Attention-Deficit/Hyperactivity Disorder as a Potential Risk Factor for Dementia and Other Neurocognitive Disorders: A Systematic Review.

Background: Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition now recognized to persist into older adulthood, has been postulated to be a risk factor for neurocognitive disorders given the overlap in clinical features and neurobiology, as well as the complex interplay between ADHD and known risk factors for dementia. Studies have emerged assessing this relationship, but there has not yet been a comprehensive systematic review addressing this topic. Objective: To assess whether ADHD is a risk factor for neurocognitive disorders and to explore possible mechanisms for such an association. Methods: A systematic review of the literature was conducted using Medline, Embase, and PsycINFO from inception until June 4, 2023. Studies were included if they assessed whether or how ADHD may be a risk factor for neurocognitive disorders. Studies were excluded if they were not primary literature, not published in a peer-reviewed journal, not in English, and/or used non-human subjects. Study quality was assessed using the QualSyst tool. Results: Sixteen studies met inclusion criteria. Seven studies found a positive association between ADHD and neurocognitive disorders (all-cause dementia in four studies, Alzheimer's disease in three studies, Lewy body dementia in two studies, and mild cognitive impairment in one study). Four studies did not find an association. Five studies pertained to possible mechanisms for an association, including genetics, with minimal significant findings. Conclusions: ADHD may be a risk factor for certain neurocognitive disorders, although the evidence base is limited, and the absolute risk is small. Possible explanations include genetic and lifestyle factors.

Estimating Lithium Concentrations in Groundwater Used as Drinking Water for the Conterminous United States.

Lithium (Li) concentrations in drinking-water supplies are not regulated in the United States; however, Li is included in the 2022 U.S. Environmental Protection Agency list of unregulated contaminants for monitoring by public water systems. Li is used pharmaceutically to treat bipolar disorder, and studies have linked its occurrence in drinking water to human-health outcomes. An extreme gradient boosting model was developed to estimate geogenic Li in drinking-water supply wells throughout the conterminous United States. The model was trained using Li measurements from ∼13,500 wells and predictor variables related to its natural occurrence in groundwater. The model predicts the probability of Li in four concentration classifications, ≤4 µg/L, >4 to ≤10 µg/L, >10 to ≤30 µg/L, and >30 µg/L. Model predictions were evaluated using wells held out from model training and with new data and have an accuracy of 47-65%. Important predictor variables include average annual precipitation, well depth, and soil geochemistry. Model predictions were mapped at a spatial resolution of 1 km2 and represent well depths associated with public- and private-supply wells. This model was developed by hydrologists and public-health researchers to estimate Li exposure from drinking water and compare to national-scale human-health data for a better understanding of dose-response to low (<30 µg/L) concentrations of Li.

Cortical thinning in relation to impaired insight into illness in patients with treatment resistant schizophrenia.

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.

COVID-19 behavior determinants dataset.

The COVID-19 Behavior Determinants Database (http://covid19-database.com) is a research project that examined the sociodemographic and psychological determinants of COVID-19 related attitudes and behaviors. It is a comprehensive web-based survey that was administered to adults ages 18 or older (total n=8070) from the United States of America (n = 5326), including the four most populous states, specifically New York, California, Florida, and Texas, and Canada (n = 2744), including all provinces, except Quebec. The survey was collected at three timepoints, May 2020 (n=1019), July 2020 (n=4027), and March 2021 (n=3024). Participants provided detailed sociodemographic information and completed a battery of psychological assessments. Participants also provided information about prior testing for COVID-19 and perceived seriousness of COVID-19 and the need for current physical (social) distancing restrictions. The database is helpful to researchers and public health policy decision-makers who are interested in investigating and identifying the determinants of COVID-19 related attitudes and behaviors in North America.

Protocol for a systematic review of interventions targeting mental health, cognition or psychological well-being among individuals with long COVID.

