An epigenetic candidate-gene association study of parental styles in suicide attempters with substance use disorders.

Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients.

Neurocognitive function and delusion severity in schizophrenia spectrum disorders.

The role of basic neurocognitive function in delusions is unclear despite the association to difficulties in reasoning and decision-making. We investigated 812 individuals with schizophrenia spectrum disorders (SSD) using a broad neuropsychological test battery encompassing motor and mental processing speed, working memory, learning and memory, and executive function. Premorbid and current intellectual function was assessed with NART and WASI. Delusion level and other clinical symptoms were measured with the PANSS and GAF. Hierarchical and k-means cluster analysis using standardized scores showed the presence of two separate clusters where the group with the higher delusion level (n = 291) was characterized by more severe neurocognitive deficits (>1.5 standard deviations below the healthy control mean), higher PANSS scores, lower GAF scores, and lower intelligence levels compared to the cluster with mild impairments (n = 521). We conclude that a higher delusion level is related to neurocognitive deficits across domains. Further, the validity of the two separate clusters was indicated by significant differences in clinical symptoms, everyday function, and intellectual ability. Compared to those with mild delusion levels, SSD patients with higher delusion levels seem particularly disadvantaged, with co-occurring general symptoms and lower daily function, underscoring the need for clinical and psychosocial support programs. A limitation of this study is the cross sectional design. Longitudinal studies are needed to determine the causal relationship between delusions and neurocognitive function.

Childhood trauma and treatment resistance in first-episode psychosis: Investigating the role of premorbid adjustment and duration of untreated psychosis.

BACKGROUND: Early identification of treatment non-response in first-episode psychosis (FEP) is essential to outcome. Despite indications that exposure to childhood trauma (CT) can have adverse effects on illness severity, its impact on treatment non-response and the interplay with other pre-treatment characteristics is sparsely investigated. We use a lack of clinical recovery as an early indicator of treatment resistance to investigate the relationship between CT and treatment resistance status at one-year follow-up and the potential mediation of this effect by other pre-treatment characteristics. METHODS: This prospective one-year follow-up study involved 141 participants recruited in their first year of treatment for a schizophrenia-spectrum disorder. We investigated clinical status, childhood trauma (CT), premorbid adjustment (PA), and duration of untreated psychosis (DUP) at baseline and clinical status at one-year follow-up. Ordinal regression analyses were conducted to investigate how PA and DUP affected the relationship between CT and one-year outcome in FEP. RESULTS: 45 % of the FEP sample reported moderate to severe CT, with significantly higher levels of CT in the early treatment resistant group compared to participants with full or partial early recovery. Ordinal regression analysis showed that CT was a significant predictor of being in a more severe outcome group (OR = 4.59). There was a partial mediation effect of PA and a full mediation effect of DUP on the effect of CT on outcome group membership. DISCUSSION: Our findings indicate that reducing treatment delays may mitigate the adverse effects of CT on clinical outcomes and support the inclusion of broad trauma assessment in FEP services.

Behind the heterogeneity in the long-term course of first-episode psychosis: Different psychotic symptom trajectories are associated with different patterns of cannabis and stimulant use.

BACKGROUND: Data-driven classification of long-term psychotic symptom trajectories and identification of associated risk factors could assist treatment planning and improve long-term outcomes in psychosis. However, few studies have used this approach, and knowledge about underlying mechanisms is limited. Here, we identify long-term psychotic symptom trajectories and investigate the role of illness-concurrent cannabis and stimulant use. METHODS: 192 participants with first-episode psychosis were followed up after 10 years. Psychotic symptom trajectories were estimated using growth mixture modeling and tested for associations with baseline characteristics and cannabis and stimulant use during the follow-up (FU) period. RESULTS: Four trajectories emerged: (1) Stable Psychotic Remission (54.2 %), (2) Delayed Psychotic Remission (15.6 %), (3) Psychotic Relapse (7.8 %), (4) Persistent Psychotic Symptoms (22.4 %). At baseline, all unfavorable trajectories (2-4) were characterized by more schizophrenia diagnoses, higher symptom severity, and longer duration of untreated psychosis. Compared to the Stable Psychotic Remission trajectory, unstable trajectories (2,3) showed distinct associations with cannabis/stimulant use during the FU-period, with dose-dependent effects for cannabis but not stimulants (Delayed Psychotic Remission: higher rates of frequent cannabis and stimulant use during the first 5 FU-years; Psychotic Relapse: higher rates of sporadic stimulant use throughout the entire FU-period). The Persistent Psychosis trajectory was less clearly linked to substance use during the FU-period. CONCLUSIONS: The risk for an adverse long-term course could be mitigated by treatment of substance use, where particular attention should be devoted to preventing the use of stimulants while the use reduction of cannabis may already yield positive effects.

