understand the clinical impact of impaired substance use disorder awareness. This study aimed to examine the psychometric properties of the Substance Use Awareness and Insight Scale (SAS), a novel scale to assess impaired illness awareness in individuals with substance use disorder., Methods: We developed the SAS, a 7-item self-report measure to assess the theoretical constructs of illness awareness in substance use disorder (www.illnessawarenessscales.com). Participants 18 years of age or older with a score of 8 or more on the Drug Use Disorders Identification Test (DUDIT) were included. Data were collected via Dynata, an online survey platform., Results: A total of 299 participants were included (mean (SD) age = 47.3-years (15.4), 54% women). The SAS demonstrated good convergent (r = 0.82, p < 0.001) and discriminant validity (r = -0.23, p < 0.001) with a measure of illness recognition and positive affect, respectively. SAS also demonstrated good internal consistency (Cronbach's alpha = 0.86) and one-month test-retest reliability (intra-class correlation = 0.87). An exploratory factor analysis suggested the retention of two components. Separate analyses of the SAS in individuals with cannabis, opioid, and other substance use showed similar results., Discussion: The results of this study provide initial support for the psychometric validation of the SAS in adults with substance use disorder. The SAS holds promise for use in research and clinical settings to assess the influence of impaired substance use disorder awareness on treatment outcomes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Although schizophrenia is associated with increased presynaptic dopamine function in the striatum, it remains unclear if neuromelanin levels, which are thought to serve as a biomarker for midbrain dopamine neuron function, are increased in patients with schizophrenia. We conducted a systematic review and meta-analysis of magnetic resonance imaging (MRI) and postmortem studies comparing neuromelanin (NM) levels between patients with schizophrenia and healthy controls (HCs). Standard mean differences were calculated to assess group differences in NM accumulation levels between patients with schizophrenia and HCs. This study included 7 articles in total. Five studies employed NM-sensitive MRI (NM-MRI) and two were postmortem brain studies. The patient group (n = 163) showed higher NM levels in the substantia nigra (SN) than HCs (n = 228) in both the analysis of the seven studies and the subgroup analysis of the 5 NM-MRI studies. This analysis suggest increased NM levels in the SN may be a potential biomarker for stratifying schizophrenia, warranting further research that accounts for the heterogeneity of this disorder., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Novel coronavirus disease 2019 (COVID-19) vaccine hesitancy is a barrier to achieving herd immunity, and thus, a prominent public health concern. This study aimed to identify the determinants of COVID-19 vaccine hesitancy based on the World Health Organization's '3Cs' model (i.e., confidence, complacency, and convenience) in the United States (U.S.) and Canada., Methods: Data from 7678 adults ages 18 or older were collected from the four most populous U.S. States, specifically New York, California, Florida, and Texas, and from English-speaking Canada at three timepoints, in May and July 2020, and March 2021 using a web-based survey (www.covid19-database.com). Sociodemographic information was collected, and comprehensive psychological assessments were administered. Univariate analyses were performed to identify the individual determinants of vaccine hesitancy, which were categorized as: 1) vaccine confidence, 2) vaccine complacency, 3) sociodemographic, and 4) other psychological factors. A series of models were computed using these categorizations., Results: Mistrust of vaccine benefit (β(SE) = 0.67(0.01), p<0.001, partial η2 = 0.26) and lower perceived seriousness of COVID-19 (β(SE) = 0.68(0.02), p<0.001, partial η2 = 0.12) were the principal determinants of vaccine hesitancy. Right-wing political affiliation (β(SE) = 0.32(0.02), p<0.001, partial η2 = 0.03), higher risk propensity (β(SE) = 0.24(0.02), p<0.001, partial η2 = 0.03), and less negative mental health effects of the COVID-19 pandemic (β(SE) = 0.20(0.01), p<0.001, partial η2 = 0.03) were the main sociodemographic and psychological determinants. Other sociodemographic determinants included younger age, women, race, and employment status. Lack of vaccine confidence and complacency explained 38% and 21% of the variance in vaccine hesitancy, respectively; whereas, sociodemographic and psychological determinants explained 13% and 11% of the variance in vaccine hesitancy, respectively., Discussion: Targeted and tailored public health interventions that enhance the public's confidence in vaccines and emphasize the risk and seriousness of COVID-19 may address COVID-19 vaccine hesitancy. Efforts directed toward specific marginalized and underserved groups may be required to promote vaccine confidence., Competing Interests: PG reports receiving research support from the Department of Psychiatry, University of Toronto, Canadian Institute of Health Research (CIHR), Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and the Centre for Addiction and Mental Health (CAMH). FC has received funding from the CIHR Post-doctoral Fellowship Award and the CAMH Foundation. AG has received support from the United States National Institute of Health, CIHR, OMHF, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain & Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, and Janssen. All other authors have declared that there are no conflicts of interest in relation to the study.