INTRODUCTION: For some people, COVID-19 infection leads to negative health impacts that can last into the medium or long term. The long-term sequelae of COVID-19 infection, or 'long COVID', negatively affects not only physical health, but also mental health, cognition or psychological well-being. Complex, integrated interventions are recommended for long COVID, including psychological components; however, the effectiveness of such interventions has yet to be critically evaluated. This protocol describes a systematic review to be conducted of scientific literature reporting on clinical trials of interventions to promote mental health, cognition or psychological well-being among individuals with long COVID. METHODS AND ANALYSIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. A health sciences librarian will identify the relevant literature through comprehensive systematic searches of Medline, Embase, APA PsycINFO, Cumulative Index to Nursing and Allied Health Literature, medRxiv, PsyArXiv, China National Knowledge Internet and WANFANG Data databases, as well as The Cochrane Central Register of Controlled Trials, clinicaltrials.gov and the WHO International Clinical Trials Registry Platform. Studies will be selected through a title and abstract review, followed by a full-text review using inclusion and exclusion criteria. Data extracted will include intervention descriptions and efficacy metrics. Data will be narratively synthesised; if the data allow, a meta-analysis will be conducted. Risk of bias assessment will be conducted using the Cochrane Risk of Bias 2.0 tool. ETHICS AND DISSEMINATION: Ethical approval for systematic reviews is not required. As researchers and clinicians respond to the new clinical entity that long COVID represents, this review will synthesise a rapidly emerging evidence base describing and testing interventions to promote mental health, cognition or psychological well-being. Results will therefore be disseminated through an open-access peer-reviewed publication and conference presentations to inform research and clinical practice. PROSPERO REGISTRATION NUMBER: CRD42022318678.

Determinants of social distancing adherence.

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 [ß (SE) = 0.39 (0.01), p < 0.001, partial η2 = 0.22], lower risk propensity [ß (SE) = -0.15 (0.01), p < 0.001, partial η2 = 0.06], germ aversion [ß (SE) = 0.12 (0.01), p < 0.001, partial η2 = 0.03], age [ß (SE) = 0.01 (0.00), p < 0.001, partial η2 = 0.02], and greater social support [ß (SE) = 0.03 (0.00), p < 0.001, partial η2 = 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.

Vaccine Hesitancy Is a Barrier to Achieving Equitable Herd Immunity Among Racial Minorities.

Introduction: Racial minority groups have been disproportionately affected by the 2019 novel coronavirus disease (COVID-19). Vaccine hesitancy may be a major barrier to achieving equitable herd immunity and must be addressed to reduce the excess morbidity and mortality of COVID-19 in disproportionately affected communities. This study aimed to determine if COVID-19 vaccine hesitancy, and its factors vaccine complacency and confidence, are more prominent among disproportionately affected racial minority groups. Methods:We collected data from participants aged 18 years or older from the four most populous U.S. states, including New York, California, Florida, and Texas, and Canada. Data were collected using a web-based survey platform. Data are available at http://www.covid19-database.com. Results:Data from 4,434 participants were included [mean (SD) age = 48.7 (17.2) and 50.4% women]. Vaccine hesitancy was higher in Black, Indigenous (Native American and Indigenous People of Canada, including First Nations, Inuit and Métis), and Latinx compared to White participants, while no difference was found between East Asian and White participants. The group differences in vaccine hesitancy for Indigenous and Black compared to White participants remained after controlling for sociodemographic factors. Determinants of vaccine complacency were equivalent between disproportionately affected racial groups and white participants. Vaccine confidence (i.e., trust in vaccine benefit) was generally lower in all racial groups compared to White participants. Differences in vaccine mistrust comparing Black and East Asian to White participants remained after controlling for sociodemographic factors. Discussion:Disproportionately affected racial minorities may have higher vaccine hesitancy and lower confidence in COVID-19 vaccines. Public health and other relevant government services should address vaccine hesitancy among racial minorities using a culturally sensitive, community-centered approach to attain equitable herd immunity.

Individual determinants of COVID-19 vaccine hesitancy.

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 (ß(SE) = 0.67(0.01), p<0.001, partial η2 = 0.26) and lower perceived seriousness of COVID-19 (ß(SE) = 0.68(0.02), p<0.001, partial η2 = 0.12) were the principal determinants of vaccine hesitancy. Right-wing political affiliation (ß(SE) = 0.32(0.02), p<0.001, partial η2 = 0.03), higher risk propensity (ß(SE) = 0.24(0.02), p<0.001, partial η2 = 0.03), and less negative mental health effects of the COVID-19 pandemic (ß(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.

Effectively Caring for Individuals With Behavioral and Psychological Symptoms of Dementia During the COVID-19 Pandemic.

