Abstract
Clozapine (CLZ) is the only antipsychotic drug that has been proven to be effective in patients with refractory psychosis, but it has also been proposed as an effective mood stabilizer; however, the complex mechanisms of action of CLZ are not yet fully known. To find predictors of CLZ-associated phenotypes (i.e., the metabolic ratio, dosage, and response), we explore the genomic and epigenomic characteristics of 44 patients with refractory psychosis who receive CLZ treatment based on the integration of polygenic risk score (PRS) analyses in simultaneous methylome profiles. Surprisingly, the PRS for bipolar disorder (BD-PRS) was associated with the CLZ metabolic ratio (pseudo-R2 = 0.2080, adjusted p-value = 0.0189). To better explain our findings in a biological context, we assess the protein–protein interactions between gene products with high impact variants in the top enriched pathways and those exhibiting differentially methylated sites. The GABAergic synapse pathway was found to be enriched in BD-PRS and was associated with the CLZ metabolic ratio. Such interplay supports the use of CLZ as a mood stabilizer and not just as an antipsychotic. Future studies with larger sample sizes should be pursued to confirm the findings of this study.
Highlights
Antipsychotic drugs are effective in treating symptoms of psychosis and preventing relapses [1,2,3]
The higher the ratio the lower the metabolism in the liver [7]. This result might be related to the SNPs contained in the bipolar disorder (BD)-polygenic risk score (PRS) (Table 2), which were enriched in the insulin secretion pathway and the thyroid hormone signaling pathway (Table S1)
Besides the effects that hyperglycemia could have in CLZ-treated patients with refractory psychosis, we identified relevant gene enrichment in the thyroid hormone signaling pathway, including the RXRA/RXRG
Summary
Antipsychotic drugs are effective in treating symptoms of psychosis and preventing relapses [1,2,3]. Psychotic symptoms (hallucinations, delusions, and distorted behavior) can be observed in different psychiatric disorders, such as schizophrenia (SZ), schizoaffective disorder (SD), bipolar disorder (BD), and even in major depressive disorder (MDD) [1,2,3,4,5,6] Among these patients, about 30% are considered refractory, and clozapine (CLZ), an atypical antipsychotic, remains the treatment of choice for the population who has failed to improve on two other previous antipsychotic treatments [7,8,9]. Despite the wide variation in CLZ dosage in clinical practice, there is a consensus that doses below 100 mg may be insufficient for patients to respond to, the standard dose is usually between 300 and 600 mg [21,22,23] In this context, an integrative omics data analysis of patients with refractory psychosis would be of aid in identifying markers to improve or predict some of the CLZ-associated phenotypes (i.e., metabolic ratio, dosage, and response). CLZ-treated patients with refractory psychosis in order to identify genes related to the potential mechanisms of action of CLZ and its possible pharmacogenomics applications
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