Introduction: Impaired illness awareness in individuals with alcohol use disorder can negatively affect treatment adherence, rehabilitation, and other clinical outcomes. However, the construct of illness awareness in alcohol use disorder and its clinical implications remain to be better conceptualized and understood. The objective of this study was to develop and psychometrically test a scale designed to assess impaired illness awareness in individuals with alcohol use disorder., Methods: We developed the Alcohol Use Awareness and Insight Scale (AAS), a self-report measure that assesses the core theoretical domains of illness awareness, including general disorder or problem awareness, accurate symptom attribution, awareness of the need for treatment, and the negative consequences of the disorder in individuals with alcohol use disorder (www.illnessawarenessscales.com). Data from 99 participants was obtained using a web-based survey platform, Dynata., Results: The AAS displayed good convergent (r = 0.88, p < 0.001) and discriminant validity with measures of illness recognition and affect states, respectively. The AAS also exhibited good internal consistency (Cronbach's α = 0.89) and one-month test-retest reliability (intra-class correlation = 0.84). Exploratory factor analysis resulted in the retention of a single component., Conclusions: The AAS is a novel instrument developed to measure impaired illness awareness in individuals with alcohol use disorder. The AAS may be useful in clinical or research settings in evaluating the influence of subjective alcohol use disorder awareness on interventions to promote treatment adherence and other clinical outcomes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The radiotracers [ 11 C]-raclopride and [ 11 C]-(+)-PHNO are commonly used to measure differences in amphetamine-induced dopamine release between healthy persons and persons with neuropsychiatric diseases. As an agonist radiotracer, [ 11 C]-(+)-PHNO should theoretically be roughly 2.7 times more sensitive to displacement by endogenous dopamine than [ 11 C]raclopride. To date, only one study has been published comparing the sensitivity of these two radiotracers to amphetamine-induced dopamine release in healthy persons. Unfortunately, conflicting findings in the literature suggests that the dose of amphetamine they employed (0.3 mg/kg, p.o.) may not reliably reduce [ 11 C]-raclopride binding in the caudate. Thus, it is unclear whether the preponderance of evidence supports the theory that [ 11 C]-(+)-PHNO is more sensitive to displacement by amphetamine in humans than [ 11 C]-raclopride. In order to clarify these issues, we conducted a comparative meta-analysis summarizing the effects of amphetamine on [ 11 C]-raclopride and [ 11 C]-(+)-PHNO binding in healthy humans. Our analysis indicates that amphetamine given at 0.3 mg/kg, p.o. does not reliably reduce [ 11 C]-raclopride binding in the caudate. Second, the greater sensitivity of [ 11 C]-(+)-PHNO is evidenced at 0.5 mg/kg, p.o., but not at lower doses of amphetamine. Third, our analysis suggests that [ 11 C]-(+)-PHNO may be roughly 1.5 to 2.5 times more sensitive to displacement by amphetamine than [ 11 C]-raclopride in healthy persons. We recommend that future displacement studies with these radiotracers employ 0.5 mg/kg, p.o. of amphetamine with a dose, post-scan interval of at least 3 hr. Using this dose of amphetamine, [ 11 C]-raclopride studies should employ at least n = 34 participants per group, while [ 11 C]-(+)-PHNO studies should employ at least n = 6 participants per group, in order to be sufficiently powered (80%) to detect changes in radiotracer binding within the caudate., (© 2021 Wiley Periodicals, Inc.)

Patients with schizophrenia have exceedingly high rates of metabolic comorbidity including type 2 diabetes and lose 15-20 years of life due to cardiovascular diseases, with early accrual of cardiometabolic disease. In this study, thirty overweight or obese (Body Mass Index (BMI) > 25) participants under 40 years old with schizophrenia spectrum disorders and early comorbid prediabetes or type 2 diabetes receiving antipsychotic medications were randomized, in a double-blind fashion, to metformin 1500 mg/day or placebo (2:1 ratio; n = 21 metformin and n = 9 placebo) for 4 months. The primary outcome measures were improvements in glucose homeostasis (HbA1c, fasting glucose) and insulin resistance (Matsuda index-derived from oral glucose tolerance tests and homeostatic model of insulin resistance (HOMA-IR)). Secondary outcome measures included changes in weight, MRI measures of fat mass and distribution, symptom severity, cognition, and hippocampal volume. Twenty-two patients (n = 14 metformin; n = 8 placebo) completed the trial. The metformin group had a significant decrease over time in the HOMA-IR (p = 0.043) and fasting blood glucose (p = 0.007) vs. placebo. There were no differences between treatment groups in the Matsuda index, HbA1c, which could suggest liver-specific effects of metformin. There were no between group differences in other secondary outcome measures, while weight loss in the metformin arm correlated significantly with decreases in subcutaneous, but not visceral or hepatic adipose tissue. Our results show that metformin improved dysglycemia and insulin sensitivity, independent of weight loss, in a young population with prediabetes/diabetes and psychosis spectrum illness, that is at extremely high risk of early cardiovascular mortality. Trial Registration: This protocol was registered with clinicaltrials.gov (NCT02167620).

Anosognosia, described as impairment in an individual's ability to perceive and understand their illness, and visuospatial inattention commonly co-occur as a result of structural brain lesions in the right posterior parietal area. Anosognosia or impaired illness awareness is a common feature of schizophrenia that contributes to medication nonadherence and poor clinical outcomes. A recent pilot study suggests patients with impaired illness awareness have a rightward visuospatial bias. We aimed to examine this relationship in a large sample of patients. This study consisted of 106 patients with schizophrenia spectrum disorder (henceforth, schizophrenia) and 20 healthy controls. Visuospatial attention was assessed using the line bisection test (LBT). Illness awareness was assessed using the VAGUS self-report version. A Welch's t-test was used to examine differences in LBT scores between patients with schizophrenia and healthy controls. Correlation analyses between LBT and VAGUS scores were performed in patients with schizophrenia. For exploratory purposes, intra-subject reliability of the LBT was also examined using a two-way mixed intra-class correlation coefficient (ICC). There were no differences in LBT scores between patients with schizophrenia and healthy controls. In patients, there were no associations between LBT and VAGUS scores. ICCs between two consecutively acquired LBTs were 0.92 (95% CI: 0.81-0.96) in patients with schizophrenia and 0.93 (95% CI: 0.81-0.97) in healthy controls. Our results, using a reliable measure, did not support our previous preliminary finding that suggested a relationship between impaired illness awareness and visuospatial bias in patients with schizophrenia. Future studies should consider