Toxoplasma gondii infection associated with inflammasome activation and neuronal injury.

Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

Hypothalamic subunit volumes and relations to violence and psychopathy in male offenders with or without a psychotic disorder.

The hypothalamus is key to body homeostasis, including regulating cortisol, testosterone, vasopressin, and oxytocin hormones, modulating aggressive behavior. Animal studies have linked the morphology and function of the hypothalamus to aggression and affiliation, with a subregional pattern reflecting the functional division between the hypothalamic nuclei. We explored the relationship between hypothalamic subunit volumes in violent offenders with (PSY-V) and without (NPV) a psychotic disorder, and the association with psychopathy traits. 3T MRI scans (n = 628, all male 18-70 years) were obtained from PSY-V, n = 38, NPV, n = 20, non-violent psychosis patients (PSY-NV), n = 134, and healthy controls (HC), n = 436. The total hypothalamus volume and its eleven nuclei were delineated into five subunits using Freesurfer v7.3. Psychopathy traits were assessed with Psychopathy Checklist-revised (PCL-R). ANCOVAs and linear regressions were used to analyze associations with subunit volumes. Both groups with a history of violence exhibited smaller anterior-superior subunit volumes than HC (NPV Cohen's d = 0.56, p = 0.01 and PSY-V d = 0.38, p = 0.01). There were no significant differences between HC and PSY-NV. PCL-R scores were positively associated with the inferior tubular subunit on a trend level (uncorrected p = 0.045, Cohen's d = 0.04). We found distinct hypothalamic subunit volume reductions in persons with a history of violence independent of concomitant psychotic disorder but not in persons with psychosis alone. The results provide further information about the involvement of the hypothalamus in aggression, which ultimately may lead to the development of targeted treatment for the clinical and societal challenge of aggression and violent behavior.

Sex differences in autonomic adverse effects related to antipsychotic treatment and associated hormone profiles.

Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological pathways. Sex-specific regulation of relevant hormones could be involved. We investigated sex differences in autonomic adverse effects related to olanzapine, quetiapine, risperidone, and aripiprazole, and the role of hormones related to APs. Patients with severe mental disorders (N = 1318) were included and grouped based on AP monotherapy: olanzapine (N = 364), quetiapine (N = 211), risperidone (N = 102), aripiprazole (N = 138), and no AP (N = 503). Autonomic symptoms from the Udvalg for Kliniske Undersøgelser (UKU) side effect scale was analyzed with logistic regression, adjusting for age, diagnosis, and polypharmacy. Further, we analyzed associations between autonomic symptoms and hormones related to APs. We found associations between autonomic adverse effects and APs, with sex-specific risk for palpitations/tachycardia associated with hormonal changes related to APs. Results showed increased salivation associated with aripiprazole, reduced salivation with quetiapine, and nausea/vomiting and palpitations/tachycardia with olanzapine, and higher risk of nausea/vomiting, diarrhea, constipation, polyuria/polydipsia, and palpitations/tachycardia in females. Significant sex x AP interaction was found for palpitations/tachycardia, with higher risk in risperidone-treated males, which was associated with different hormone profiles of prolactin, cortisol, and insulin. Our findings implicate a role of several hormones in the sex-specific autonomic adverse effects related to APs.

Violent Offending in Males With or Without Schizophrenia: A Role for Social Cognition?

BACKGROUND AND HYPOTHESIS: Reduced social cognition has been reported in individuals who have committed interpersonal violence. It is unclear if individuals with schizophrenia and a history of violence have larger impairments than violent individuals without psychosis and non-violent individuals with schizophrenia. We examined social cognition in two groups with violent offenses, comparing their performance to non-violent individuals with schizophrenia and healthy controls. STUDY DESIGN: Two social cognitive domains were assessed in four groups: men with a schizophrenia spectrum disorder with (SSD-V, n = 27) or without (SSD-NV, n = 42) a history of violence, incarcerated men serving preventive detention sentences (V, n = 22), and healthy male controls (HC, n = 76). Theory of mind (ToM) was measured with the Movie for the Assessment of Social Cognition (MASC), body emotion perception with Emotion in Biological Motion (EmoBio) test. STUDY RESULTS: Kruskal-Wallis H-tests revealed overall group differences for social cognition. SSD-V had a global and clinically significant social cognitive impairment. V had a specific impairment, for ToM. Binary logistic regressions predicting violence category membership from social cognition and psychosis (SSD status) were conducted. The model with best fit, explaining 18%-25% of the variance, had ToM as the only predictor. CONCLUSIONS: Social cognitive impairment was present in individuals with a history of violence, with larger and more widespread impairment seen in schizophrenia. ToM predicted violence category membership, psychosis did not. The results suggest a role for social cognition in understanding interpersonal violence.

