Ultrafiltration in Heart Failure: A Review.

Ultrafiltration is an effective method to get rid of fluid retention and congestion in patients with acute decompensated heart failure (HF) without affecting the circulating volume. Although its efficacy in comparison to diuretics is debatable, the evaluation of our analysis is based on various studies that comprise published clinical trials on ultrafiltration and studies comparing the efficacy of diuretics and ultrafiltration. Apart from this, we also look at literature that provides shortcomings of the said procedure and its scope for future advancements. Heart failure ultimately leads to volume overload, which is a highly concerning complication. Diuretics have been used as a first-line treatment for fluid overload but are becoming inefficacious due to the development of resistance and renal dysfunction. Ultrafiltration, on the other hand, is an attractive alternative to counter volume overload and congestion, which are unresponsive to medical therapy. There is also evidence that it significantly decreases the probability of future episodes of decompensation. There are, however, disagreements about whether ultrafiltration is an effective method to improve mortality in these patients. There is a lack of conclusive studies demonstrating the superiority of one fluid removal method over another. Hence, it is imperative to continue searching for the most effective method to treat congestion. Priority should be given to more mechanistic studies regarding ultrafiltration.

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.

A Measure to Assess Illness Awareness in Problem Gambling: Gambling Awareness and Insight Scale (GAS).

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.

Receiving Long-Term Disability or Pursuing a Legal Claim May Prevent Recovery From Chronic Dizziness.

OBJECTIVES/HYPOTHESIS: Chronic dizziness (CD) and imbalance have multiple etiologies. CD is strongly linked with psychiatric and psychological comorbidities, thus an interdisciplinary approach, including psychopharmacological interventions, is recommended. Despite the use of this comprehensive treatment approach, the recovery of individuals with CD that pursue long-term disability (LTD) insurance or legal claims (LC) appears hampered. As such, we aimed to compare symptom recovery from CD in an interdisciplinary setting between patients receiving LTD/LC versus those who were not, and to explore the factors that may contribute to changes in symptom severity. STUDY DESIGN: Retrospective cohort study. METHODS: Dizziness-related diagnoses were extracted from the charts of 195 adults in an outpatient interdisciplinary neurotology clinic in Toronto, Canada. Patients with baseline Dizziness Handicap Inventory (DHI) and Dizziness Catastrophizing Scale (DCS) assessments between August 2012 and July 2018 and a mean follow-up visit within approximately 10 months were included. The study participants were categorized as "LTD/LC+" (n = 92) or "LTD/LC-" (n = 103), referring to either receiving or pursuing LTD/LC or not, respectively. RESULTS: There were differences in the mean percentage changes in DHI (t[187] = 3.02, P = .003) and DCS (t[179] = 2.63, P = .009) scores between LTD/LC+ and LTD/LC- patients. LTD/LC+ patients showed 8.0% and 7.6% mean increases in DHI and DCS scores, respectively, whereas LTD/LC- patients showed 21.5% and 25.9% reductions in DHI and DCS scores, respectively, controlling for age, sex, and baseline illness severity. CONCLUSIONS: Patients receiving or pursuing LTD insurance or a legal claim did not improve from CD and dizziness catastrophizing compared to those who were not. Future studies are required to test these findings prospectively and to determine the factors that may contribute to symptom recovery, including the anxiety-aggravating effects of the LTD/LC process and the deleterious consequences of developing a sick-role while afflicted with a chronic illness. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:655-661, 2022.

Glutathione Levels and Glutathione-Glutamate Correlation in Patients With Treatment-Resistant Schizophrenia.

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.

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.

DAS: The Diabetes Awareness and Insight Scale.

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.

What proportion of striatal D2 receptors are occupied by endogenous dopamine at baseline? A meta-analysis with implications for understanding antipsychotic occupancy.

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 D2 receptors (D2R) in humans in vivo. However, it is unclear what proportion of striatal D2R 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 D2R 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 D2R 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 D2R in vivo than previously acknowledged. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

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.

