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

Abstract

Background It remains unknown why ~30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations of 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 identified schizophrenia-associated CNVs in patients with treatment-resistant psychotic symptoms and then compared the prevalence of these CNVs to previously published schizophrenia cases not selected for treatment resistance. Methods CNVs were identified using chromosomal microarray (CMA) and whole exome sequencing (WES) in 509 patients with treatment-resistant psychosis (a lack of clinical response to ≥3 adequate antipsychotic medication trials over at least 5 years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared to that in a previously published large schizophrenia cohort study. Results Integrating CMA and WES data, we identified 47 cases (9.2%) with at least one CNV of known or possible neuropsychiatric risk. 4.7% (n = 24) carried a known neurodevelopmental risk CNV. The prevalence of well-replicated schizophrenia-associated CNVs was 4.1%, with duplications of the 16p11.2 and 15q11.2-q13.1 regions, and deletions of the 22q11.2 chromosomal region as the most frequent CNVs. Pairwise loci-based analysis identified duplications of 15q11.2-q13.1 to be independently associated with treatment resistance. Conclusions These findings suggest that CNVs may uniquely impact clinical phenotypes beyond increasing risk for schizophrenia and may potentially 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.

Response to Treatment in 3q29 Deletion Syndrome-Associated Psychosis: A Mini-Review

“…Regardless, based on these results, it appears that 3q29 deletion syndrome may not only be associated with an increased risk of psychosis, and possibly early-onset psychosis [1], but also treatment-resistant psychosis. This possibility is congruent with findings from previous studies that have demonstrated an association between the presence of clinically relevant CNVs and treatment resistance in schizophrenia [8,9]. Although this association may in part be directly related to CNV-specific pathophysiological changes relevant to treatment resistance, it may also be indirectly mediated by the increased prevalence of neurodevelopmental disorder phenotypes in this population [9].…”

Maternal 15q11.2-q13.1 duplication syndrome-associated psychosis and mania: a new case and review of the literature

“…While three individuals had a good response to treatment, three others had a poor or partial response. Additionally, another recent study found an association between 15q11.2-q13.1 duplications and treatment-resistant psychosis (Farrell et al ., 2023). In contrast, our patient’s symptoms of psychosis and mania responded well to relatively low-dose antipsychotic therapy, and she eventually made a full recovery.…”

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.…”