Tobacco smoking related to childhood trauma mediated by cognitive control and impulsiveness in severe mental disorders.

BACKGROUND: People with severe mental disorders (SMDs) show an increased prevalence of tobacco smoking compared to the general population. Tobacco smoking and other adult adverse health behaviors have been associated with traumatic experiences in childhood. In the present study we investigated the relationship between childhood trauma and tobacco smoking in people with SMDs, including the possible mediating role of cognitive- and personality characteristics, i.e. cognitive control, impulsiveness, affective lability and self-esteem. METHODS: Enrolled in the study were 871 participants with schizophrenia (SCZ, N = 484) and bipolar (BD, N = 387) spectrum disorders. We assessed tobacco smoking behavior (yes/no and amount), and history of childhood trauma with the Childhood Trauma Questionnaire. Data on cognitive control, impulsiveness, affective lability, and self-esteem were available in subsamples. We performed linear and logistic regressions, and conducted mediation analyses in PROCESS. All analyses were as standard adjusted for age, sex, and diagnostic group. RESULTS: Experience of one or more subtypes of childhood trauma was significantly associated with smoking tobacco in SMDs (p = 0.002). There were no significant associations between childhood trauma and amount of tobacco smoking. Cognitive control and impulsiveness were significant mediators between childhood trauma and tobacco smoking. CONCLUSIONS: These findings indicate the experience of childhood trauma as a predisposing factor for tobacco smoking in SMDs. Cognitive control and impulsiveness were suggested as mediating mechanisms, indicating the importance of considering inhibition related self-regulatory aspects in efforts to improve health behavior in individuals with SMDs and childhood trauma.

Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy.

BACKGROUND: Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. METHODS: Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. RESULTS: Impulsivity  was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. CONCLUSIONS: We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

Expression of ANK3 moderates the association between childhood trauma and affective traits in severe mental disorders.

Exposure to early life trauma increases the risk of psychopathology later in life. Here we investigated if ANK3 mRNA levels influence the relationship between childhood trauma experiences and clinical characteristics in mental disorders. A sample of 174 patients with bipolar disorder and 291 patients with schizophrenia spectrum disorder were included. Patients were diagnosed using the Structured Clinical Interview for DSM-IV, and childhood trauma was assessed using the childhood trauma questionnaire. Age at illness onset and number of psychotic and affective episodes were assessed from interview and medical records. Current depressive symptoms were measured using the calgary depression scale for schizophrenia and the inventory for depressive symptomatology. ANK3 expression was analyzed in whole blood using the Illumina HumanHT-12 v4 Expression BeadChip. Analyses were carried out with the Process adjusted for confounders. Within the total sample, patients with both high ANK3 expression and with the most severe childhood sexual abuse had more manic/hypomanic episodes and an earlier age at onset of the first episode. ANK3 mRNA levels also moderated the relationship between emotional neglect and manic/hypomanic episodes. Our results suggest that ANK3 expression levels moderate the association between specific types of childhood trauma and affective traits in mental disorders.

Psychopathy subdomains in violent offenders with and without a psychotic disorder.

BACKGROUND: Violence in psychosis has been linked to antisocial behavior and psychopathy traits. Psychopathy comprises aspects of interpersonal, affective, lifestyle, and antisocial traits which may be differently involved in violent offending by persons with psychotic disorders. We explored psychopathy subdomains among violent offenders with and without a psychotic disorder. METHODS: 46 males, with a history of severe violence, with (n = 26; age 35.85 ± 10.34 years) or without (n = 20; age 39.10 ± 11.63 years) a diagnosis of a psychotic disorder, were assessed with the Psychopathy Checklist-Revised (PCL-R). PCL-R was split into subdomains following the four-facet model. Group differences in total and subdomain scores were analyzed with a general linear model with covariates. RESULTS: Total PCL-R scores did not differ between the groups (p = 0.61, Cohen's d = 0.17). The violent offenders without psychotic disorders had higher facet 2 scores than the patient group with psychotic disorders (p = 0.029, Cohen's d = 0.77). Facet 1, 3, or 4 scores did not differ between the groups. Controlling for age did not alter the results. CONCLUSION: Patients with a psychotic disorder and a history of severe violence have lower affective psychopathy scores than violent offenders without psychotic disorders. This observation may point toward distinct underlying mechanisms for violence and may provide a target for focused treatment and prevention.

