Calcium Signaling Pathway Is Associated with the Long-Term Clinical Response to Selective Serotonin Reuptake Inhibitors (SSRI) and SSRI with Antipsychotics in Patients with Obsessive-Compulsive Disorder

Abstract

BackgroundSelective serotonin reuptake inhibitors (SSRI) are established first-line pharmacological treatments for obsessive-compulsive disorder (OCD), while antipsychotics are used as an augmentation strategy for SSRI in OCD patients who have either no response or a partial response to SSRI treatment. The goal of the present study was to identify genetic variants and pathways that are associated with the long-term clinical response of OCD patients to SSRI or SSRI with antipsychotics.MethodsWe first performed a genome-wide association study of 96 OCD patients to examine genetic variants contributing to the response to SSRI or SSRI with antipsychotics. Subsequently, we conducted pathway-based analyses by using Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) to examine the combined effects of genetic variants on the clinical response in OCD.ResultsWhile we failed to detect specific genetic variants associated with clinical responses to SSRI or to SSRI with an atypical antipsychotic at genome-wide levels of significance, we identified 8 enriched pathways for the SSRI treatment response and 5 enriched pathways for the treatment response to SSRI with an antipsychotic medication. Notably, the calcium signaling pathway was identified in both treatment responses.ConclusionsOur results provide novel insight into the molecular mechanisms underlying the variability in clinical response to SSRI and SSRI with antipsychotics in OCD patients.

The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder

“…In addition to PRS, gene-set analysis can be utilized to group multiple genetic variants in genes and further to related gene sets to unravel biological processes and cellular functions related to intervention responses 8 . Relevant gene-set associations have been identified for interventions in psychiatry 8 – 12 . For example, genetic variations in genes underlying glutamatergic or NMDA neurotransmission have been implicated in short-term antipsychotic medication efficacy in schizophrenia, and the calcium signaling pathway has been indicated to respond to selective serotonin reuptake inhibitors in obsessive-compulsive disorder 10 , 12 .…”

Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome

“…Recent analyses of genetic risk for autism identified ANKS1B as a target gene due to rare genetic variants found in ASD 5–7 , predicted participation in gene networks dysregulated in ASD 8,9 , and salience in bioinformatic analyses of mouse phenomics 10 . Genomic and transcriptomic association studies of neuropsychiatric disorders implicate ANKS1B in obsessive-compulsive disorder 11,12 , mood disorders 13,14 , and schizophrenia 15–18 . ANKS1B is a large ~1.3 megabase gene located on human chromosome 12q23.1 that encodes AIDA-1 (APP intracellular domain associated 1), a protein initially suggested to regulate γ-secretase processing of amyloid precursor protein (APP) 19 .…”

Antipsychotic augmentation in the treatment of obsessive-compulsive disorder

“…However, using pathway-based analysis, five enriched pathways involved in calcium signaling were identified to be associated with response to antipsychotic combination of SSRIs. [37]…”