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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.

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.

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.

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.

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.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.Our results revealed no association among the VAGUS average and subscale scores and degree of subjective happiness, perceived level of success, and life satisfaction.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.

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.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.Both CLZ-Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [gLGI 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.

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

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 (

AIM: 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 (PPK) models for olanzapine and risperidone were combined with a pharmacodynamic (PD) model for D2 RO and implemented in the R programming language. Maximum a posteriori (MAP) 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 (RMSE, 95% CI) of predicted versus 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 RMSE 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.

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.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.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.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.

Highlights • Different etiology is assumed in treatment-resistant and responsive schizophrenia. • Patients with treatment-resistant schizophrenia were classified from controls. • Patients with non-treatment-resistant schizophrenia were classified from controls. • Two classifications reached area under the curve as high as 0.69 and 0.85. • Area under the curve remained as high as 0.69 when two classifiers were swapped., 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

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.

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.

Aim A robust and user-friendly software tool was developed for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone. This tool can facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. Methods Previously developed population pharmacokinetic (PPK) models for olanzapine and risperidone were combined with a PD model for D2 receptor occupancy (RO) and implemented in the R programming language. MAP Bayesian estimation was used to provide predictions of plasma concentration and receptor occupancy and based on sparse PK measurements. Results The average (standard deviation) response times of the tools 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 (RMSE, 95% CI) of predicted versus observed concentrations were 3.73 ng/mL (-2.42 – 9.87) and 10.816 (6.71 – 14.93) for olanzapine, and 0.46 ng/mL (-4.56 – 5.47) and 6.68 (3.57 – 9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and RMSE 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 Treatment of schizophrenia with antipsychotics offers unique challenges and requires careful monitoring to establish the optimal dosing regimen. Our monitoring software predicts RO in a reliable and accurate form.

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.

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).

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.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.The AAS displayed good convergent (r = 0.88, p0.001) 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.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.

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.

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.

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), p2 = 0.26) and lower perceived seriousness of COVID-19 (β(SE) = 0.68(0.02), p2 = 0.12) were the principal determinants of vaccine hesitancy. Right-wing political affiliation (β(SE) = 0.32(0.02), p2 = 0.03), higher risk propensity (β(SE) = 0.24(0.02), p2 = 0.03), and less negative mental health effects of the COVID-19 pandemic (β(SE) = 0.20(0.01), p2 = 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.

The radiotracers [

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.

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.

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 e4 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; m e a n d i f f e r e n c e ( M D ) ± s t a n d a r d e r r o r o f M D ( S E ) = − 0.0879 ± 0.0257 m m ; s t a n d a r d i z e d M D ( d ) = − 0.4456 ) and left rostral anterior cingulate (rACC; M D ± S E = − 0.0905 ± 0.0325 m m ; d = − 0.3574 ) cortices and thicker left middle temporal cortices (MTC; M D ± S E = 0.0688 ± 0.0239 m m ; 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.

BackgroundA 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.MethodsWe 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 developed 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.ResultsWe 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 (rs=0.248, p=0.067, r2=0.06).ConclusionsOur 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.

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 1H-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.

Background Studies using proton magnetic resonance spectroscopy (1H-MRS) have reported altered neurometabolite levels in patients with schizophrenia. However, results are possibly confounded by the influence of antipsychotic (AP). Thus, this meta-analysis aimed to examine neurometabolite levels in AP-naive/free patients with schizophrenia. Methods A literature search was conducted using Embase, Medline, and PsycINFO to identify studies that compared neurometabolite levels in AP-naive/free patients with schizophrenia to healthy controls (HCs). Eight neurometabolites (glutamate, glutamine, glutamate + glutamine, N-acetylaspartate [NAA], choline, creatine, myo-inositol, and γ-Aminobutyric acid [GABA]) and seven regions of interest (ROI; medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter, occipital lobe, basal ganglia, hippocampus/medial temporal lobe, and thalamus) were examined. Results Twenty-one studies (N = 1281) were included in the analysis. The results showed lower thalamic NAA levels (3 studies, n = 174, effect size = −0.56, P = 0.0005) in the patient group. No group differences were identified for other neurometabolites. Conclusions Our findings suggest that impaired neuronal integrity in the thalamus may be a potential trait maker in the early stages of schizophrenia.