Insight and medication adherence in schizophrenia: An analysis of the CATIE trial.

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 (χ2(2) = 8.80, p = 0.012) and 18 months (χ2(2) = 10.04, p = 0.007) after study initiation. Moderate-to-severe insight impairment was associated with earlier nonadherence compared to minimal (χ2 = 4.70, p = 0.030) or no impairment (χ2 = 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'.

Impaired Awareness of Problem and Pathological Gambling: A Review.

Although well-recognized and clinically relevant, impaired awareness of problem and pathological gambling (IAPPG) is a poorly understood phenomenon that contributes to treatment denial and negative clinical and social outcomes. In this study, we aimed to conduct a systematic review of the measures available to assess problem gambling awareness, evaluate their psychometric properties, and determine the extent to which they cover the core domains of illness awareness: General Disorder Awareness, Symptom Attribution, Awareness of Need for Treatment, and Awareness of Negative Consequences. A systematic search using OVID database (Medline®, PsycINFO, and Embase) was performed to identify English language papers describing gambling awareness measures. We identified only 8 measures partially assessing IAPPG. Measures differed in their effectiveness and comprehensiveness in evaluating IAPPG. Most measures were principally developed to evaluate barriers or motivators to treatment-seeking among gamblers and were not specific to IAPPG. Two were psychometrically validated, but the items were not specific to the evaluation of subjective awareness of the disorder and they only covered up to two domains of IAPPG. With the development and psychometric validation of an easy-to-use, comprehensive measure of subjective IAPPG, future studies will be able to investigate the role of IAPPG in help-seeking behavior, treatment adherence, and clinical and social outcomes.

Interdisciplinary integration of nursing and psychiatry (INaP) improves dizziness-related disability.

OBJECTIVES/HYPOTHESIS: The traditional medical care model of "assess and refer" in a sequential fashion fails to recognize the complexities that arise due to overlapping physical and psychiatric comorbidities experienced by patients with chronic dizziness or imbalance, thus resulting in inadequate treatment outcomes. We aimed to evaluate the impact of a novel interdisciplinary approach to care that integrates nursing and psychiatry (INaP) on dizziness-related disability. STUDY DESIGN: Retrospective cohort study. METHODS: We compared the change in clinical assessment scores (i.e., Dizziness Handicap Inventory [DHI], Dizziness Catastrophizing Scale) at approximately 8 months follow-up between those who did (INaP+) and did not receive INaP (INaP-). Data from 229 patients with dizziness or imbalance referred to an interdisciplinary neurotology clinic in Toronto, Ontario, Canada were acquired from August 2012 to December 2016 and January 2011 to December 2013 for the INaP+ and INaP- groups, respectively. RESULTS: A mean group difference in the percentage change in DHI scores was found, with greater reductions in dizziness-related disability in the INaP+ group (n = 121) versus the INaP- group (n = 108). This remained significant after controlling for age, gender, baseline illness severity, and duration between baseline and follow-up visits. CONCLUSIONS: The novel interdisciplinary approach of incorporating INaP appears to be more effective than interdisciplinary care without INaP in reducing dizziness-related disability in patients with chronic dizziness or imbalance. Clinical settings should consider the addition of INaP to achieve better patient outcomes. Future studies are required to test the hypothesis that INaP is more efficient and cost-effective than the traditional model of care. LEVEL OF EVIDENCE: 3 Laryngoscope, 130:1800-1804, 2020.

Interdisciplinary integration of nursing and psychiatry (INaP) for the treatment of dizziness.

