Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

OBJECTIVES: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. METHODS: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. RESULTS: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. CONCLUSION: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

An Analysis of Motivating Factors in 1,725 Worldwide Cases of Mass Murder Between 1900-2019.

Mass murder, particularly mass shootings, constitutes a major, growing public health concern. Specific motivations for these acts are not well understood, often overattributed to severe mental illness. Identifying diverse factors motivating mass murders may facilitate prevention. We examined 1,725 global mass murders from 1900-2019, publicly described in English in print or online. We empirically categorized each into one of ten categories reflecting reported primary motivating factors, which were analyzed across mass murderers generally, as well as between U.S- and non-U.S.-based mass-shooters. Psychosis or disorganization related to mental illness were infrequently motivational factors (166; 9.6%), and were significantly more associated with mass murder committed using methods other than firearms. The vast majority (998, 57.86%) of incidents were impulsive and emotionally-driven, following adverse life circumstances. Most mass murderers prompted by emotional upset were found to be driven by despair or extreme sadness over life events (161, 16.13% within the category); romantic rejection or loss, or severe jealousy (204, 20.44% within the category); some specific non-romantic grudge (212, 21.24% within the category); or explosive, overwhelming rage following a dispute (266, 26.65% within the category). Results suggest that policies seeking to prevent mass murder should focus on criminal history, as well as subacute emotional disturbances not associated with severe mental illness in individuals with poor coping skills who have recently experienced negative life events.

Illness Phase as a Key Assessment and Intervention Window for Psychosis.

The phenotype of schizophrenia, regardless of etiology, represents the most studied psychotic disorder with respect to neurobiology and distinct phases of illness. The early phase of illness represents a unique opportunity to provide effective and individualized interventions that can alter illness trajectories. Developmental age and illness stage, including temporal variation in neurobiology, can be targeted to develop phase-specific clinical assessment, biomarkers, and interventions. We review an earlier model whereby an initial glutamate signaling deficit progresses through different phases of allostatic adaptation, moving from potentially reversible functional abnormalities associated with early psychosis and working memory dysfunction, and ending with difficult-to-reverse structural changes after chronic illness. We integrate this model with evidence of dopaminergic abnormalities, including cortical D1 dysfunction, which develop during adolescence. We discuss how this model and a focus on a potential critical window of intervention in the early stages of schizophrenia impact the approach to research design and clinical care. This impact includes stage-specific considerations for symptom assessment as well as genetic, cognitive, and neurophysiological biomarkers. We examine how phase-specific biomarkers of illness phase and brain development can be incorporated into current strategies for large-scale research and clinical programs implementing coordinated specialty care. We highlight working memory and D1 dysfunction as early treatment targets that can substantially affect functional outcome.

Polygenic risk scores analyses of psychiatric and metabolic traits with antipsychotic-induced weight gain in schizophrenia: an exploratory study.

Given the polygenic nature of antipsychotic-induced weight gain (AIWG), we investigated whether polygenic risk scores (PRS) for various psychiatric and metabolic traits were associated with AIWG. We included individuals with schizophrenia (SCZ) of European ancestry from two cohorts (N = 151, age = 40.3 ± 11.8 and N = 138, age = 36.5 ± 10.8). We investigated associations of AIWG defined as binary and continuous variables with PRS calculated from genome-wide association studies of body mass index (BMI), coronary artery disease (CAD), fasting glucose, fasting insulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, type 1 and 2 diabetes mellitus, and SCZ, using regression models. We observed nominal associations (uncorrected p < 0.05) between PRSs for BMI, CAD, and LDL-C, type 1 diabetes, and SCZ with AIWG. While results became non-significant after correction for multiple testing, these preliminary results suggest that PRS analyses might contribute to identifying risk factors of AIWG and might help to elucidate mechanisms at play in AIWG.

Increased parietal and occipital lobe gyrification predicts conversion to syndromal psychosis in a clinical high-risk cohort.