AIMS: Impaired illness awareness or not accepting that one has obesity is an understudied phenomenon that may negatively influence treatment adherence and clinical outcomes. The purpose of this study was to perform a systematic review of available measures of obesity awareness, and subsequently develop and validate a novel scale that measures the core domains of obesity awareness. METHODS: A systematic review of the literature revealed no illness specific measure of subjective obesity awareness. As such, we designed the Obesity Awareness and Insight Scale (OASIS) to assess the following core domains of illness awareness: General Illness Awareness,, Symptom Attribution,, Awareness of Need for Treatment and the Negative Consequences attributable to the illness (www.illnessawarenessscales.com). Participants (n=100) were recruited from an online survey platform to assess the psychometric properties of OASIS. RESULTS: The OASIS demonstrated strong internal consistency (Cronbach's alpha=0.89), convergent (r(98)=0.65, p

Previous proton magnetic resonance spectroscopy (1H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla 1H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the 1H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired 1H-MRS acquisitions: average = 90.33; range = 7–306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576–0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naive first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication.

Aims Impaired illness awareness or not accepting that one has obesity is an understudied phenomenon that may negatively influence treatment adherence and clinical outcomes. The purpose of this study was to perform a systematic review of available measures of obesity awareness, and subsequently develop and validate a novel scale that measures the core domains of obesity awareness. Methods A systematic review of the literature revealed no illness specific measure of subjective obesity awareness. As such, we designed the Obesity Awareness and Insight Scale (OASIS) to assess the following core domains of illness awareness: General Illness Awareness, Symptom Attribution, Awareness of Need for Treatment and the Negative Consequences attributable to the illness ( www.illnessawarenessscales.com ). Participants (n = 100) were recruited from an online survey platform to assess the psychometric properties of OASIS. Results The OASIS demonstrated strong internal consistency (Cronbach's alpha = 0.89), convergent (r(98) = 0.65, p Conclusions OASIS is an obesity-specific instrument that comprehensively measures subjective obesity awareness. OASIS can be used in epidemiological studies, intervention trials, and clinical practice to assess the impact of obesity awareness on treatment adherence and outcomes.

Rodent studies suggest that dopamine signaling at D2/3 receptors in the ventral striatum is critical for reward motivation. Whether this is also true in humans is unclear. Positron emission tomography studies in healthy humans have generally not observed a relationship between D2/3 receptor availability in the ventral striatum and motivation. We developed the "mounting-effort for reward task" to assess high motivational demand for (a) gaining money (CS+), (b) losing money or avoiding electric shock (CS-), and (c) non-reward (Neutral). Receipt was contingent on participants making sufficient button responses relative to a "reward-threshold" determined by prior motor performance. This reward-threshold was dynamically increased if surpassed, making the task increasingly more difficult on every trial. The mounting-effort for reward task was preliminarily validated in 29 healthy volunteers (mean age: 25.83±3.58; 15 female). In this sample, %CS+ and %CS- significantly correlated with different dimensions of self-reported apathy. In a sub-sample of eight healthy volunteers (mean age: 25.75±1.91; four female), the mounting-effort for reward task demonstrated good test-retest reliability (%variance: 0.20-2.61%). Seven healthy male volunteers (mean age: 31.14±5.43) completed the mounting-effort for reward task and provided both [11C]-raclopride and [11C]-(+)-PHNO PET scans to assess D2/3 receptor availability. %CS+ and %CS- were positively correlated with [11C]-raclopride binding in the dorsal striatum. %CS+, %Cs-, and %Neutral were positively correlated with [11C]-(+)-PHNO binding in the globus pallidus. Thus, increased expression of D2 receptors in the dorsal striatum, and D3 receptors in the globus pallidus, may be related to motivation for rewards. Larger positron emission tomography studies are required to formally validate the mounting-effort for reward task and replicate our pilot findings.

Levels of striatal dopamine (DA) may be positively correlated with levels of striatal glutamate (Glu). While reduced insulin sensitivity (%S) has been associated with reduced striatal DA levels in healthy non-obese persons, whether reduced %S is also associated with reduced striatal Glu levels has not yet been established. Using 1H-MRS, we measured levels of several neurometabolites in the striatum and dorsolateral prefrontal cortex (DLPFC) of seventeen healthy non-obese persons (9 female, mean age: 28.35 ± 9.53). Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. We hypothesized that %S would be positively related with levels of Glu and Glu + glutamine (Glx) in the striatum. Exploratory analyses were also conducted between other fasting markers of metabolic health and neurometabolites measured with 1H-MRS. In the right striatum, %S was positively correlated with levels of Glu (r(15) = .49, p = .04) and Glx (r(15) = .50, p = .04). In the left striatum, there was a trend positive correlation between %S and Glu (r(15) = .46, p = .06), but not Glx levels (r(15) = .20, p = .44). The relationships between %S and striatal Glu levels remained after controlling for age, sex, and BMI (right: r(12) = .73, β = .52, t = 2.55, p = .03; left: (r(12) = .63, β = .53, t = 2.25, p = .04) These preliminary findings suggest that %S may be related to markers of glutamatergic functioning in the striatum of healthy non-obese persons. These findings warrant replication in larger samples and extension into neuropsychiatric populations where altered striatal DA, Glu, and %S are implicated.

