Rare Copy Number Variants in Treatment-Resistant Psychosis

Genetic testing for severe psychosis? Researchers investigated rare disease-associated copy number variants in patients with treatment-resistant schizophrenia.



“Mr Hunter” is a 34-year-old African-American male with a history of chronic schizophrenia and intellectual disability. He also has comorbid type 2 diabetes mellitus and hypothyroidism. The onset of his psychosis was in his early teens. He has been clinically stable on clozapine for approximately 14 years, with no psychiatric hospitalizations during that time.

Mr Hunter was adopted, and nothing is known about his biological family psychiatric history. His adoptive mother died 7 years ago, and his adoptive aunt is now his legal guardian. He is noted to have short stature (height 154 cm) and a distinct facies that is not pathognomonic for any common causes of intellectual disability. At a recent outpatient clinic visit, his aunt inquires whether his schizophrenia was caused by “genetics.”

One in 3 patients with psychosis have treatment-resistant psychotic symptoms (TRS).1 These patients have greater cognitive deficits, impaired functioning, and rates of suicide.2 Clinical predictors of TRS are limited.3 Recent studies in patients with TRS have found an increased burden of rare, damaging copy number variants (CNVs).4,5 These CNVs might inform on biological mechanisms underlying treatment resistance.

The Current Study

Farrell and colleagues6 investigated rare CNVs in a sample of 509 patients with clinically confirmed TRS and compared the prevalence of schizophrenia-associated CNVs in this sample with a cohort not selected for TRS.7 They recruited participants from 5 Pennsylvania state hospitals and their affiliated long-term structured residences. They included participants aged ≥18 years who were able and willing to give informed consent and who had a diagnosis of schizophrenia, schizoaffective disorder, mood disorder with psychotic features, or psychotic disorder NOS. Participants had continuous psychiatric hospitalization for ≥5 years and lack of clinical improvement despite ≥3 antipsychotic trials.

Exclusion criteria were psychosis associated with substance dependence, medical conditions known to cause psychosis, and any instance of sustained treatment response. Participants were assessed clinically with the Positive and Negative Syndrome Scale (PANSS). Among 690 initial participants, 509 were included in the final sample.

DNA was extracted from a blood sample and genome-wide SNP genotypes obtained from the Illumina Infinium Global Screening Array. CNVs were determined from array intensity data using 3 calling algorithms. Quality control steps were used to remove low-confidence CNV determinations. Exome sequencing data, using Agilent SureSelectXT Clinical Research Exome, were available for 478 participants and used as another approach for CNV identification. CNVs were cross-referenced with a list of CNVs associated with neurodevelopmental disorders.

The authors also compared the prevalence of (aggregate) schizophrenia CNVs in their sample to a sample of 21,094 participants with schizophrenia not selected for treatment resistance, using a chi-squared test. Loci-based comparisons of schizophrenia CNVs between the 2 samples were made using Fisher’s exact test, correcting for multiple comparisons.

The mean participant age was 52 years, 66% were male, and 75% were white. The most common diagnoses were schizophrenia (47%) and schizoaffective disorder (46%). Of the participants, 51% had been exposed to clozapine. Forty-seven of the 509 participants (9.2%) had at least 1 CNV with potential relevance to their clinical presentation; 24 (4.7%) had 1 of the neurodevelopmental risk CNVs, most commonly a 16p11.2 duplication (n=6), 15q11.2-13.1 duplication (n=4), and 22q11.21 deletion (n=4); and 21 of these 24 cases were also carriers of other schizophrenia CNVs.

Eleven patients had large (>1 Mb) CNVs that did not overlap with neurodevelopmental or schizophrenia CNVs, and 12 had variants of uncertain significance, most commonly a 15q11.2 duplication (n=4) and 15q13.3 duplication (n=3). Participants with CNVs had higher mean PANSS positive scores than non-carriers (21.0 versus 19.1). The prevalence of schizophrenia CNVs in the present study (4.1%) was almost 2-fold greater than that in the sample of participants not selected for treatment resistance (2.2%).

Study Conclusions

The authors found a 9.2% prevalence of CNVs of neuropsychiatric risk in cases with TRS. There was also an increased prevalence schizophrenia-associated CNVs in this sample. These CNVs may contribute to generalized or specific risks of and outcomes in TRS. The 15q11.2-13.1 genomic region, in particular, warrants further investigation. Whether more widespread genetic testing in schizophrenia is justified is an unresolved question. Strengths of the present study include the use of a well-defined TRS cohort and comprehensive approach to CNV detection.

The Bottom Line

Rare CNVs may impact clinical phenotypes and may serve as biological entry points for studying treatment resistant schizophrenia.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Howes OD, McCutcheon R, Agid O, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus guidelines on diagnosis and terminologyAm J Psychiatry. 2017;174(3):216-229.

2. de Bartolomeis A, Balletta R, Giordano S, et al. Differential cognitive performances between schizophrenic responders and non-responders to antipsychotics: correlation with course of the illness, psychopathology, attitude to the treatment and antipsychotics dosesPsychiatry Res. 2013;210(2):387-395.

3. Smart SE, Kępińska AP, Murray RM, MacCabe JH. Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studiesPsychol Med. 2021;51(1):44-53.

4. Zoghbi AW, Dhindsa RS, Goldberg TE, et al. High-impact rare genetic variants in severe schizophreniaProc Natl Acad Sci U S A. 2021;118(51):e2112560118.

5. Ruderfer DM, Charney AW, Readhead B, et al. Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approachLancet Psychiatry. 2016;3(4):350-357.

6. Farrell M, Dietterich TE, Harner MK, et al. Increased prevalence of rare copy number variants in treatment-resistant psychosis [published online ahead of print, 2022 Dec 1]. Schizophr Bull. 2022;sbac175.

7. Marshall CR, Howrigan DP, Merico D, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects [published correction appears in Nat Genet. 2017 Mar 30;49(4):651] [published correction appears in Nat Genet. 2017 Sep 27;49(10):1558]. Nat Genet. 2017;49(1):27-35.

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