more sensitive visuospatial attention tasks when testing this hypothesis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Since apathy increases in prevalence with severity of dementia pathology, we sought to distinguish concomitant neurodegenerative processes from brain differences associated with apathy in persons with mild cognitive impairment (MCI) and Alzheimer's Disease (AD). We examined relative structural brain differences between case-control matched cognitively impaired patients with and without apathy., Design: Cross-sectional case-control study., Setting: Fifty-eight clinical sites in phase 2 of the AD Neuroimaging Initiative across the United States and Canada., Participants: The ≥ 55 years of age with MCI or AD dementia and no major neurological disorders aside from suspected incipient AD dementia. Participants with apathy (n=69) were age-, sex-, apolipoprotein E ε4 allele carrier status-, Mini-Mental State Exam score-, and MCI or AD dementia diagnosis-matched to participants without apathy (n=149)., Interventions: The 3-tesla T1-weighted MRI scan and neurocognitive assessments. Using the Neuropsychiatric Inventory apathy domain scores, participants were dichotomized into a with-apathy group (score ≥ 1) and a without-apathy group (score = 0)., Measurements: Cortical thicknesses from 24 a priori regions of interest involved in frontostriatal circuits and frontotemporal association areas., Results: False-discovery rate adjusted within-group comparisons between participants with apathy and participants without apathy showed thinner right medial orbitofrontal (mOFC; meandifference(MD)±standarderrorofMD(SE)=-0.0879±0.0257mm; standardizedMD(d)=-0.4456) and left rostral anterior cingulate (rACC; MD±SE=-0.0905±0.0325mm; d=-0.3574) cortices and thicker left middle temporal cortices (MTC; MD±SE=0.0688±0.0239mm; d=0.3311) in those with apathy., Conclusion: Atrophy of the right mOFC and left rACC and sparing of atrophy in the left MTC are associated with apathy in cognitively impaired persons., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Treatment-resistant schizophrenia (TRS) has been suggested to involve glutamatergic dysfunction. Glutathione (GSH), a dominant antioxidant, is known to be involved in glutamatergic neurotransmission. To date, no study has examined GSH levels in patients with TRS. The aim of this study was to examine GSH levels in the dorsal anterior cingulate cortex (dACC) of patients with TRS. Patients with schizophrenia were categorized into 3 groups with respect to their antipsychotic response: (1) clozapine (CLZ) nonresponders, (2) CLZ responders, and (3) first-line responders (FLR). GSH and glutamine + glutamate (Glx) levels were measured using 3T proton magnetic resonance spectroscopy. Firstly, dACC GSH levels were compared among the patient groups and healthy controls (HCs). Further, relationships between GSH and Glx levels were compared between the groups and GSH levels were explored stratifying the patient groups based on the glutamate-cysteine ligase catalytic (GCLC) subunit polymorphism. There was no difference in GSH levels between the groups. FLR showed a more negative relationship between GSH and Glx levels in the dACC compared to HCs. There were no effects of GCLC genotype on the GSH levels. However, CLZ responders had a higher ratio of high-risk GCLC genotype compared to CLZ nonresponders. This study demonstrated different relationships between GSH and Glx in the dACC between groups. In addition, the results suggest a potential link between CLZ response and GCLC genotype. However, it still remains unclear how these differences are related to the underlying pathophysiology of schizophrenia subtypes or the mechanisms of action of CLZ., (© The Author(s) 2021. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Background: One-third of patients with schizophrenia are treatment-resistant to non-clozapine antipsychotics (TRS), while the rest respond (NTRS). Examining whether TRS and NTRS represent different pathophysiologies is an important step toward precision medicine., Methods: Focusing on cortical thickness (CT), we analyzed international multi-site cross-sectional datasets of magnetic resonance imaging comprising 110 patients with schizophrenia (NTRS = 46, TRS = 64) and 52 healthy controls (HCs). We utilized a logistic regression with L1-norm regularization to find brain regions related to either NTRS or TRS. We conducted nested 10-fold cross-validation and computed the accuracy and area under the curve (AUC). Then, we applied the NTRS classifier to patients with TRS, and vice versa., Results: Patients with NTRS and TRS were classified from HCs with 65% and 78% accuracies and with the AUC of 0.69 and 0.85 (p = 0.014 and < 0.001, corrected), respectively. The left planum temporale (PT) and left anterior insula/inferior frontal gyrus (IFG) contributed to both NTRS and TRS classifiers. The left supramarginal gyrus only contributed to NTRS and right superior temporal sulcus and right lateral orbitofrontal cortex only to the TRS. The NTRS classifiers successfully distinguished those with TRS from HCs with the AUC of 0.78 (p < 0.001), while the TRS classifiers classified those with NTRS from HCs with the AUC of 0.69 (p = 0.015)., Conclusion: Both NTRS and TRS could be distinguished from HCs on the basis of CT. The CT pathological basis of NTRS and TRS has commonalities, and TRS presents unique CT features., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A growing body of neuroimaging research has revealed a relationship between blunted activation of the ventral striatum (VS) and apathy in schizophrenia. In contrast, the association between reduced striatal volume and apathy is less well established, while the relationship between VS function and structure in patients with schizophrenia remains an open question. Here, we aimed to replicate previous structural findings in a larger independent sample and to investigate the relationship between VS hypoactivation and VS volume., Methods: We included brain structural magnetic resonance imaging (MRI) data from 60 patients with schizophrenia (SZ) that had shown an association of VS hypoactivation with apathy during reward anticipation and 58 healthy controls (HC). To improve replicability, we applied analytical methods employed in two previously published studies: Voxel-based morphometry and the Multiple Automatically Generated Templates (MAGeT) algorithm. VS and dorsal striatum (DS) volume were correlated with apathy correcting for age, gender and total brain volume. Additionally, left VS activity was correlated with left VS volume., Results: We failed to replicate the association between apathy and reduced VS volume and did not find a correlation with DS volume. Functional and structural left VS measures exhibited a trend-level correlation (r s  = 0.248, p = 0.067, r 2  = 0.06)., Conclusions: Our present data suggests that functional and structural striatal neuroimaging correlates of apathy can occur independently. Replication of previous findings may have been limited by other factors (medication, illness duration, age) potentially related to striatal volume changes in SZ. Finally, associations between reward-related VS function and structure should be further explored., Competing Interests: Declaration of competing interest SK has