Sex-specific associations between metabolic hormones, severe mental disorders and antipsychotic treatment.

BACKGROUND: Metabolic dysregulation has been associated with severe mental disorders (SMD) and with antipsychotic (AP) treatment, but the role of sex is unknown. To identify possible sex-related processes linked to SMD and AP treatment, we investigated sex differences in associations between hormones involved in metabolic regulation in patients with SMD compared to healthy controls (HC) and AP treatment. METHODS: We included patients with SMD (N = 1753) and HC (N = 1194) and measured hormones involved in metabolic regulation (insulin, cortisol, thyroid-stimulating hormone (TSH), thyroxine, leptin, adiponectin, testosterone, sex hormone-binding globulin (SHBG), prolactin). Patients were grouped according to use of first-generation AP (N = 163), second-generation AP (N = 1087) or no use of AP (N = 503). Hormones were used one by one as dependent variables in multiple regression analyses with interactions between sex and SMD patients versus HC, and between sex and AP treatment, followed by analyses in males and females separately. RESULTS: We found significant interactions between sex and SMD patients versus HC for testosterone, SHBG and adiponectin, with significantly higher testosterone and lower adiponectin levels in females. Furthermore, we found significant interaction between sex and AP groups for TSH, testosterone and insulin, with significantly lower TSH levels in AP-treated females, and lower testosterone and higher insulin levels in AP-treated males. CONCLUSIONS: Our findings suggest sex differences in metabolic hormones related to both SMD and AP treatment, indicating sex-dependent mechanisms. Clinicians should be aware of potential sex-specific metabolic changes during AP treatment and experimental studies are warranted to clarify the underlying mechanisms.

The age of violence: Mapping brain age in psychosis and psychopathy.

Young chronological age is one of the strongest predictors for antisocial behaviour in the general population and for violent offending in individuals with psychotic disorders. An individual's age can be predicted with high accuracy using neuroimaging and machine-learning. The deviation between predicted and chronological age, i.e., brain age gap (BAG) has been suggested to reflect brain health, likely relating partly to neurodevelopmental and aging-related processes and specific disease mechanisms. Higher BAG has been demonstrated in patients with psychotic disorders. However, little is known about the brain-age in violent offenders with psychosis and the possible associations with psychopathy traits. We estimated brain-age in 782 male individuals using T1-weighted MRI scans. Three machine learning models (random forest, extreme gradient boosting with and without hyper parameter tuning) were first trained and tested on healthy controls (HC, n = 586). The obtained BAGs were compared between HC and age matched violent offenders with psychosis (PSY-V, n = 38), violent offenders without psychosis (NPV, n = 20) and non-violent psychosis patients (PSY-NV, n = 138). We ran additional comparisons between BAG of PSY-V and PSY-NV and associations with Positive and Negative Syndrome Scale (PANSS) total score as a measure of psychosis symptoms. Psychopathy traits in the violence groups were assessed with Psychopathy Checklist-revised (PCL-R) and investigated for associations with BAG. We found significantly higher BAG in PSY-V compared with HC (4.9 years, Cohen'sd = 0.87) and in PSY-NV compared with HC (2.7 years, d = 0.41). Total PCL-R scores were negatively associated with BAG in the violence groups (d = 1.17, p < 0.05). Additionally, there was a positive association between psychosis symptoms and BAG in the psychosis groups (d = 1.12, p < 0.05). While the significant BAG differences related to psychosis and not violence suggest larger BAG for psychosis, the negative associations between BAG and psychopathy suggest a complex interplay with psychopathy traits. This proof-of-concept application of brain age prediction in severe mental disorders with a history of violence and psychopathy traits should be tested and replicated in larger samples.

Composite immune marker scores associated with severe mental disorders and illness course.

