Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment.

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.

Dynamic change in genome-wide methylation in response to increased suicidal ideation in schizophrenia spectrum disorders.

Suicide is a significant public health crisis, with 800,000 people dying annually. Most people completing suicide have previous psychiatric conditions, and those with psychotic and mood disorders are particularly vulnerable. Unfortunately, there are currently no biomarkers available for accurately detecting suicidal ideation. Given the genetic and environmental factors that play a role in suicidal ideation, we attempted to determine epigenetic modifications, specifically DNA methylation, in response to changes in suicidal ideation. Using a longitudinal study design, 31 participants with schizophrenia spectrum disorders were interviewed at a baseline visit and again at a follow-up visit 3-12 months later. Current suicidal ideation was recorded at both visits with the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicide Ideation, and whole blood was collected for methylation analysis. Our analysis shows a significant negative correlation between cg26910920 methylation and increasing Columbia Suicide Severity Rating Scale scores and a positive correlation between cg13673029 methylation and increasing Beck Scale for Suicide Ideation scores. This pilot study indicates that there is  the possibility  that DNA methylation can respond to changes in suicidal ideation over time and potentially be used as a biomarker of suicidal ideation in the future.

Genome-wide methylation analysis of treatment resistant schizophrenia.

Various studies have investigated the relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and treatment resistance schizophrenia. The primary aim of this pilot study is to investigate the association between treatment resistance status and genome-wide DNA methylation in schizophrenia patients. Treatment resistance status was determined for 109 patients with schizophrenia. Treatment resistance was the primary outcome variable in a model, including methylation status of white blood cells using the Illumina 450 array. The genome-wide DNA methylation levels in 109 Schizophrenia subjects did not show that DNA methylation sties were associated with resistance status. From our study, it is evident the importance of continuing to investigate the relationship between DNA methylation and antipsychotic response to personalize treatment in schizophrenia. Future studies require larger prescription databases to build on the results presented in this pilot study.

Copy Number Variation Analysis of Aggressive Behaviour in Schizophrenia.

INTRODUCTION: An increased proclivity towards violence is often associated with those diagnosed with schizophrenia (SCZ), despite contradictory findings from prior studies exploring the association between violence and SCZ. Evidence has shown that certain comorbidities, specifically the presence of a substance use disorders, can result in increased aggression in those with SCZ. Copy number variation (CNV) load has also previously been implicated in the genetic vulnerability of individuals with SCZ. For this study, we aimed to determine whether CNV load correlates with increased violence in SCZ. METHODS: Community-dwelling patients diagnosed with SCZ spectrum disorders (n = 203) were recruited from a non-forensic population. The assessment for aggression was completed using a cross-sectional and retrospective design, and CNV analysis was conducted analysing genomic DNA using the Illumina Omni 2.5 array. RESULTS: No correlation between the number of CNV events (either deletion or duplication) and the severity of the physical violence episode index was found. However, there was a significant association between larger deletion events across the violent behaviours under investigation. DISCUSSION: These results need to be confirmed in more extensive studies using standardized tools developed for non-forensic populations, such as the Brown-Goodwin Scale of Aggression.

GWAS of biological aging to find longevity genes in schizophrenia.

Schizophrenia (SCZ) is a severe psychotic disorder associated with premature mortality and aging. Moreover, the symptoms and progression of psychiatric disorders in general are associated with decreased lifespan, biological aging, and poorer medical outcomes. In this study, we investigated the relationship between several epigenetic clocks and scanned the entire genome for association in a cohort of SCZ individuals (n = 107). Biological age was computed from blood DNA methylation (DNAm) and tested for association against  common  variants across the genome using general linear models. Genes affecting epigenetic age acceleration in our cohort were found mainly when using the telomeric length clock rather than the other biological clocks. These findings pair with existing evidence that there are some genes associated with longevity and suggest further investigations of  putative biological mechanisms for morbidity and premature mortality, not only in patients with SCZ but also in the general population.