received royalties for cognitive test and training software from Schuhfried. The other authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Adherence to antipsychotic medication is critical for the treatment of patients with schizophrenia. Impaired insight into illness is one of the principal drivers of medication nonadherence, which contributes to negative clinical outcomes. The aims of this study were to examine the relationships between impaired insight and (1) rates of antipsychotic medication nonadherence, and (2) time to medication nonadherence using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Insight was assessed using the Positive and Negative Syndrome Scale (PANSS) item G12 (lack of judgment and insight). Patients were divided into 3 groups based on their degree of insight impairment, i.e. no impairment (PANSS G12 = 1), minimal impairment (PANSS G12 = 2-3), and moderate-to-severe insight impairment (PANSS G12 ≥ 4). Medication nonadherence was defined as taking less than 80% of monthly pill counts. Kaplan-Meier survival and Cox regression analyses were performed to examine differences in time to medication nonadherence between insight groups. There were significant differences between insight groups in the percentage of nonadherent patients at 6 months (χ 2 (2) = 8.80, p = 0.012) and 18 months (χ 2 (2) = 10.04, p = 0.007) after study initiation. Moderate-to-severe insight impairment was associated with earlier nonadherence compared to minimal (χ 2  = 4.70, p = 0.030) or no impairment (χ 2  = 11.92, p = 0.001). The association remained significant after adjustment for illness severity, substance use, attitudes toward medication, cognition, level of hostility, and depression. The results of this study indicate a strong link between impaired insight and antipsychotic medication nonadherence. Interventions to enhance insight early during treatment may help improve medication adherence, and in turn, long-term clinical and functional outcomes in patients with schizophrenia. This article is part of the issue entitled 'Special Issue on Antipsychotics'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Insulin action in the central nervous system is a major regulator of energy balance and cognitive processes. The development of central insulin resistance is associated with alterations in dopaminergic reward systems and homeostatic signals affecting food intake, glucose metabolism, body weight and cognitive performance. Emerging evidence has highlighted a role for antipsychotics (APs) to modulate central insulin-mediated pathways. Although APs remain the cornerstone treatment for schizophrenia they are associated with severe metabolic complications and fail to address premorbid cognitive deficits, which characterize the disorder of schizophrenia. In this review, we first explore how the hypothesized association between schizophrenia and CNS insulin dysregulation aligns with the use of APs. We then investigate the proposed relationship between CNS insulin action and AP-mediated effects on metabolic homeostasis, and different domains of psychopathology, including cognition. We briefly discuss a potential role of CNS insulin signaling to explain the hypothesized, but somewhat controversial association between therapeutic efficacy and metabolic side effects of APs. Finally, we propose how this knowledge might inform novel treatment strategies to target difficult to treat domains of schizophrenia. This article is part of the issue entitled 'Special Issue on Antipsychotics'., (Copyright © 2019. Published by Elsevier Ltd.)

Treatment-resistant schizophrenia may be related to structural brain alterations. However, the mechanisms underlying these changes remain unclear. The present study had two main aims: (1) to explore differences in cortical thickness between patients with treatment-resistant schizophrenia non-responsive to clozapine (ultra-treatment-resistant schizophrenia, UTRS), patients with treatment-resistant schizophrenia responsive to clozapine (Cloz-Resp), patients responsive to first-line non-clozapine antipsychotics (FL-Resp), and healthy controls (HCs); and (2) to test our hypothesis of structural compromise as a manifestation of neurotoxic effects from elevated glutamate (Glu) (i.e. glutamate-mediated excitotoxicity) by examining the relationships between glutamatergic neurometabolite levels (Glu and glutamate + glutamine (Glx)) in the dorsal anterior cingulate cortex (dACC) and cortical thickness. T1-weighted images and 1 H-MRS data were obtained from UTRS (n = 24), Cloz-Resp (n = 25), FL-Resp (n = 19), and HCs (n = 26). Vertex-wise analyses showed that patients with UTRS had widespread cortical thinning in the bilateral frontal, temporal, parietal, and occipital gyri compared to HCs and FL-Resp patients. In the patient group, negative associations were found between dACC Glx levels and cortical thickness in the right dorsolateral prefrontal cortex after correcting for multiple comparisons and controlling for age, sex, antipsychotic dose, and illness severity. In conclusion, glutamate-mediated excitotoxicity may be one of the mechanisms underlying structural compromise seen in treatment-resistant schizophrenia. Future studies should longitudinally examine the associations between glutamatergic neurometabolite levels and cortical thickness in the context of treatment and illness progression., Competing Interests: Declaration of competing interest Dr. Plitman reports receiving funding from Canadian Institute of Health Research (CIHR) and the Healthy Brains for Healthy Lives Postdoctoral Fellowship. Dr. Iwata reports receiving fellowship grants from Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. Dr. Nakajima has received fellowship grants from CIHR, research support from Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, Daiichi Sankyo, and manuscript fees or speaker's honoraria from Dainippon Sumitomo Pharma and Yoshitomi Yakuhin within the past three years. Dr. Hahn reports being on an advisory board for Alkermes in the past. Dr. Remington reports external funding from CIHR, travel support from Neurocrine Biosciences, and research support from HLS. Dr. Gerretsen reports receiving research support from CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and the Centre for Addiction and Mental Health (CAMH). Dr. Graff-Guerrero has received research support from the following external funding agencies: the CIHR, US NIH, OMHF, NARSAD, Mexico Instituto de Ciencia y Tecnología del Distrito Federal, Consejo Nacional De Ciencia Y Tecnología, Ministry of Economic Development and Innovation of Ontario, Ontario AHSC AFP Innovation Fund and W. Garfield Weston Foundation. All other authors report no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aims: Diabetes mellitus affects approximately 8.5% of the world's population with the majority of cases diagnosed with type 2 diabetes (T2DM). Impaired awareness or denial of T2DM is a common yet understudied construct that may negatively contribute to clinical outcomes. The aim of this study was to develop the Diabetes Awareness and Insight Scale (DAS), a self-report scale that measures illness awareness in persons with T2DM., Methods: Nine items were developed for the DAS that measure four domains of illness awareness, namely General Illness Awareness, Accurate