OBJECTIVE Anosognosia, or impaired illness awareness, is a common feature of Alzheimer's disease (AD) and less so of mild cognitive impairment (MCI). Importantly, anosognosia negatively influences clinical outcomes for patients and their caregivers and may predict the conversion from MCI to AD. This study aimed to examine (1) the relationship between brain glucose metabolism as measured by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and anosognosia in patients with MCI and AD and (2) the predictive utility of anosognosia in patients with MCI for later conversion to AD, even when controlling for other factors, including gender, education, apolipoprotein E e4 carrier status, dementia severity, and cognitive dysfunction. METHODS Data for 1,062 participants from the Alzheimer's Disease Neuroimaging Initiative database (2003 to August 2015) classified as having AD (n = 191) or MCI (n = 499) or as healthy comparison (HC) subjects (n = 372) were analyzed. HC participants had Mini-Mental State Examination (MMSE) scores from 24 to 30 and a Clinical Dementia Rating (CDR) of 0. MCI participants had MMSE scores from 24 to 30, a memory complaint, objective memory loss, a CDR of 0.5, absence of significant levels of impairment in other cognitive domains, and essentially preserved activities of daily living. AD participants had MMSE scores ≤ 26 and a CDR of ≥ 0.5, and met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD. Anosognosia was measured with the composite discrepancy score of the study partner and participants' scores on the Everyday Cognition scale (ECog). Bivariate correlations and multiple regression analyses were performed to assess the relationship between anosognosia and FDG-PET findings in each group. Lastly, logistic regression and receiver operating characteristic curve analyses were performed in the MCI sample to determine if anosognosia was predictive of conversion from MCI to AD. RESULTS Hypometabolism was independently associated with anosognosia in AD, particularly in the posterior cingulate cortex and right angular gyrus. Anosognosia was associated with conversion from MCI to AD within 5 years (OR = 2.74 [95% CI, 1.95 to 3.85], χ²₁ = 33.65, P < .001), even after including covariates (OR = 1.64 [95% CI, 1.12 to 2.40], χ²₁ = 6.43, P = .011). ECog-composite scores ≤ -0.75 were 93% sensitive and 15% specific for conversion from MCI to AD. CONCLUSIONS Anosognosia in AD is related to brain glucose hypometabolism. Further, anosognosia independently predicts conversion from MCI to AD. The absence of anosognosia may be clinically useful to identify those patients that are unlikely to convert from MCI to AD.

The clinical and structural trajectories of suspected non-Alzheimer' pathology (SNAP) remain elusive due to its heterogeneous etiology. Baseline and longitudinal clinical (global cognition, daily functioning, symptoms of dementia, and learning memory) and hippocampal volume trajectories over two years were compared between patients with amnestic mild cognitive impairment (aMCI) with SNAP with reduced hippocampal volumes (SNAP+HIPPO) and aMCI patients with SNAP without reduced hippocampal volumes. SNAP+HIPPO showed overall worse baseline cognitive functions. Longitudinally, SNAP+HIPPO showed faster deterioration of clinical symptoms of dementia. Having both hippocampal atrophy and cortical hypometabolism without amyloid pathology may exacerbate symptoms of dementia in aMCI.

Impulsivity is considered a vulnerability trait for addiction. Recently, we found trait non-planning impulsiveness measured with the Karolinska Scales of Personality was negatively correlated with dopamine D2/3 receptor availability in the ventral striatum of healthy humans. While also observed in rodents, human studies have failed to find this association with other measures of trait impulsivity. We explored whether another rodent finding, reduced ventral striatum volume with greater impulsivity, could also be observed in humans using this scale. Non-planning impulsiveness was measured in 52 healthy subjects (21 female; mean age: 33.06 ± 9.69) using the Karolinska Scales of Personality. Striatal subregion volumes, including the globus pallidus, were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Although failing to support our a priori hypothesis, there was a significant sex interaction in the post-commissural putamen with impulsiveness. Exploratory analyses revealed impulsiveness was negatively correlated with post-commissural putamen volumes in males, but positively correlated in females. We replicated this finding in males in an increased sample (including all 52 previous subjects) who provided impulsiveness measured by the Temperament and Character Inventory (n = 73; 32 female; mean age: 33.48 ± 9.75). These correlations by sex were statistically different from one another, the main finding with the Kasolinksa Scales of Personality surviving correction for multiple comparisons. While impulsivity may be related to reduced ventral striatal D2/3 receptors across sexes, males but not females may show significant reductions in post-commissural putamen volume. These findings have important implications for understanding biological markers underlying sex differences in drug addiction vulnerability.