The COVID-19 pandemic has significantly affected the elderly and particularly individuals with Alzheimer's disease and related disorders (ADRD). Behavioral and psychological symptoms of dementia (BPSD) are heterogeneous and common in individuals with ADRD and are associated with more severe illness. However, unlike the cognitive symptoms of ADRD that are usually progressive, BPSD may be treatable. Individuals with BPSD are facing unique challenges during the pandemic due to the inherent nature of the illness and the biological and psychosocial impacts of COVID-19. These challenges include a higher risk of severe COVID-19 infection in individuals with BPSD due to their frailty and medical vulnerability, difficulty participating in screening or testing, and adhering to infection control measures such as physical distancing. Further, biological effects of COVID-19 on the brain and its psychosocial impact such as isolation and disruption in mental health care are likely to worsen BPSD. In this paper, we discuss these challenges and strategies to manage the impact of COVID-19 and to effectively care for individuals with BPSD in community, long-term care, or hospital settings during the pandemic. Despite the ongoing uncertainty associated with this pandemic, we can reduce its impact on individuals with BPSD with a proactive approach.

Anticipating and Mitigating the Impact of the COVID-19 Pandemic on Alzheimer's Disease and Related Dementias.

The COVID-19 pandemic is causing global morbidity and mortality, straining health systems, and disrupting society, putting individuals with Alzheimer's disease and related dementias (ADRD) at risk of significant harm. In this Special Article, we examine the current and expected impact of the pandemic on individuals with ADRD. We discuss and propose mitigation strategies for: the risk of COVID-19 infection and its associated morbidity and mortality for individuals with ADRD; the impact of COVID-19 on the diagnosis and clinical management of ADRD; consequences of societal responses to COVID-19 in different ADRD care settings; the effect of COVID-19 on caregivers and physicians of individuals with ADRD; mental hygiene, trauma, and stigma in the time of COVID-19; and the potential impact of COVID-19 on ADRD research. Amid considerable uncertainty, we may be able to prevent or reduce the harm of the COVID-19 pandemic and its consequences for individuals with ADRD and their caregivers.

Glutamatergic neurometabolites and cortical thickness in treatment-resistant schizophrenia: Implications for glutamate-mediated excitotoxicity.

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.

Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study.

Although clozapine is the main antipsychotic medication for treatment-resistant schizophrenia, 40-70% of patients on clozapine have persistent psychotic symptoms (i.e. ultra-treatment-resistant schizophrenia, UTRS). We aimed to examine clozapine response/non-response patterns in patients with treatment-resistant schizophrenia, as well as determine patient clinico-demographic factors associated with long-term clozapine non-response. Clinico-demographic characteristics of 241 patients on clozapine were collected through a retrospective chart review. The median (interquartile range, IQR) follow-up from illness onset was 25.0 (IQR = 24.0) years. Clozapine response was assessed at median 10.8 (IQR = 14.0) months (Time 1, T1) and 7.2 (IQR = 13.5) years (Time 2, T2) after its initiation. It was evaluated by chart reviewers based on the information provided in clinical notes. Binomial logistic regression was used to determine clinico-demographic factors associated with clozapine non-response at both T1 and T2 (i.e. stable UTRS, S-UTRS) compared to clozapine response at both times (i.e. stable clozapine responders, S-ClozResp). Among clozapine responders (n = 122) at T1, 83.6% remained clozapine responsive and 16.4% became non-responsive at T2. In the UTRS group (n = 119) at T1, 87.4% remained clozapine non-responsive and 12.6% became responsive at T2. Duration of delay in clozapine initiation (OR = 0.94, Wald χ2 = 5.33, p = 0.021) and number of pre-clozapine hospitalizations (OR = 0.95, Wald χ2 = 5.20, p = 0.023) were associated with S-UTRS. Most UTRS patients were non-responsive to clozapine from the start of treatment. Preventing delay in initiating clozapine and relapses could help promote long-term clozapine response in patients with treatment-resistant schizophrenia. Future longitudinal studies are required to explore the neuropathological correlates of relapses and delay in clozapine initiation.

Resting-state functional connectivity in treatment response and resistance in schizophrenia: A systematic review.