Symptom Attribution, Awareness of Need for Treatment, and Awareness of Negative Consequences attributable to T2DM (www.illnessawarenessscales.com). A total of 100 participants with a diagnosis of T2DM were recruited using a digital data collection platform., Results: The DAS demonstrated good convergent and discriminant validity, internal consistency, and one-month test-retest reliability. An exploratory factor analysis showed that the DAS exhibited three factors., Conclusions: Overall, the DAS is a novel and easy-to-administer scale that comprehensively measures subjective illness awareness in persons with T2DM. As the first scale of its kind, the DAS holds promise for use in epidemiology studies to examine the extent to which impaired illness awareness or illness denial contributes to clinical outcomes and T2DM management., Competing Interests: Declaration of competing interest JK reports receiving research support from the Ontario Graduate Scholarship (OGS). PS reports receiving research support from the Canadian Institutes of Health Research (CIHR) Canadian Graduate Scholarship – Master’s. LQ reports no conflicts of interest. FC reports receiving fellowship grants from the OGS and CIHR. EP reports receiving research support from OGS and a CIHR Canada Graduate Scholarship – Master’s, and currently receiving research support from a CIHR Vanier Canada Graduate Scholarship. YI reports receiving fellowship grants from Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. BP reports no conflicts of interest. SD is a Banting & Best Diabetes Center (University of Toronto) Dennis Scholar and Diabetes Canada New Investigator. SS reports receiving research funding from CIHR. AGG reports receiving research support from the following external funding agencies: the CIHR, US NIH, OMHF, NARSAD, Mexico Instituto de Ciencia y Tecnología del Distrito Federal, Consejo Nacional De Ciencia Y Tecnología, Ministry of Economic Development and Innovation of Ontario, Ontario AHSC AFP Innovation Fund and W. Garfield Weston Foundation. PG reports receiving fellowship awards and research support from the CIHR, Ontario Mental Health Foundation (OMHF) and the Centre for Addiction and Mental Health (CAMH)., (Copyright © 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Widespread structrual abnormalities in subcortical brain regions have been identified in patients with schizophrenia. However, only a few studies have examined the neuroanatomical profiles of patients with treatment-resistant schizophrenia. The aim of this study was to compare differences in subcortical and hippocampal volumes between: (i) treatment-resistant patients who are non-responders to both first-line antipsychotics and clozapine (URS), (ii) treatment-resistant patients who are non-responders to first-line antipsychotics but are responders to clozapine (CLZ-Resp), (iii) responders to first-line antipsychotics (FL-Resp), and (iv) healthy controls. T1-weighted images of 103 participants (27 URS, 29 CLZ-Resp, 21 FL-Resp, and 26 healthy controls) were obtained. Group differences in striatal, thalamic, globus pallidus, amygdala, and hippocampus volumes were examined. Multiple regression analyses were performed to examine the associations between subcortical and hippocampal volumes and participant characteristics. The FL-Resp group showed larger striatal and globus pallidus volumes compared to the URS group and larger post-commissural putamen and globus pallidus volumes compared to healthy controls. The URS group showed smaller thalamic volume compared to healthy controls. There were no subcortical or hippocampal volume differences between the URS and CLZ-Resp groups. Differences in subcortical and hippocampal structural volumes were not related to symptom severity or chlorpromazine antipsychotic dose equivalents. Our findings suggest different structural volume alterations in subcortical brain regions between treatment-resistant schizophrenia and responders to first-line antipsychotics. Whether subcortical structure compromise is a distinct pathophysiological marker of treatment-resistant schizophrenia, or a result of antipsychotic exposure, remains to be explored., Competing Interests: Declaration of Competing Interest J.K. has received funding from the CAMH Foundation and the Ontario Graduate Scholarship (OGS). E.P. has received funding from the Healthy Brains for Healthy Lives Postdoctoral Fellowship, the Vanier Canada Graduate Scholarship, the OGS, and the Canada Graduate Scholarship – Master's. Y.I. has received fellowship grants from Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. S.N. has received fellowship grants from the Canadian Institutes of Health Research (CIHR), research support from Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, and Daiichi Sankyo Scholarship Donation Program within the past 3 years. He has also received research support, manuscript fees, or speaker's honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past 3 years. J.K.C. has received funding from the CIHR Doctoral Award and the Canada Graduate Scholarship – Master's. F.C. has received funding from CIHR, the Ontario Mental Health Post-Doctoral Fellowship Award, CAMH Foundation, the Brain & Behavior Research Foundation (Formerly NARSAD), and the Vancouver Coastal Health Research Institute. G.R. has received consultant fees from Neurocrine Biosciences and Synchroneuron, as well as research support from Novartis. P.G. reports receiving research support from CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and CAMH. A.G.-G. has received support from the United States National Institute of Health, CIHR, OMHF, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain & Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, and Janssen. All other authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The neurotransmitter dopamine is present in the retina and is involved in several modulatory functions. Unlike in rodents, dopamine D 3 receptors are expressed in the retina of humans. Recently, uptake of the D 3 receptor-preferring radiotracer [ 11 C]-(+)-PHNO has been observed in a retina-like region of interest (ROI) in humans. Here, we attempted to quantify [ 11 C]-(+)-PHNO uptake into this ROI using an independent sample, employing an extended scan acquisition time (120 min) and arterial kinetic modeling. Data from 14 healthy controls were analyzed (Mean Age: 38.41 ± 9.55, 3 female), 8 of which provided arterial line input function data (Mean Age: 41.07 ± 7.82, 3 female). Using Ichise's multilinear analysis (MA1) method, it was possible to quantify the volume of distribution (V T ) of [ 11 C]-(+)-PHNO in this retina-like region (Mean V T  = 13.56 ± 3.52; Mean χ 2  = 2.08 ± 2.20). Notably, the shape of the time activity curve resembled closely that of the globus pallidus. Moreover, the V T values in the retina correlated well with binding potential (BP ND ) values calculated using the simplified reference tissue model (Mean BP ND  = 2.11 ± .94; Mean χ 2  = 5.76 ± 2.56), employing the cerebellum as the reference region (r = .76, r 2  = .58). In summary, we provide evidence that the in vivo uptake of [ 11 C]-(+)-PHNO into a retina-like ROI in humans can be quantified using both arterial blood sampling (V T ) and simplified reference tissue methods (BP ND )., (© 2019 Wiley Periodicals, Inc.)