OBJECTIVES: The traditional medical care model of "assess and refer" requires revamping to address the multifaceted needs of patients with chronic dizziness and imbalance by adopting an interdisciplinary approach to care that integrates nursing and psychiatry (INaP). We aim to present a novel interdisciplinary approach that incorporates INaP in the care of patients with chronic dizziness and imbalance. METHODS: Presentation of an interdisciplinary model of care that incorporates INaP provided at the Toronto General Hospital in Toronto, Canada. RESULTS: Interdisciplinary care incorporating INaP, which includes the provision of support from an interdisciplinary health care team (ie, neurotologist, neurologist, psychiatrist, physiotherapist, and nurse clinician), psychoeducation about the interaction between chronic dizziness and psychiatric comorbidities, and ongoing access to medical and psychosocial assessment and intervention, addresses the physical and emotional aspects of patients' experience with chronic dizziness. CONCLUSIONS: The novel comprehensive interdisciplinary approach incorporating INaP may be more effective than interdisciplinary care without INaP in improving clinical outcomes in patients with chronic dizziness. In the subsequent study, we present data comparing patients treated for chronic dizziness and imbalance with and without the integration of INaP in an interdisciplinary setting. LEVEL OF EVIDENCE: 5 Laryngoscope, 130:1792-1799, 2020.

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.

Using digital polymerase chain reaction to characterize microbial communities in wetland mesocosm soils under different vegetation and seasonal nutrient loadings.

Constructed wetlands are multi-functional systems that can effectively store and transform pollutants primarily through natural processes. However, the removal of nitrogen pollutant by wetlands is highly variable, likely due to a combination of factors such as plant species-specific assimilation behavior, the effects of soil microbial diversity, and variable nitrogen inputs. In this study, the effects of plant species richness (i.e., number of plant species in a system) and seasonal nutrient loading (i.e., nitrogen fertilization) on the microbial community responsible for regulating nitrogen turnover in wetland mesocosm soils was investigated. Digital polymerase chain reaction was used to quantify bacterial abundance. Principal component analysis was employed to identify dominant patterns within the data, and resampling-based analysis of variance was used to assess statistical significance of any observed differences caused by fertilization, season, and/or plant species richness. Results indicated that fertilization or season, which was convolved with fertilization, was the dominant factor influencing the microbial community in the study environment. The effects of plant species richness were more nuanced. Its greater richness significantly impacted the abundance of only a subset of bacterial groups (i.e., the ammonia oxidizing bacteria, Nitrospira spp. of nitrite-oxidizing bacteria, and comammox, but not the denitrifying bacteria).

Impaired illness awareness in schizophrenia and posterior corpus callosal white matter tract integrity.

Impaired illness awareness (Imp-IA) in schizophrenia is associated with interhemispheric imbalance, resulting in left hemisphere dominance, primarily within the posterior parietal area (PPA). This may represent an interhemispheric "disconnection syndrome" between PPAs. To test this hypothesis, we aimed to determine if diffusion-based measures of white matter integrity were disrupted in the corpus callosal tracts linking PPAs (i.e., splenium) in patients with Imp-IA in schizophrenia. T1-weighted and diffusion-weighted scans were acquired on a 1.5T GE scanner for 100 participants with a DSM-IV-TR diagnosis of schizophrenia and 134 healthy controls aged 18 to 79 years. The corpus callosal white matter tracts were compared among patients with Imp-IA (n = 40), intact illness awareness (n = 60), and healthy controls. White matter disruption was measured with fractional anisotropy (FA) and mean diffusivity (MD). Group differences in FA were found in the splenium, with patients with Imp-IA having the lowest FA, which remained significant after controlling for sex, age, global cognition, and premorbid intelligence. No group differences in MD were observed. Splenial white matter tracts of the corpus callosum appear compromised in patients with Imp-IA. Transcallosal interhemispheric PPA white matter disruption may represent a "disconnection syndrome", manifesting as Imp-IA in schizophrenia. Future studies are required to investigate the effects of noninvasive brain stimulation interventions, such as transcranial direct current or magnetic stimulation, on Imp-IA in association with white matter changes in patients with schizophrenia.

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.

A meta-analysis of transcranial direct current stimulation for schizophrenia: "Is more better?"

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.

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.

Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia: A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study.

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 (F3,96 = 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.