Decreased cortical gyrification and surface area in the left medial parietal cortex in patients with treatment-resistant and ultratreatment-resistant schizophrenia.

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

Sex differences in schizophrenia: a longitudinal methylome analysis.

DNA methylation analysis at the genome-wide level is a useful tool to explore potential sex differences in SCZ patients. The primary aim of the current study was to identify differentially methylated regions of DNA between males and females with schizophrenia. We collected DNA samples from 134 schizophrenia patients to measure genome-wide methylation at single-base resolution in 96 males and 38 females. We further repeated the analysis in 13 subjects (9 females, 4 males) to confirm the sex differences and to reduce the effect of potential confounders. The longitudinal methylation analysis found significant replication of several genes across the genome. These genes included RFTN1, TLE1, DAZL, PRR4, UTP14C, RNU12, and LOC644649. The overall results showed robust association between autosomal CpG sites and sex. Longitudinal methylation analysis can be used as internal replication to confirm epigenetic variants that are stable over time.

MAP Bayesian modelling combining striatal dopamine receptor occupancy and plasma concentrations to optimize antipsychotic dose regimens in individual patients.

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

Metformin for the prevention of clozapine-induced weight gain: A retrospective naturalistic cohort study.

OBJECTIVE: Clozapine is presently the sole antipsychotic with an indication for treatment-resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine-induced weight gain. METHODS: We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes. RESULTS: Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine-only group at 6 months (clozapine+metformin: -0.15 kg [SE = 1.08] vs. clozapine-only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: -0.67 kg, SE = 1.22 vs. clozapine-only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only. CONCLUSION: In this large retrospective naturalistic cohort study, co-prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine-induced weight gain; larger randomized controlled trials are needed to confirm these results.

A Measure of Illness Awareness in Individuals With Nicotine Dependence-Nicotine Use Awareness and Insight Scale.

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 unrelated to subjective happiness, success, and life satisfaction in schizophrenia.

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

Epigenetics for Drug Discovery: Dissecting the Effect of High Antipsychotic Dosage and D2 Blockage on Peripheral DNA Methylation.

INTRODUCTION: The relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug receptors has been often investigated. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and antipsychotic dosage. The primary aim of this pilot study was to investigate the association between antipsychotic dosage and genome-wide DNA methylation in patients with schizophrenia (SCZ). METHODS: Current dosage of antipsychotic medications was assessed in 136 patients with SCZ. Dosage was standardized using three different methods: chlorpromazine equivalent dose (CPZe), defined daily dose (DDD), and percentage of Lexicomp maximum dose (PM%). DNA methylation was measured in white blood cells. Antipsychotic dosage was the primary outcome variable in a model, including genome-wide methylation status as the main predictor. RESULTS: This study did not show any association between DNA methylation and dosage variation for CPZe, PM%, and DDD. However, the probe cg271403389 was consistently associated with antipsychotic dosage across the three standardization methods. When looking at the genomic location of the most significant probes, we found that 15% were intergenic, 23% were in the distal promoter, 9% in the 3'untranslated region, 32% in the gene body, 3% in the 5' untranslated region, 15% in the proximal promoter, and 3% in the first exon. DISCUSSION: This study shows the importance of investigating the relationship between DNA methylation and optimal antipsychotic dosage to personalize treatment in SCZ. Future studies require larger prescription databases to build on the results of this analysis.

Impact of standardizing care for agitation in dementia using an integrated care pathway on an inpatient geriatric psychiatry unit.

