Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

Abstract

BackgroundIt remains unknown why ∼30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations into treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we test whether schizophrenia-associated CNVs are more prevalent in patients with treatment-resistant psychotic symptoms compared to previously published schizophrenia cases not selected for treatment-resistance.MethodsCNVs were identified using chromosomal microarrays and exome sequencing in 509 patients with treatment-resistant psychosis (a lack of clinical response to ≥ 3 adequate antipsychotic medication trials over at least five years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared against a previous large schizophrenia cohort study.ResultsIn total, 47 cases (9.2%) carried at least one CNV with known or possible neuropsychiatric risk. The prevalence of schizophrenia-associated CNVs (n=21; 4.1%) was significantly increased compared to a previous schizophrenia cohort study (p = 0.005322; OR = 1.93). This increase in prevalence was primarily due to duplications at 15q11.2-q13.1 and 16p11.2, which were independently associated with treatment-resistance in pairwise loci-based analysis.ConclusionsThese findings suggest that rare schizophrenia-associated CNVs, particularly duplications of 15q11.2-q13.1 and 16p11.2, may serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.

X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization

“…26,27 It has been reported that patients with SCZ have a higher frequency of pathogenic CNVs and that patients with pathogenic CNVs are more likely to be resistant to treatment. 28,29 Therefore, CNV analysis may be recommended as a clinical diagnostic test, especially in patients with TRS. Patients with 47, XXY were also more likely to have manic symptoms.…”

“…A few case reports of patients with SCZ with 47, XXY who showed resistance to antipsychotic medications have been published 26,27 . It has been reported that patients with SCZ have a higher frequency of pathogenic CNVs and that patients with pathogenic CNVs are more likely to be resistant to treatment 28,29 . Therefore, CNV analysis may be recommended as a clinical diagnostic test, especially in patients with TRS.…”