Treatment-resistant schizophrenia in patients with 3q29 deletion: A case series of four patients.

Abstract

The 3q29 deletion is one of the strongest risk factors (odds ratio > 40) for schizophrenia (SCZ)1 and is associated with other psychiatric disorders including intellectual disability (ID), autism spectrum disorder, and bipolar disorder.2 However, details of psychiatric manifestations and treatment responses have not been described in these patients. Therefore, we present the longitudinal clinical course of four Japanese SCZ patients with 3q29 deletion. The 3q29 deletion in Patients 1, 2, and 4 was identified with array comparative genomic hybridization in our previous studies.3, 4 We retrospectively obtained clinical data of patients from medical records. Treatment-resistant schizophrenia (TRS) is defined as the persistence of symptoms despite ≥2 antipsychotic medications of adequate dose (≥600 mg/day chlorpromazine equivalent) and duration (≥4 weeks at a therapeutic dosage) with documented adherence. Other details are described in Supplementary materials. Full description and summary of clinical data are presented in Supplementary materials and Figure 1a, respectively. The 3q29 deletions identified in our study are displayed in Figure 1b. Patient 1, a 55-year-old female, was born with low birth weight. She had patent ductus arteriosus, exotropia, and cranial deformation. At age 20, she developed persecutory delusions and auditory hallucinations, and was diagnosed with SCZ. Her psychotic symptoms became refractory to treatments despite high doses of antipsychotics. She continued to show irritability, and valproate was prescribed. Brain magnetic resonance imaging (MRI) revealed mild pituitary gland enlargement (Fig. S1a,b). Electroencephalography (EEG) detected diffuse spike-and-wave discharges during 6-Hz photic stimulation (Fig. S2a). Patient 2, a 46-year-old male with a family history of SCZ in his mother, was diagnosed with mild ID in early childhood and had autistic features. At age 27, he developed auditory hallucinations and persecutory delusions. Despite high doses of antipsychotics, his psychotic symptoms did not improve significantly, resulting in many hospitalizations. Valproate was prescribed for his manic symptoms such as irritability and grandiosity. He also had ocular proptosis, right eye exotropia, and a high nasal bridge. Brain MRI revealed reduced volume in parietal and occipital lobes and cerebellum (Fig. S1c–f). Patient 3, a 17-year-old female, was born with nail hypoplasia and short phalanges of her left 2nd to fifth toes. At preschool age, she showed autistic features including hyperacusis. In her early teens, she had a brief psychotic episode with persecutory and grandiose delusions, and became socially withdrawn. In her mid-teens, she had consciousness disturbance and bizarre behavior, and ultrasound scan showed an ovarian cyst. She was suspected to have anti-N-methyl-D-aspartic acid (anti-NMDA) receptor encephalitis and received treatment. However, her psychotic symptoms worsened to include agitation or stupor, and she did not respond to high doses of antipsychotics. She received clozapine 400 mg/day for TRS, and her psychiatric symptoms markedly improved. Epileptic seizures and an abnormal EEG (Fig. S2b) were also observed, and lamotrigine was prescribed. Brain MRI revealed a left caudate nucleus defect (Fig. S1g). Patient 4, a 30-year-old female, had normal developmental milestones. At age 15, she developed auditory hallucinations, persecutory delusions, and aggression. Her psychotic symptoms did not improve significantly despite high doses of antipsychotics. She received clozapine 450 mg/day for TRS, and her psychotic symptoms improved. In this case series, TRS was a common characteristic among the four patients with 3q29 deletion. Another SCZ patient with 3q29 deletion was also reported to be treatment resistant.5 As D2 receptor antagonists were not effective, a hyperdopaminergic state in the mesolimbic dopamine pathways may not play a crucial role in 3q29 deletion-associated psychosis. Consistent with this, mice with 3q29 deletion display an attenuated response to the psychostimulant amphetamine, suggesting hypodopaminergic activity in the striatum.6 Involvement of hypodopaminergic activity in TRS is also suggested by positron emission tomography studies showing lower dopamine synthesis capacity in the striatum of TRS patients.7 Another potential mechanism of TRS is glutamate dysregulation.8 DLG1, a candidate risk gene within the 3q29 deletion, encodes a scaffolding protein that interacts with glutamate receptors.9 Clozapine, an antipsychotic for TRS, upregulates glutamate receptors and improves glutamatergic transmission.10 These findings suggest the potential usefulness of early introduction of clozapine for treatment of TRS patients with 3q29 deletion. A more detailed discussion is provided in the Supplementary materials. In conclusion, our findings may suggest a potential link between 3q29 deletion and TRS and that neurobiological studies of 3q29 deletion may provide insight into the mechanism of TRS. We thank all patients and their families for participating in this study. We also thank Mami Yoshida, Kiyori Monta, and Yukari Mitsui for their technical assistance. This research was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and the Ministry of Health, Labour and Welfare of Japan; the Japan Agency for Medical Research and Development (AMED) under Grant Nos. JP21dm0207069, JP21dm0207075, JP21ak0101113, JP21dk030710, JP21ek0109488, JP21km0405216, JP21ek0109411, and JP 21wm0425007; the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Nos. 15K19720, 18H04040, 20K20602, 21K07543, 21H00194, 17H05090, 17K10295, 21K07498, 18K19511, and 21H04815; the Uehara Memorial Foundation; and the SENSHIN Medical Research Foundation. Y.N., I.K., B.A., M.Y., H.K., M.B., and R.H. declare no conflict of interest. N.O. has received research support or speakers' honoraria from, or has served as a consultant to, Sumitomo Dainippon, Eisai, Otsuka, KAITEKI, Mitsubishi Tanabe, Shionogi, Eli Lilly, Mochida, DAIICHI SANKYO, Nihon Medi-Physics, Takeda, Meiji Seika Pharma, EA Pharma, Pfizer, MSD, Lundbeck Japan, Tsumura, Novartis, Boehringer Ingelheim, Viatris, Kyowa, Janssen, Yoshitomi Yakuhin, Kyowa Kirin, Ono, Astellas, UCB, Taisho Toyama, Medical Review, and Woolsey outside the submitted work. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Supporting information. Fig. S1. Brain MRI findings for patients with 3q29 deletion. Fig. S2. Electroencephalography (EEG) findings for patients with 3q29 deletion. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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