BACKGROUND: Local gyrification index (lGI), indicative of the degree of cortical folding is a proxy marker for early cortical neurodevelopmental abnormalities. We studied the difference in lGI between those who do and do not convert to psychosis (non-converters) in a clinical high-risk (CHR) cohort, and whether lGI predicts conversion to psychosis. METHODS: Seventy-two CHR participants with attenuated positive symptom syndrome were followed up for two years. The difference in baseline whole-brain lGI was examined on the T1-weighted MRIs between, i)CHR (N = 72) and healthy controls (N = 19), ii)Converters to psychosis (N = 24) and non-converters (N = 48), adjusting for age and sex, on Freesurfer-6.0. The significant cluster obtained in the converters versus non-converters comparison was registered as a region of interest to individual images of all 72 participants and lGI values were extracted from this region. A cox proportional hazards model was applied with these values to study whether lGI predicts conversion to psychosis. RESULTS: lGI was not different between CHR and healthy controls. lGI was increased in converters in the right-sided inferior parietal and lateral occipital areas (corrected cluster-wise-p-value = 0.009, cohen's f = 0.42) compared to non-converters, which significantly increased the risk of onset of psychosis (p = 0.029, hazard ratio = 1.471). CONCLUSIONS: Increased gyrification in the right-sided inferior parietal and lateral occipital area differentiates converters to psychosis in CHR, significantly increasing the risk of conversion to psychosis. This measure may reflect underlying traits in parts of the brain that develop earliest in-utero (parietal and occipital), conferring a heightened vulnerability to convert to syndromal psychosis subsequently.

Victimology of Mass Shootings and Mass Murders Not Involving Firearms.

Most research to date has focused on perpetrators of mass murder incidents. Hence, there is little information on victims. We examined 973 mass murders that occurred in the United States between 1900 and 2019 resulting in 5,273 total fatalities and 4,498 nonfatal injuries for a total of 9,771 victims (on average 10 victims per incident). Approximately 64% of victims of mass murder were White individuals, 13% were Black individuals, 6% were Asian individuals, and 14% were Latinx individuals. Given the higher number of nonfatal injuries per non-firearm mass murder event (11.0 vs. 2.8, p < .001), the total number of victims was only 50% higher for mass shootings (5,855 victims) vs. non-firearm mass murder events (3,916 victims). Among the 421 incidents of mass murder in the United States since 2000, Black, Asian, and Native American individuals were overrepresented among victims of mass shootings compared with their representation in the general U.S. population, and White individuals were underrepresented (all p ≤ .002). Findings of racial/ethnic differences were similar among victims of mass murder committed with means other than firearms for Black, Asian, and White individuals. These findings highlight different areas of victimology within the context of these incidents.

The neurobiology of duration of untreated psychosis: a comprehensive review.

Duration of untreated psychosis (DUP) is defined as the time from the onset of psychotic symptoms until the first treatment. Studies have shown that longer DUP is associated with poorer response rates to antipsychotic medications and impaired cognition, yet the neurobiologic correlates of DUP are poorly understood. Moreover, it has been hypothesized that untreated psychosis may be neurotoxic. Here, we conducted a comprehensive review of studies that have examined the neurobiology of DUP. Specifically, we included studies that evaluated DUP using a range of neurobiologic and imaging techniques and identified 83 articles that met inclusion and exclusion criteria. Overall, 27 out of the total 83 studies (32.5%) reported a significant neurobiological correlate with DUP. These results provide evidence against the notion of psychosis as structurally or functionally neurotoxic on a global scale and suggest that specific regions of the brain, such as temporal regions, may be more vulnerable to the effects of DUP. It is also possible that current methodologies lack the resolution needed to more accurately examine the effects of DUP on the brain, such as effects on synaptic density. Newer methodologies, such as MR scanners with stronger magnets, PET imaging with newer ligands capable of measuring subcellular structures (e.g., the PET ligand [11C]UCB-J) may be better able to capture these limited neuropathologic processes. Lastly, to ensure robust and replicable results, future studies of DUP should be adequately powered and specifically designed to test for the effects of DUP on localized brain structure and function with careful attention paid to potential confounds and methodological issues.

Mass murders involving firearms and other methods in school, college, and university settings: Findings from the Columbia Mass Murder Database.