Cognitive biases may contribute to the formation and maintenance of positive symptoms in patients with schizophrenia. However, cognitive reflection (i.e., the ability to use analytical thinking to override intuitive responses) has not been explicitly examined in schizophrenia patients using the cognitive reflection test (CRT). Using the CRT, we examined the degree of analytical and intuitive reasoning employed during problem solving in patients with schizophrenia versus healthy controls. Fifty-eight outpatients with schizophrenia and fifty-eight age- and sex-matched healthy controls (18-35 years of age) participated in this study. In addition to CRT performance, neurocognition, apathy, impulsivity, depression, insight, and clinical symptoms were evaluated. Patients with schizophrenia produced significantly fewer analytical responses (U = 1167.00, p<0.05) and more intuitive responses (U = 1273.50, p<0.05) compared to healthy controls. Patients without significant cognitive impairment also produced fewer analytical responses compared to controls (U = 894.50, p<0.05). Among patients, analytical thinking was positively correlated with working memory (r = 0.27, p<0.05), and affective symptoms (r = 0.31, p<0.05). Analytical reasoning was not significantly correlated with positive symptoms, avolition, or impulsivity. Patients with schizophrenia demonstrate less analytical and more intuitive reasoning while problem solving compared to healthy controls. This reduction in cognitive reflection is not significantly explained by global cognitive impairment or motivational deficits., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in relation to the current investigation., (Copyright © 2019. Published by Elsevier B.V.)

Insulin signaling in the central nervous system is at the intersection of brain and body interactions, and represents a fundamental link between metabolic and cognitive disorders. Abnormalities in brain insulin action could underlie the development of comorbid schizophrenia and type 2 diabetes. Among its functions, central nervous system insulin is involved in regulation of striatal dopamine levels, peripheral glucose homeostasis, and feeding regulation. In this review, we discuss the role and importance of central nervous system insulin in schizophrenia and diabetes pathogenesis from a historical and mechanistic perspective. We describe central nervous system insulin sites and pathways of action, with special emphasis on glucose metabolism, cognitive functioning, inflammation, and food preferences. Finally, we suggest possible mechanisms that may explain the actions of central nervous system insulin in relation to schizophrenia and diabetes, focusing on glutamate and dopamine signaling, intracellular signal transduction pathways, and brain energetics. Understanding the interplay between central nervous system insulin and schizophrenia is essential to disentangling this comorbid relationship and may provide novel treatment approaches for both neuropsychiatric and metabolic dysfunction. This article is part of the issue entitled 'Special Issue on Antipsychotics'., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Using molecular imaging techniques - positron emission tomography (PET) and single-photon emission computed tomography (SPECT) - in conjunction with an acute dopamine depletion challenge (alpha-methyl-para-tyrosine) it is possible to estimate endogenous dopamine levels occupying striatal dopamine D 2 receptors (D 2 R) in humans in vivo. However, it is unclear what proportion of striatal D 2 R are occupied by endogenous dopamine under normal conditions. This is important since it has been suggested that in schizophrenia there may be a substantial proportion of striatal D 2 R which are occupied by endogenous dopamine and not accessible by therapeutic doses of antipsychotics. In order to clarify these issues, we conducted a meta-analysis of dopamine depletion studies using substituted benzamide radiotracers in healthy persons. This meta-analysis suggests that anywhere from 8 to 21% (weighted average 11%) of striatal D 2 R may be occupied by endogenous dopamine at baseline. Using these estimates, we propose an updated occupancy model and tentatively suggest that antipsychotics inhibit a smaller proportion of the total pool of striatal D 2 R in vivo than previously acknowledged. This article is part of the issue entitled 'Special Issue on Antipsychotics'., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Amyloid deposition, tau neurofibrillary tangles, and cerebrovascular dysfunction are important pathophysiologic features in Alzheimer's disease. Pittsburgh compound B ([ 11 C]-PIB) is a positron emission tomography (PET) radiotracer used to quantify amyloid deposition in vivo. In addition, certain models of [ 11 C]-PIB delivery reflect cerebral blood flow rather than amyloid plaques. As cerebral blood flow and perfusion deficits are associated with white matter pathology, we hypothesized that [ 11 C]-PIB delivery in white matter regions may reflect white matter integrity., Methods: We obtained [ 11 C]-PIB-PET scans and quantified white matter hyperintensities and global fractional anisotropy on magnetic resonance images as biomarkers of white matter pathology in 34 older participants with mild cognitive impairment with or without a history of major depressive disorder. We analyzed the [ 11 C]-PIB time-activity curve data with models associated with cerebral blood flow: the early maximum standard uptake value and the relative delivery parameter R1. We used a global white matter region of interest., Results: Both of the partial-volume corrected PET parameters were correlated with white matter hyperintensities and fractional anisotropy., Conclusion: Future studies are warranted to explore whether [ 11 C]-PIB PET is a "triple biomarker" that may provide information about amyloid deposition, cerebral blood flow, and white matter pathology., (© 2019 by the American Society of Neuroimaging.)

