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.

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.

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.

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.

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.

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.

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.

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.