OBJECTIVES: This study examined the effectiveness of an integrated care pathway (ICP), including a medication algorithm, to treat agitation associated with dementia. DESIGN: Analyses of data (both prospective and retrospective) collected during routine clinical care. SETTING: Geriatric Psychiatry Inpatient Unit. PARTICIPANTS: Patients with agitation associated with dementia (n = 28) who were treated as part of the implementation of the ICP and those who received treatment-as-usual (TAU) (n = 28) on the same inpatient unit before the implementation of the ICP. Two control groups of patients without dementia treated on the same unit contemporaneously to the TAU (n = 17) and ICP groups (n = 36) were included to account for any secular trends. INTERVENTION: ICP. MEASUREMENTS: Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory Questionnaire (NPIQ), and assessment of motor symptoms were completed during the ICP implementation. Chart review was used to obtain length of inpatient stay and rates of psychotropic polypharmacy. RESULTS: Patients in the ICP group experienced a reduction in their scores on the CMAI and NPIQ and no changes in motor symptoms. Compared to the TAU group, the ICP group had a higher chance of an earlier discharge from hospital, a lower rate of psychotropic polypharmacy, and a lower chance of having a fall during hospital stay. In contrast, these outcomes did not differ between the two control groups. CONCLUSIONS: These preliminary results suggest that an ICP can be used effectively to treat agitation associated with dementia in inpatients. A larger randomized study is needed to confirm these results.

Recent Stressful Life Events and Suicidal Ideation in Schizophrenia: A 1-Year Follow-up Study.

ABSTRACT: Half of patients with schizophrenia experience suicidal ideation. Only few studies have examined the effects of recent stress on both current and emergent suicidal ideation.A cohort of 85 patients with schizophrenia spectrum disorders was assessed. The study was divided into a cross-sectional and longitudinal arms to test the effect of recent stress on suicidal ideation. Analysis was done using logistic regression models.After correcting for covariates, recent stress had no significant effect on current suicidal ideation. However, increased total stress (odds ratio [OR] = 1.099 [1.032-1.170], p = 0.003) and health-related stress (OR = 1.331 [1.074-1.650], p = 0.009) at follow-up were predictive of emergent suicidal ideation.With this sample size, we were unable to draw firm conclusions regarding the effect of specific life events on suicidal ideation. Further studies involving larger samples that investigate the interplay between several risk factors are needed.

Gamma-aminobutyric acid (GABA) levels in the midcingulate cortex and clozapine response in patients with treatment-resistant schizophrenia: A proton magnetic resonance spectroscopy (1 H-MRS) study.

BACKGROUND: Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment-resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy (1 H-MRS), and clozapine response in patients with TRS. METHODS: This study enrolled patients with TRS who did not respond to clozapine (ultra-resistant schizophrenia: URS) and who responded to clozapine (non-URS), patients with schizophrenia who responded to first-line antipsychotics (first-line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1 H-MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups. RESULTS: A total of 98 participants (URS: n = 22; non-URS: n = 25; FLR: n = 16; HCs: n = 35) completed the study. We found overall group differences in MCC GABA levels (F(3,86) = 3.25, P = 0.04). Specifically, patients with URS showed higher GABA levels compared to those with non-URS (F(1,52) = 8.40, P = 0.03, Cohen's d = 0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group. CONCLUSION: Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance.

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.

Anti-vaccination attitudes are associated with less analytical and more intuitive reasoning.

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

Measuring amphetamine-induced dopamine release in humans: A comparative meta-analysis of [11 C]-raclopride and [11 C]-(+)-PHNO studies.

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.

Structural Brain Differences Between Cognitively Impaired Patients With and Without Apathy.

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

Chromosome 22 Deletions and Suicidal Behavior in Schizophrenia.

BACKGROUND: Studies have shown that the overall copy number variant (CNV) load is associated with schizophrenia. Schizophrenia is a mental disorder that is frequently associated with suicidal behavior. METHODS: We recruited 263 patients with schizophrenia from the Centre for Addiction and Mental Health. The Columbia Suicide Severity Rating Scale was used to assess the presence of lifetime suicide attempt. Genotyping was completed using the Illumina Omni 2.5 chip. We tested the association between deletion events on chromosome 22 with suicide attempt in our schizophrenia sample. RESULTS: There was no significant difference between suicide attempters and non-attempters considering the presence/absence of deletion events on chromosome 22. CONCLUSION: Although our results did not show a significant association between deletions on chromosome 22 and suicide attempt in schizophrenia, CNV studies may reveal important, novel insights and open further investigation for the treatment of neuropsychiatric diseases.