The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study.

BACKGROUND: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. AIMS: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS). METHOD: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. RESULTS: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. CONCLUSIONS: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.

Deconstructing the genetic architecture of treatment-resistant schizophrenia in East Asian ancestry.

BACKGROUND: Treatment-resistant schizophrenia (TRS) affects a substantial proportion of patients who do not respond adequately to antipsychotic medications, yet the underlying biological mechanism remains poorly understood. This study investigates the link between the genetic predisposition to schizophrenia and TRS. METHODS: 857 individuals diagnosed with schizophrenia were divided into TRS (n = 142) and non-TRS (n = 715) based on well-defined TRS criteria. Polygenic risk scores (PRS) were calculated using schizophrenia genome-wide association summary statistics from East-Asian and European ancestry populations. PRS was estimated using both P-value thresholding and Bayesian framework methods. Logistic regression analyses were performed to differentiate between TRS and non-TRS individuals. RESULTS: The schizophrenia PRS derived from the East-Asian training dataset effectively distinguished between TRS and non-TRS individuals (R2 = 0.029, p = 4.86 ×10-5, pT = 0.1, OR = 1.52, 95% CI = 1.242-1.861), with higher PRS values observed in the TRS group. Similar PRS analysis was conducted based on the European ancestry GWAS summary statistics, but we found superior prediction based on the East-Asian ancestry discovery data. CONCLUSION: This study reveals an association between common risk variants for schizophrenia and TRS status, suggesting that the genetic burden of schizophrenia may partly contribute to treatment resistance in individuals with schizophrenia. These findings propose the potential use of genetic risk factors for early TRS identification and timely access to clozapine. However, the ancestral background of the discovery sample is crucial for successfully implementing PRS in clinical settings.

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.

Interacting Roles of COMT and GAD1 Genes in Patients with Treatment-Resistant Schizophrenia: a Genetic Association Study of Schizophrenia Patients and Healthy Controls.

The projection from dopaminergic neurons to gamma-aminobutyric acid (GABA) interneurons in the prefrontal cortex is involved in the etiology of schizophrenia. The impact of interacting effects between dopamine signals and the expression of GABA on the clinical phenotypes of schizophrenia has not been studied. Since these interactions could be closely involved in prefrontal cortex functions, patients with specific alleles of these relevant molecules (which lead to lower or vulnerable genetic functions) may develop treatment-refractory symptoms. We conducted a genetic association study focusing on COMT and GAD1 genes for a treatment-resistant schizophrenia (TRS) group (n=171), a non-TRS group (n=592), and healthy controls (HC: n=447), and we examined allelic combinations specific to TRS. The results revealed that the percentage of subjects with Met allele of rs4680 on the COMT gene and C/C homozygote of rs3470934 on the GAD1 gene was significantly higher in the TRS group than the other two groups. There was no significant difference between the non-TRS group and HC groups. Considering the direction of functions of these single-nucleotide polymorphisms revealed by previous studies, we speculate that subjects with the Met/CC allelic combination could have a higher dopamine level and a lower expression of GABA in the prefrontal cortex. Our results suggest that an interaction between the dopaminergic signal and GABA signal intensities could differ between TRS patients and patients with other types of schizophrenia and healthy subjects.

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Expression of BDNF-Associated lncRNAs in Treatment-Resistant Schizophrenia Patients.

Long non-coding RNAs (lncRNAs) play a decisive role in the development of the central nervous system and modulation, differentiation, and function of neurons. Thus, any abnormal pattern of expression of these transcripts might alter normal development leading to neuropsychiatric disorders. In this regard, transcripts of brain-derived neurotrophic factor (BDNF) and four BDNF-associated lncRNAs (BDNF-AS, MIR137HG, MIAT, and PNKY) were evaluated in the peripheral blood of schizophrenia (SCZ) patients as well as normal subjects. The results indicated that the relative expression (RE) of PNKY was higher in SCZ patients as compared with controls (posterior beta of RE = 2.605, P value = 0.006) and in female patients compared with female controls (posterior beta of RE = 2.831, P value < 0.0001). BDNF expression was also higher in SCZ patients when compared with controls (posterior beta of RE = 0.64, P value < 0.036). Finally, a correlation was detected between the disease status and gender in terms of BDNF-AS expression (P value = 0.026). An inverse correlation was also found between levels of PNKY and age in the control group (r = - 0.30, P value < 0.0001). Expressions of BDNF and all lncRNAs were correlated with each other in both patients and controls. PNKY had the best diagnostic power among all assessed genes in the identification of disease status (area under curve = 0.78). BDNF, BDNF-AS, MIR137HG, and MIAT genes could discriminate SCZ patients from normal subjects with diagnostic power of 71%, 72%, 67%, and 68%, respectively. The current investigation suggests the possibility of the application of transcript levels of lncRNAs as an SCZ diagnostic marker. However, it warrants further studies in larger sample sizes.