Background: Low-grade inflammation has been implicated in the pathophysiology of severe mental disorders (SMDs) and a link between immune activation and clinical characteristics is suggested. However, few studies have investigated how patterns across immune markers are related to diagnosis and illness course. Methods: A total of 948 participants with a diagnosis of schizophrenia (SCZ, N = 602) or bipolar (BD, N = 346) spectrum disorder, and 814 healthy controls (HC) were included. Twenty-five immune markers comprising cell adhesion molecules (CAMs), interleukin (IL)-18-system factors, defensins, chemokines and other markers, related to neuroinflammation, blood-brain barrier (BBB) function, inflammasome activation and immune cell orchestration were analyzed. Eight immune principal component (PC) scores were constructed by PC Analysis (PCA) and applied in general linear models with diagnosis and illness course characteristics. Results: Three PC scores were significantly associated with a SCZ and/or BD diagnosis (HC reference), with largest, however small, effect sizes of scores based on CAMs, BBB markers and defensins (p < 0.001, partial η2 = 0.02-0.03). Number of psychotic episodes per year in SCZ was associated with a PC score based on IL-18 system markers and the potential neuroprotective cytokine A proliferation-inducing ligand (p = 0.006, partial η2 = 0.071). Conclusion: Analyses of composite immune markers scores identified specific patterns suggesting CAMs-mediated BBB dysregulation pathways associated with SMDs and interrelated pro-inflammatory and neuronal integrity processes associated with severity of illness course. This suggests a complex pattern of immune pathways involved in SMDs and SCZ illness course.

Interleukin-18 signaling system links to agitation in severe mental disorders.

OBJECTIVE: Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders. METHODS: Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses. RESULTS: Agitation was positively associated with IL-18BP (ß = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (ß = 0.06, t = 1.27, p = 0.20), IL-18 (ß = 0.05, t = 1.25, p = 0.21), IL-18R1 (ß = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results. CONCLUSION: Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms.

Sex differences in antipsychotic-related triglyceride levels are associated with metabolic hormone differences in patients with severe mental disorders.

BACKGROUND: Adverse effects of antipsychotics (AP) contribute to cardiovascular disease (CVD) risk in patients with severe mental disorders (SMD). We investigated sex differences in AP-related CVD risk factors and the role of metabolic hormones. METHODS: Patients with SMD (N = 1791) receiving AP with different CVD risk were recruited and grouped into olanzapine and/or clozapine (N = 532), other APs (N = 744) or no use of APs (N = 515). Associations between CVD risk factor (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), body mass index (BMI), glucose, blood pressure), sex and AP groups were tested in multiple linear regression with interactions, controlling for diagnostic group, lifestyle factors, polypharmacy, age and ethnicity. Next, we tested associations between sex differences in AP-related CVD risk factors and metabolic regulatory hormones. RESULTS: AP groups and male sex were significantly associated with higher levels of LDL-C, TG and BMI, and lower levels of HDL-C. Significant interaction between AP groups and sex were found for TG (p = 0.017), with larger increase in males. Serum adiponectin, insulin, cortisol, leptin, testosterone, free thyroxine and thyroid-stimulating hormone (TSH) were associated with TG levels (all p ≤ 0.001), and a significant interaction with sex for insulin (p = 0.005), cortisol (p = 0.016), leptin (p < 0.001) and TSH (p = 0.001). CONCLUSIONS: We found more severe AP-related CVD risk factors in male patients with SMD. The male-dependent increase in TG levels was associated with leptin, insulin, cortisol and TSH levels. Clinicians treating patients with SMD should be aware of increased vulnerability for AP-related lipid abnormalities in males.

Limited association between infections, autoimmune disease and genetic risk and immune activation in severe mental disorders.

BACKGROUND: Low-grade inflammation may be part of the underlying mechanism of schizophrenia and bipolar disorder. We investigated if genetic susceptibility, infections or autoimmunity could explain the immune activation. METHODS: Seven immune markers were selected based on indicated associations to severe mental disorders (IL-1Ra, sIL-2R, IL-18, sgp130, sTNFR-1, APRIL, ICAM-1) and measured in plasma of patients with schizophrenia (SCZ, N = 732) and bipolar spectrum disorders (BD, N = 460) and healthy controls (HC, N = 938). Information on rate of infections and autoimmune diseases were obtained from Norwegian national health registries for a twelve-year period. Polygenic risk scores (PRS) of SCZ and BD were calculated from genome-wide association studies. Analysis of covariance were used to test effects of infection rate, autoimmune disease and PRS on differences in immune markers between patients and HC. RESULTS: Infection rate differed between all groups (BD > HC > SCZ, all p < 0.001) whereas autoimmune disease was more frequent in BD compared to SCZ (p = 0.004) and HC (p = 0.003). sIL-2R was positively associated with autoimmune disease (p = 0.001) and negatively associated with PRS of SCZ (p = 0.006) across SCZ and HC; however, associations represented only small changes in the difference of sIL-2R levels between SCZ and HC. CONCLUSION: There were few significant associations between rate of infections, autoimmune disease or PRS and altered immune markers in SCZ and BD, and the detected associations represented only small changes in the immune aberrations. The findings suggest that most of the low-grade inflammation in SCZ and BD is explained by other factors than the underlying PRS, autoimmunity and infection rates.