Background: Impaired illness awareness or insight into illness (IIA) is a common feature of schizophrenia that contributes to medication nonadherence and poor clinical outcomes. Neuroimaging studies suggest IIA may arise from interhemispheric imbalance in frontoparietal regions, particularly in the posterior parietal area (PPA) and the dorsolateral prefrontal cortex (dlPFC). In this pilot study, we examined the effects of transcranial direct current stimulation (tDCS) on brain regions implicated in IIA., Methods: Eleven patients with schizophrenia with IIA (≥3 PANSS G12) and 10 healthy controls were included. A crossover design was employed where all participants received single-session bi-frontal, bi-parietal, and sham stimulation in random order. For each condition, we measured (i) blood oxygen level-dependent (BOLD) response to an illness awareness task pre- and post-stimulation, (ii) regional cerebral blood-flow (rCBF) prior to and during stimulation, and (iii) changes in illness awareness., Results: At baseline, patients with schizophrenia showed higher BOLD-response to an illness awareness task in the left-PPA compared to healthy controls. Bi-parietal stimulation reduced the interhemispheric imbalance in the PPA compared to sham stimulation. Relatedly, bi-parietal stimulation increased rCBF beneath the anode (21% increase in the right-PPA), but not beneath the cathode (5.6% increase in the left-PPA). Bi-frontal stimulation did not induce changes in rCBF. We found no changes in illness awareness., Conclusion: Although single-session tDCS did not improve illness awareness, this pilot study provides mechanistic justification for future investigations to determine if multi-session bi-parietal tDCS can induce sustained changes in brain activity in the PPA in association with improved illness awareness., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Obesity is up to 4 times higher in patients with schizophrenia than in the general population. However, the link between obesity and schizophrenia in the absence of antipsychotic use is unclear. Therefore, we aimed to examine differences in obesity measures (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) in antipsychotic-naive and minimally treated (up to 2 weeks of lifetime antipsychotic exposure) patients with psychosis compared to healthy controls (HCs)., Methods: A systematic search was conducted using Ovid Medline®, PsycINFO, and Embase. Standardized mean differences (SMDs) in obesity measures between groups were calculated. Separate sensitivity analyses were performed to examine the effects of age, sex, and ethnicity; antipsychotic exposure; and schizophrenia-related psychosis on SMDs., Results: A total of 23 studies were included in the meta-analysis (BMI = 23, WC = 9, WHR = 5). BMI was lower (SMD = -0.19, 95% CI = -0.34 to -0.05, P = 0.009) and WHR was elevated (SMD = 0.34, 95% CI = 0.14 to 0.55, P = 0.001) in patients. These differences remained after analyses were restricted to patients matched with HCs for age, sex, and ethnicity; to antipsychotic-naive patients; and to patients with schizophrenia-related diagnoses., Conclusions: Differences in BMI and WHR were observed in never and minimally treated patients with psychosis compared to HCs. Future research is warranted to understand these alterations in the context of body fat biomarkers and neuropathology of psychiatric disorders, independent of the effects of antipsychotics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy., Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups., Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F 3,96  = 2.93, p = .038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p = .038). There were no group differences in the caudate or dorsolateral prefrontal cortex., Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between dopamine D 2 receptor (D 2 R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses., Aim and Methods: We investigated the influence of estimated D 2 R (Est.D 2 R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18-62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D 2 R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIA's relationship to illness severity, cognition, and Est.D 2 R., Results: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D 2 R did not predict IIA, and Est.D 2 R did not serve either a moderating or mediating role in both regression and path analyses., Conclusions: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D 2 R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late-life schizophrenia (i.e. ≥60 years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity., (Copyright © 2018. Published by Elsevier Inc.)

Transcranial direct current stimulation (tDCS) has generated interest in recent years as a potential adjunctive treatment for patients with schizophrenia. The primary objective of this meta-analysis was to evaluate the efficacy of tDCS on positive symptoms, particularly auditory hallucinations, and negative symptoms. A literature search of randomized sham-controlled trials was conducted using the OVID database on October 9, 2018. The standardized mean differences (SMDs) were calculated to examine changes in symptom severity between active and sham groups for the following symptom domains: auditory hallucinations, positive symptoms (including auditory hallucinations), and negative symptoms. Moderator analyses were performed to examine the effects of study design and participant demographics. We identified 10 eligible studies. Main-analyses showed no effects of tDCS on auditory hallucinations (7 studies, n = 242), positive symptoms (9 studies, n = 313), or negative symptoms (9 studies, n = 313). Subgroup analyses of studies that applied twice-daily stimulation showed a significant reduction in the severity of auditory hallucinations (4 studies, n = 138, SMD = 1.04, p = 0.02). Studies that applied ≥10 stimulation sessions showed a reduction in both auditory hallucination (5 studies, n = 186, SMD = 0.86, p = 0.009) and negative symptom severity (7 studies, n = 257, SMD = 0.41, p = 0.04). Meta-regression analyses revealed a negative association between mean age and the SMDs for auditory hallucinations and negative symptoms, and a positive association between baseline negative symptom severity and the SMDs for negative symptoms. Our findings highlight the need to optimize tDCS parameters and suggest twice-daily or 10 or more stimulation sessions may be needed to improve clinical outcomes in patients with schizophrenia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

High levels of trait impulsivity are considered a risk factor for substance abuse and drug addiction. We recently found that non-planning trait impulsivity was negatively correlated with post-commissural putamen volumes in men, but not women, using the Karolinska Scales of Personality (KSP). Here, we attempted to replicate this finding in an independent sample using an updated version of the KSP: the Swedish Universities Scales of Personality (SSP). Data from 88 healthy male participants (Mean Age: 28.16±3.34), who provided structural T1-weighted magnetic resonance images (MRIs) and self-reported SSP impulsivity scores, were analyzed. Striatal sub-region volumes were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Contrary to our previous findings trait impulsivity measured using SSP was not a significant predictor of post-commissural putamen volumes (β = .14, df = 84, p = .94). A replication Bayes Factors analysis strongly supported this null result. Consistent with our previous findings, secondary exploratory analyses found no relationship between ventral striatum volumes and SSP trait impulsivity (β = -.05, df = 84, p = .28). An exploratory analysis of the other striatal compartments showed that there were no significant associations with trait impulsivity. While we could not replicate our previous findings in the current sample, we believe this work will aide future studies aimed at establishing meaningful brain biomarkers for addiction vulnerability in healthy humans., Competing Interests: The authors have declared that no competing interests exist.