Mismatch negativity and polygenic risk scores for schizophrenia and bipolar disorder.

OBJECTIVE: Auditory mismatch negativity (MMN) impairment is a candidate endophenotype in psychotic disorders, yet the genetic underpinnings remain to be clarified. Here, we examined the relationships between auditory MMN and polygenic risk scores (PRS) for individuals with psychotic disorders, including schizophrenia spectrum disorders (SSD) and bipolar disorder (BD) and in healthy controls (HC). METHODS: Genotyped and clinically well-characterized individuals with psychotic disorders (n = 102), including SSD (n = 43) and BD (n = 59), and HC (n = 397) underwent a roving MMN paradigm. In addition MMN, we measured the memory traces of the repetition positivity (RP) and the deviant negativity (DN), which is believed to reflect prediction encoding and prediction error signals, respectively. SCZ and BD PRS were computed using summary statistics from the latest genome-wide association studies. The relationships between the MMN, RP, and DN and the PRSs were assessed with linear regressions. RESULTS: We found no significant association between the SCZ or BD PRS and grand average MMN in the psychotic disorders group or in the HCs group (all p > 0.05). SCZ PRS and BD PRS were negatively associated with RP in the psychotic disorders group (ß = -0.46, t = -2.86, p = 0.005 and ß = -0.29, t = -0.21, p = 0.034, respectively). No significant associations were found between DN and PRS. CONCLUSION: These findings suggest that genetic variants associated with SCZ and BD may be associated with MMN subcomponents linked to predictive coding among patients with psychotic disorders. Larger studies are needed to confirm these findings and further elucidate the genetic underpinnings of MMN impairment in psychotic disorders.

Auditory Cortex Thickness Is Associated With N100 Amplitude in Schizophrenia Spectrum Disorders.

Background and Hypothesis: The auditory cortex (AC) may play a central role in the pathophysiology of schizophrenia and auditory hallucinations (AH). Previous schizophrenia studies report thinner AC and impaired AC function, as indicated by decreased N100 amplitude of the auditory evoked potential. However, whether these structural and functional alterations link to AH in schizophrenia remain poorly understood. Study Design: Patients with a schizophrenia spectrum disorder (SCZspect), including patients with a lifetime experience of AH (AH+), without (AH-), and healthy controls underwent magnetic resonance imaging (39 SCZspect, 22 AH+, 17 AH-, and 146 HC) and electroencephalography (33 SCZspect, 17 AH+, 16 AH-, and 144 HC). Cortical thickness of the primary (AC1, Heschl's gyrus) and secondary (AC2, Heschl's sulcus, and the planum temporale) AC was compared between SCZspect and controls and between AH+, AH-, and controls. To examine if the association between AC thickness and N100 amplitude differed between groups, we used regression models with interaction terms. Study Results: N100 amplitude was nominally smaller in SCZspect (P = .03, d = 0.42) and in AH- (P = .020, d = 0.61), while AC2 was nominally thinner in AH+ (P = .02, d = 0.53) compared with controls. AC1 thickness was positively associated with N100 amplitude in SCZspect (t = 2.56, P = .016) and AH- (t = 3.18, P = .008), while AC2 thickness was positively associated with N100 amplitude in SCZspect (t = 2.37, P = .024) and in AH+ (t = 2.68, P = .019). Conclusions: The novel findings of positive associations between AC thickness and N100 amplitude in SCZspect, suggest that a common neural substrate may underlie AC thickness and N100 amplitude alterations.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.