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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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The 15q11.2 BP1-BP2 (Burnside-Butler) deletion is a rare copy number variant impacting four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5), and carries increased risks for developmental delay, intellectual disability, and neuropsychiatric disorders (attention-deficit/hyperactivity disorder, autism, and psychosis). In this case report (supported by extensive developmental information and medication history), we present the complex clinical portrait of a 44-year-old woman with 15q11.2 BP1-BP2 deletion syndrome and chronic, treatment-resistant psychotic symptoms who has resided nearly her entire adult life in a long-term state psychiatric institution. Diagnostic and treatment implications are discussed.

There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results. Here, we review the return of results debate in genomics research and propose that, as for genomic studies of other medical conditions, psychiatric genomics researchers should offer findings that meet the minimum criteria stated above. Additionally, if resources allow, psychiatry researchers could consider offering to return pre-specified 'clinically valuable' findings even if not medically actionable-for instance, findings that help corroborate a psychiatric diagnosis, and findings that indicate important health risks. Similarly, we propose offering 'likely clinically valuable' findings, specifically, variants of uncertain significance potentially related to a participant's symptoms. The goal of this Perspective is to initiate a discussion that can help identify optimal ways of managing the return of results from psychiatric genomics research.

BACKGROUND Tardive dyskinesia (TD) is a chronic involuntary movement disorder frequently induced by dopamine receptor blockers, particularly first-generation antipsychotics. Until recently, management of TD was restricted to lowering the dose of the current medication, switching to another medication, or using off-label treatments with insufficient evidence of efficacy. Valbenazine, a vesicular monoamine transporter-2 (VMAT2) inhibitor, became the first drug to be approved by the FDA specifically for the treatment of TD. CASE REPORT We describe the case of a 49-year-old African-American woman who was diagnosed with bipolar disorder at the age of 34 and treated with lithium carbonate (900 mg daily) and citalopram (10 mg daily). She also received low doses of second-generation antipsychotics for weeks at a time, but these were always discontinued due to severe sedation. Over a decade later, at the age of 45, she experienced rapid onset of severe TD symptoms. She enrolled in a phase III double-blind clinical trial and received valbenazine 80 mg, with encouraging results. CONCLUSIONS Once-daily dosing of valbenazine (80 mg) was effective and safe over a long period, even in this atypical case of severe and rapid-onset TD.

Objective: Hyponatremia (serum sodium concentration [Na+] <136 mEq/L) is a potentially life-threatening condition often found chronically in patients with psychotic disorders. Vasopressin antagonists have recently been shown in short-term studies to correct hyponatremia in diverse patient populations, including individuals with both psychosis and idiopathic hyponatremia. However, the safety and efficacy of long-term administration of vaptans is only beginning to be investigated. The objective of this study was to assess whether one of the vaptans, specifically tolvaptan, maintained its safety and efficacy over a prolonged period in patients with psychosis and chronic idiopathic hyponatremia., Methods: SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia. Of the 111 patients enrolled in SALTWATER, eight were patients with both psychosis and idiopathic hyponatremia. These eight subjects provided a total of 7,406 patient days of exposure to oral tolvaptan., Results: Mean serum [Na+] in the eight psychotic patients increased from 131.6 mEq/L at baseline to >135 mEq/L throughout the observation period (p<0.05 versus baseline at most points). No drug-related adverse events led to study discontinuation., Conclusions: Chronic hyponatremia is known to have deleterious effects on the quality of life for many patient groups. These preliminary results suggest that oral tolvaptan provides rapid, effective, and safe treatment of chronic hyponatremia in patients with psychotic disorders and that the effect is safely sustained over long periods of time. These findings represent an important step forward in treating a significant unmet need in psychotic populations.

Hyponatremia (serum sodium concentration [Na+] < 136 mEq/L) is a potentially life-threatening condition. Recent evidence (Renneboog, Musch, Vandemergel, Manto, & Decaux, 2006) shows that even mild hyponatremia is associated with disorders of balance/gait. This retrospective analysis explored the influence of serum [Na+] on neuropsychological (NP) measurements at baseline from 44 patients with chronic hyponatremia who participated in an efficacy and safety study of an experimental compound over a decade ago. Group mean serum [Na+] was 124.8 ± 4.9 mEq/L. Age-adjusted partial correlations were computed between serum [Na+] and NP measurements, 39% of which were statistically significant--all involving psychomotor functioning. These findings replicate and extend previous observations that psychomotor deficits are, at least in part, associated with hyponatremia in these patients. While chronic hyponatremia is known to have deleterious effects on quality of life, motor and gait disturbances represent manifestations of mild hyponatremia that have until now gone unrecognized. A new class of medication, vasopressin antagonists, has been shown to correct hyponatremia. It will be important to explore the effects of correcting hyponatremia on psychomotor functioning in individuals with hyponatremia.

Chronic hyponatremia (CHN) has traditionally been considered asymptomatic. If symptoms are observed, they are often mistakenly attributed to the underlying disorder. However, in recent studies neuropsychological deficits have been associated with CHN. The authors sought to determine the association between CHN and motor deficits. They used previously collected data, and 41 subjects with hyponatremia were included. An exploratory factor analysis with principal component analysis (PCA) was performed (eigenvalues >1.0). Factor scores were generated for each subject based on the resultant PCA factor structure. Finally, partial correlations were computed to measure the degree of association between baseline serum sodium concentration [Na+] and individual neuropsychological factor scores with the effect of age removed. All significance tests were performed using 2-tailed comparisons with alpha level of p ≤ .05. A 3-factor model emerged accounting for 70.17% of the total variance, including 1 factor that loaded primarily with motor speed and reaction time. A significant correlation was observed between this motor factor and serum [Na+] (r = -.477, p = .002). These findings add to previous observations suggesting that CHN is associated with subtle yet harmful motor deficits.

Importance of the Field: Hyponatremia (serum sodium concentration < 136 mEq/liter) is a common and potentially life-threatening medical comorbidity seen in patients with psychotic disorders. Tolvaptan, a selective antagonist of the V(2)-receptor, is FDA-approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. This represents a major development in the care of psychotic individuals with hyponatremia., Areas Covered in the Review: This review provides an overview of the existing literature on prevalence rates and risk factors associated with hyponatremia in psychotic patients (1923 - present). Tolvaptan is discussed as a potential advance in the treatment of hyponatremia in patients with psychotic disorders, and preliminary data are reviewed., What the Reader Will Gain: The reader will gain an appreciation of the prevalence of hyponatremia among psychotic individuals, an understanding of the distinctions between acute and chronic hyponatremia in this population, and awareness that effective treatments are becoming available., Take Home Message: A modest literature exists regarding prevalence rates and risk factors associated with hyponatremia in psychotic populations. Hyponatremia is common and serious enough to merit clinical concern. Perhaps, now that tolvaptan has been FDA-approved, progress will accelerate and new insights will develop that begin to bring relief from this medical comorbidity among psychotic patients.