Immune marker levels in severe mental disorders: associations with polygenic risk scores of related mental phenotypes and psoriasis.

Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra (P = 0.01) and IL-18 (P = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 (P = 0.02) and PRS of anxiety and IL-18 (P = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R (P = 0.02) and PRS of educational attainment and sIL-2R (P = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE), P = 0.002), and nominally for PRS of openness and IL-1Ra (IE, P = 0.02) and sTNFR-1 (IE, P = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

Associations between amygdala nuclei volumes, psychosis, psychopathy, and violent offending.

The amygdala is involved in fear perception and aggression regulation, and smaller volumes have been associated with psychotic and non-psychotic violence. We explored the relationship between amygdala nuclei volumes in violent offenders with and without psychosis, and the association to psychopathy traits. 3T MRI scans (n = 204, males, 18-66 years) were obtained from psychotic violent offenders (PSY-V, n = 29), non-psychotic violent offenders (NPV, n = 19), non-violent psychosis patients (PSY-NV, n = 67), and healthy controls (HC, n = 89). Total amygdala and 9 amygdala nuclei volumes were obtained with FreeSurfer. Psychopathy traits were measured with the Psychopathy Checklist-revised (PCL-R). Multivariate analyses explored diagnostic differences in amygdala nuclei volumes and associations to psychosis, violence, and psychopathy traits. PSY-V had a smaller basal nucleus, anterior amygdaloid area, and cortical amygdalar transition area (CATA), whereas PSY-NV had a smaller CATA than HC. Volumes in NPV did not differ from HC, and there were no associations between PCL-R total or factor scores and any of the nuclei or whole amygdala volumes. The lower volumes of amygdala nuclei involved in fear modulation, stress responses, and social interpretation may point towards some mechanisms of relevance to violence in psychosis, but the results warrant replication in larger subject samples.

Childhood trauma and cardiometabolic risk in severe mental disorders: The mediating role of cognitive control.

BACKGROUND: Cardiometabolic risk is increased in severe mental disorders (SMDs), and there appears to be a relationship between childhood trauma and cardiometabolic risk, possibly related to adverse health behavior. The current study examined the association between childhood trauma and serum lipids and adiposity in SMDs and the potential mediating role of cognitive and personality characteristics. METHODS: Participants with schizophrenia and bipolar spectrum disorders (N = 819) were included, cardiometabolic risk factors (serum lipids, body mass index, and waist circumference) were measured, and history of childhood trauma was assessed by the Childhood Trauma Questionnaire. Cognitive and personality characteristics were available in subsamples, with assessments of cognitive control, impulsiveness, self-esteem, and affective lability. Linear regressions and mediation analyses with Hayes' PROCESS were performed, adjusting for age, sex, antipsychotic agent propensity of metabolic side-effect, and diagnostic group. RESULTS: Experience of three or more subtypes of childhood trauma was positively associated with waist circumference in patients with SMDs (p = 0.014). There were no other significant associations between trauma variables and lipid or adiposity measures in the total sample. Cognitive control was a significant mediator between experience of one or two subtypes of childhood trauma and waist circumference. CONCLUSIONS: The results indicate childhood trauma as a predisposing factor for increased waist circumference in individuals with SMDs. Poorer cognitive control, suggestive of adverse health behavior, might be a mediating factor of the association, and the findings indicate the potential importance of increased focus on these factors in prevention and treatment regimens targeting cardiometabolic health.

Disentangling the relationship between cholesterol, aggression, and impulsivity in severe mental disorders.

