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

Abstract

Background: One third of people diagnosed with schizophrenia fail to respond adequately to antipsychotic medication, resulting in persisting disabling symptoms, higher rates of hospitalisation 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 treatmentresistance 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.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorder

“…higher symptom severity). 69 Several studies indicate that schizophrenia-PRS increases when comparing firstepisode psychosis to schizophrenia, and schizophrenia to TRS 20,[69][70][71] , although there is also conflicting evidence for the latter. 72,73 Bearing those former observations in mind, higher schizophrenia-PRS may characterize a subset of TRS-patients more likely to respond well to clozapine.…”

Association between psychiatric hospitalizations of patients with schizophrenia and polygenic risk scores based on genes with altered expression by antipsychotics

“…Frank et al 45 reported a statistically significant association with history of clozapine treatment in patients with schizophrenia. However, different attempts to replicate this finding were generally negative, 46–49 although a positive result has been also reported 50 . Regarding psychopathology, SCZ PRS was associated with poorer response to antipsychotic treatment, measured as reduction in total symptom scores in first‐episode psychosis at 12‐weeks follow‐up in several cohorts 51 .…”

“…However, different attempts to replicate this finding were generally negative, [46][47][48][49] although a positive result has been also reported. 50 Regarding psychopathology, SCZ PRS was associated with poorer response to antipsychotic treatment, measured as reduction in total symptom scores in firstepisode psychosis at 12-weeks follow-up in several cohorts. 51 However, another study did not find association at about 9 weeks follow-up.…”

Polymorphisms in Schizophrenia-Related Genes Are Potential Predictors of Antipsychotic Treatment Resistance and Refractoriness

“…This is a major step in clarifying the application of GWAS results to SZ risk estimation ( Bigdeli et al, 2020 ). On the other hand, the evidence regarding the applicability of SZ polygenic risk scores to prediction of TRS is controversial, as results have been inconsistent ( Gasse et al, 2019 ; Werner et al, 2020 ; Wimberley et al, 2017 ).…”