BACKGROUND: Treatment-resistant schizophrenia (TRS) and treatment-responsive schizophrenia may exhibit distinct pathophysiology. Several functional magnetic resonance imaging (fMRI) studies have used resting-state functional connectivity analyses (rs-FC) in TRS patients to identify markers of treatment resistance. However, to date, existing findings have not been systematically evaluated. METHODS: A systematic literature search using Embase, MEDLINE, PsycINFO, ProQuest, PUBMED, and Scopus was performed. The query sought fMRI articles investigating rs-FC in treatment response or resistance in patients with schizophrenia. Only studies that examined treatment response, operationalized as the explicit categorization of patients by their response to antipsychotic medication, were considered eligible. Pairwise comparisons between patient groups and controls were extracted from each study. RESULTS: The search query identified 159 records. Ten studies met inclusion criteria. Five studies examined not TRS (NTRS), and 8 studies examined TRS. Differences in rs-FC analysis methodology precluded direct comparisons between studies. However, disruptions in areas involved in visual and auditory information processing were implicated in both patients with TRS and NTRS. Changes in connectivity with sensorimotor network areas tended to appear in the context of TRS but not NTRS. Moreover, there was some indication that this connectivity could be affected by clozapine. CONCLUSIONS: Functional connectivity may provide clinically meaningful biomarkers of treatment response and resistance in schizophrenia. Studies generally identified similar areas of disruption, though methodological differences largely precluded direct comparison between disruption effects. Implementing data sharing as standard practice will allow future reviews and meta-analyses to identify rs-FC correlates of TRS.

Brain Amyloid PET Tracer Delivery is Related to White Matter Integrity in Patients with Mild Cognitive Impairment.

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.

Lead (Pb) in Alzheimer's Dementia: A Systematic Review of Human Case- Control Studies.

BACKGROUND: Alzheimer's Dementia (AD) has a complex pathophysiology that is incompletely understood. Chronic, low-level environmental lead (Pb) exposure is associated with cognitive impairment, hypertension and mortality, and has been proposed as a potential cause of AD. OBJECTIVE: We aimed to review the literature to clarify the potential role of Pb in AD and to guide future research. METHODS: Through a series of systematic reviews, we identified case-control studies comparing AD to controls on 6 measures of Pb exposure or accumulation: blood, bone, cerebrospinal fluid, hair/nail, postmortem pathology, and urine. We completed meta-analyses where possible. RESULTS: The number of identified case-control studies of AD, by measurement method, was: 15 by blood, 0 by bone, 5 by Cerebrospinal Fluid (CSF), 3 by hair/nail, 3 by postmortem, and 1 by urine. Two meta-analyses were possible for 7 studies reporting whole blood Pb and for 8 studies of serum Pb. Both were negative. The largest study of CSF Pb showed lower levels in AD. Similarly, lower hair Pb levels were found in AD. CONCLUSION: The available case-control studies are insufficient to draw conclusions on the role of Pb in AD. Most methods do not address long-term or early-life exposure. The preferred measure of chronic Pb is in bone, which has not been utilized in case-control AD studies. Future research should measure bone Pb in AD, together with other biomarkers, such as amyloid and tau imaging, and markers of cerebrovascular pathology.

Alterations in body mass index and waist-to-hip ratio in never and minimally treated patients with psychosis: A systematic review and meta-analysis.

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.

The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: A systematic review.

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.

Psychiatric benefits of lithium in water supplies may be due to protection from the neurotoxicity of lead exposure.

INTRODUCTION: Lithium is a medication used to treat bipolar disorder and may also prevent cognitive decline and suicide. Lithium is also found naturally, in levels well below clinical doses, in drinking water worldwide, and levels have been inversely associated with rates of psychiatric disorders. Lead (Pb) is another element in the environment but is a toxin of public health concern. Negative effects of chronic lead exposure and possible benefits of environmental lithium exposure appear complementary. HYPOTHESIS: Exposure to environmental lithium has associated benefits, which may be due to the mitigation of lead toxicity by lithium. METHODS: A series of reviews tested each element of the hypothesis. A systematic review clarified the psychiatric and medical correlates of lithium in drinking water. Non-systematic reviews clarified the harms of environmental lead, summarized experimental studies of lithium used to prevent lead toxicity, and explored overlapping biological mechanisms in lithium and lead exposure. RESULTS: Higher levels of lithium in drinking water were associated with lower suicide rates in 13 of 15 identified studies. While fewer studies were available for other outcomes, lithium was associated with lower rates of homicide, crime, dementia, and mortality. Lead was reported to be ubiquitous in the environment, and chronic low-level exposure has been associated with adverse effects, including effects opposite to the outcomes associated with lithium. Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity. Neurophysiological correlates of lead and lithium exposure overlap. CONCLUSIONS: Microdose lithium is associated with better psychiatric and medical outcomes, which are complementary to harms of environmental lead exposure. Experimental animal evidence is supportive, and lead and lithium impact overlapping neurophysiologic pathways. Therefore, several lines of circumstantial evidence suggest that lithium protects against the neurotoxic effects of lead. Further studies are required to clarify the benefits and mechanisms of low-dose lithium. There are significant public health implications if this paper's hypothesis is true.