OBJECTIVE: Low total cholesterol has been linked with adverse mental symptoms such as aggression and impulsivity in severe mental disorders (SMDs). This putative association may affect the clinician's decision making about cholesterol lowering in this patient group. Here, we investigated the associations between cholesterol levels, aggression, and impulsivity in a large representative sample of in- and outpatients with SMD. METHODS: Patients with schizophrenia- or bipolar spectrum disorders (N = 1 001) underwent thorough clinical characterization and blood sampling (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol). Aggression was characterized by the Positive and Negative Syndrome Scale Excited Component. Impulsivity was measured with the Barratt Impulsiveness Scale in a subsample of patients (N = 288). We used a multinomial logistic regression model to analyze the association between cholesterol and aggression and a multiple linear regression model to analyze the association between cholesterol and impulsivity, while controlling for confounders. RESULTS: We found no significant associations between cholesterol levels and aggression or impulsivity. There were no significant interactions between cholesterol and diagnostic group or inpatient versus outpatient status. Controlling for medication use, body mass index, alcohol or illicit substance use did not affect the results. CONCLUSION: In this large sample of patients with schizophrenia- and bipolar spectrum disorders, we found no associations between cholesterol levels and aggression or impulsivity. This has clinical implications as patients with SMD are at increased CVD risk and currently undertreated with statins.

Indicated association between polygenic risk score and treatment-resistance in a naturalistic sample of patients with schizophrenia spectrum disorders.

BACKGROUND: One third of people diagnosed with schizophrenia fail to respond adequately to antipsychotic medication, resulting in persisting disabling symptoms, higher rates of hospitalization and higher costs for society. In an effort to better understand the mechanisms behind resistance to antipsychotic treatment in schizophrenia, we investigated its potential relationship to the genetic architecture of the disorder. METHODS: Patients diagnosed with a schizophrenia spectrum disorder (N = 321) were classified as either being treatment-resistant (N = 108) or non-treatment-resistant (N = 213) to antipsychotic medication using defined consensus criteria. A schizophrenia polygenic risk score based on genome-wide association studies (GWAS) was calculated for each patient and binary logistic regression was performed to investigate the association between polygenetic risk and treatment resistance. We adjusted for principal components, batch number, age and sex. Additional analyses were performed to investigate associations with demographic and clinical variables. RESULTS: High levels of polygenic risk score for schizophrenia significantly predicted treatment resistance (p = 0.003). The positive predictive value of the model was 61.5% and the negative predictive value was 71.7%. The association was significant for one (p = 0.01) out of five tested SNP significance thresholds. Season of birth was able to predict treatment-resistance in the regression model (p = 0.05). CONCLUSIONS: The study indicates that treatment-resistance to antipsychotic medication is associated with higher polygenetic risk of schizophrenia, suggesting a link between antipsychotics mechanism of action and the genetic underpinnings of the disorder.

Hippocampal subfield and amygdala nuclei volumes in schizophrenia patients with a history of violence.

Schizophrenia (SCZ) is associated with an increased risk of violence compared to the general population. Previous studies have indicated smaller hippocampal and amygdala volumes in violent than non-violent psychotic patients. However, little is known about volumetric differences at the subdivision level of these structures. In the present study, hippocampal subfields and amygdala nuclei volumes were estimated with FreeSurfer from 3 T MRI of SCZ patients with (SCZ-V, n = 24) and without (SCZ-NV, n = 51) a history of severe violence and 90 healthy controls (HC). Volumetric differences between groups were explored with a general linear model covarying for confounders, in addition to follow-up analyses in patient groups controlling for clinical characteristics such as antipsychotic medication, duration of illness and illicit substance use. SCZ-V had smaller total hippocampal volume and smaller CA1, HATA, fimbria, and molecular layer of DG volumes compared to HC. Total amygdala volume together with basal nucleus, accessory basal nucleus, CTA, and paralaminar nucleus volumes were smaller in SCZ-V compared to HC. In SCZ-NV, compared to HC, the observed smaller volumes were limited to basal and paralaminar nucleus. There were no significant differences in hippocampal subfield and amygdala nuclei volumes between SCZ-V and SCZ-NV. Follow-up analyses showed that the results in patient groups were not affected by clinical characteristics. The results suggest that smaller hippocampal subfield and amygdala nuclei volumes may be relevant to violence risk in SCZ. However, the neurobiological signature of violence in SCZ should be further investigated in larger cohorts.