While mass murders involving academic settings, especially using firearms, are of grave, growing public concern, identifying consistent patterns to aid prevention has proved challenging. Although some characteristics, such as male sex, have been routinely associated with these events, another hypothesized risk factor, severe mental illness, has been less reliably predictive. We isolated cases of mass murder perpetrated at least in part at schools, colleges, and universities from the Columbia Mass Murder Database (CMDD) and categorized them by location (within or outside of the US), and whether firearms were used. Demographic similarities and differences between groups were analyzed statistically wherever possible. We examined 82 incidents of mass murder, by any means, involving academic settings. Nearly half of all incidents (47.6%), and most involving firearms (63.2%), were U.S.-based, whereas those not involving firearms largely occurred elsewhere (88.0%). Consistent with previous reports, perpetrators of mass shootings involving academic settings are primarily Caucasian (66.7%) and male (100%). Severe mental illness (i.e., psychosis) was absent in the majority of perpetrators (firearms: 80.7%; nonfirearms: 68.0%). About half (45.6%) of mass school shootings ended with the perpetrator's suicide. When present, psychotic symptoms are more associated with mass murders in academic settings involving means other than firearms. The question of whether perpetrators of such incidents may perceive their actions as a kind of final act might enhance policy development and/or how law enforcement intervenes.

Neurodegenerative model of schizophrenia: Growing evidence to support a revisit.

Multidimensional progressive declines in the absence of standard biomarkers for neurodegeneration are observed commonly in the development of schizophrenia, and are accepted as consistent with neurodevelopmental etiological hypotheses to explain the origins of the disorder. Far less accepted is the possibility that neurodegenerative processes are involved as well, or even that key dimensions of function, such as cognition and aspects of biological integrity, such as white matter function, decline in chronic schizophrenia beyond levels associated with normal aging. We propose that recent research germane to these issues warrants a current look at the question of neurodegeneration. We propose the view that a neurodegenerative hypothesis provides a better explanation of some features of chronic schizophrenia, including accelerated aging, than is provided by neurodevelopmental hypotheses. Moreover, we suggest that neurodevelopmental influences in early life, including those that may extend to later life, do not preclude the development of neurodegenerative processes in later life, including some declines in cognitive and biological integrity. We evaluate these views by integrating recent findings in representative domains such as cognition and white and gray matter integrity with results from studies on accelerated aging, together with functional implications of neurodegeneration for our understanding of chronic schizophrenia.

High-impact rare genetic variants in severe schizophrenia.

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10-5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10-9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10-3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10-7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10-8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder.

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.

The neurobiology of auditory and visual perceptual abnormalities in a clinical high-risk for psychosis cohort: A pilot morphometric magnetic resonance imaging study.

Our goal was to examine the neurobiology of auditory and visual perceptual abnormalities in individuals at clinical high-risk for psychosis (CHR) using morphometric magnetic resonance imaging (MRI). We enrolled 72 CHR subjects as delineated by the Structured Interview for Psychosis-Risk Syndromes (SIPS). Greater severity of visual perceptual abnormalities was associated with larger volumes in all regions tested (amygdala, hippocampus, and occipital cortex), while no relationships were observed between auditory perceptual abnormalities and brain volumes. These data support findings that while perceptual abnormalities may share a central set of neurobiological mechanisms, each type may also have distinct pathogeneses.

An exploratory magnetic resonance imaging study of suicidal ideation in individuals at clinical high-risk for psychosis.

Suicide is a major cause of death in psychosis and associated with significant morbidity. Suicidal ideation (SI) is very common in those at clinical high-risk for psychosis (CHR) and predicts later suicide. Despite substantial work on the pathobiology of suicide in schizophrenia, little is known of its neurobiological underpinnings in the CHR or putatively prodromal state. Therefore, in this pilot study, we examined the neurobiology of SI in CHR individuals using structural MRI. Subjects were aged 14-30 and met criteria for the Attenuated Positive Symptom Psychosis-Risk Syndrome (APSS) delineated in the Structured Interview for Psychosis-Risk Syndromes (SIPS). Suicidality was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). Volumetric MRI scans were obtained on a 3T Phillips scanner. MRI data were available for 69 individuals (19 CHR without SI, 31 CHR with SI and 19 healthy control subjects). CHR individuals with SI had thicker middle temporal and right insular cortices than CHR individuals without SI and healthy control subjects. The location of these findings is consistent with neurobiological findings regarding suicide in syndromal psychosis. These findings underscore the potential for the use of brain imaging biomarkers of suicide risk in CHR individuals.

Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia.

BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).