Cognitive impairment is a core symptom domain of schizophrenia. The effect of antipsychotics, the cornerstone of treatment in schizophrenia, on this domain is not fully clear. There is some evidence suggesting that antipsychotics may partially improve cognitive function, and that this improvement may vary depending on the specific cognitive domain. However, this research is confounded by various factors, such as age, duration/stage of illness, medication adherence, and extrapyramidal side effects that complicate the relationship between antipsychotics and cognitive improvement. Furthermore, antipsychotics-particularly the second generation, or "atypical" antipsychotics-can induce serious metabolic side effects, such as obesity, dyslipidemia and type 2 diabetes, illnesses which themselves have been linked to impairments in cognition. Thus, the inter-relationships between cognition and metabolic side effects are complex, and this review aims to examine them in the context of schizophrenia and antipsychotic treatment. The review also speculates on potential mechanisms underlying cognitive functioning and metabolic risk in schizophrenia. We conclude that the available literature examining the inter-section of antipsychotics, cognition, and metabolic effects in schizophrenia is sparse, but suggests a relationship between metabolic comorbidity and worse cognitive function in patients with schizophrenia. Further research is required to determine if there is a causal connection between the well-recognized metabolic adverse effects of antipsychotics and cognitive deficits over the course of the illness of schizophrenia, as well as, to determine underlying mechanisms. In addition, findings from this review highlight the importance of monitoring metabolic disturbances in parallel with cognition, as well as, the importance of interventions to minimize metabolic abnormalities for both physical and cognitive health.

Approximately one-third of patients with schizophrenia have treatment-resistant schizophrenia (TR-SCZ), which is a condition characterized by suboptimal response to antipsychotics other than clozapine. Importantly, treatment with clozapine-the only antipsychotic with an indication for TR-SCZ-is often delayed, which could contribute to negative outcomes. Given that the specific impact of delay in clozapine initiation is not well understood, we aimed to conduct a systematic search of the Ovid Medline ® database to identify English language publications exploring the impact of delay in clozapine initiation on treatment outcomes in patients with TR-SCZ. Additionally, clinico-demographic factors associated with clozapine delay were examined. Our search identified four retrospective studies that showed an association between longer delay in clozapine initiation and poorer treatment outcomes, even after including covariates, such as age, sex, and duration of illness. In addition, we found six studies that showed an association between age and clozapine delay, but results with regard to other clinico-demographic variables were inconsistent. Overall, the available literature reveals a possible link between delay in clozapine use and poorer treatment outcomes in patients with TR-SCZ. However, given the relatively small number of studies on this clinically important topic, future research is warranted to draw more definitive conclusions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dopamine D 2 receptors (D 2 R) are expressed in the human retina and play an important role in the modulation of neural responses to light-adaptation. However, it is unknown whether dopamine D 3 receptors (D 3 R) are expressed in the human retina. Using positron emission tomography (PET), we have observed significant uptake of the D 3 R-preferring agonist radiotracer [ 11 C]-(+)-PHNO into the retina of humans in vivo. This led us to examine whether [ 11 C]-(+)-PHNO binding in the retina was quantifiable using reference tissue methods and if D 3 R are expressed in human post-mortem retinal tissue. [ 11 C]-(+)-PHNO data from 49 healthy controls (mean age: 39.96 ± 14.36; 16 female) and 12 antipsychotic-naïve patients with schizophrenia (mean age: 25.75 ± 6.25; 4 female) were analyzed. We observed no differences in [ 11 C]-(+)-PHNO binding in the retina between first-episode, drug-naïve patients with schizophrenia and healthy controls. Post-mortem retinal tissues from four healthy persons (mean age: 59.75 ± 9.11; 2 female) and four patients with schizophrenia (mean age: 54 ± 17.11; 2 female) were analyzed using a targeted mass spectrometry technique: parallel reaction monitoring (PRM) analysis. Using targeted mass spectrometry, we confirmed that D 3 R are expressed in human retinal tissue ex vivo. Notably, there was far greater expression of D 2 R relative to D 3 R in the healthy human retina (∼12:1). Moreover, PRM analysis revealed reduced D 2 R, but not D 3 R, expression in the retinas of non-first episode patients with schizophrenia compared to healthy controls. We confirm that D 3 R are expressed in the human retina. Future studies are needed to determine what proportion of the [ 11 C]-(+)-PHNO signal in the human retina in vivo is due to binding to D 3 R versus D 2 R. Knowledge that both D 2 R and D 3 R are expressed in the human retina, and potentially quantifiable in vivo using [ 11 C]-(+)-PHNO, poses new research avenues for better understanding the role of retinal dopamine in human vision. This work may have important implications for elucidating pathophysiological and antipsychotic induced visual deficits in schizophrenia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Motivational deficits represent a core negative symptom in patients with schizophrenia. Previous morphology studies have demonstrated that apathy in patients with schizophrenia is associated with reduced frontal grey matter (GM). We attempted to replicate this previous finding, and explored whether it was distinct from potential associations with a distinct subdomain of negative symptoms, namely Affective Flattening, and GM., Methods: Twenty medicated patients with schizophrenia provided structural T1-weighted images acquired on a 3-Tesla MRI scanner and negative symptoms were evaluated using the Scale for the Assessment of Negative Symptoms. Voxel-based morphometry (VBM) was used to explore the correlations between whole-brain GM and i) Apathy, and ii) Affective Flattening, respectively., Results: Apathy scores were negatively correlated with several GM clusters in frontal regions, including the frontal inferior operculum and the left dorsal anterior cingulate cortex. Only positive correlations with GM clusters were observed for Affective Flattening, particularly in the inferior temporal lobe. Notably, the regions associated with apathy scores were distinct from those associated with Affective Flattening, and these findings remained after controlling for antipsychotic medication dosage., Conclusions: We replicated previous associations between reduced frontal GM and apathy in patients with schizophrenia. Moreover, we demonstrated that these GM associations are distinct from those with Affective Flattening. The present findings set the stage for future larger-scale studies confirming the structural and neurochemical substrates of apathy in schizophrenia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)