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

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.

Treatment-resistant psychotic symptoms and early-onset dementia: A case report of the 3q29 deletion syndrome.

The 3q29 deletion is a rare copy number variant associated with neurodevelopmental and psychiatric disorders, including a >40-fold increased risk for schizophrenia. Current understanding of the clinical phenotype is derived primarily from published cases of patients in childhood or early adolescence. Symptoms include mild to moderate learning disability, developmental delay, facial dysmorphism, microcephaly, ocular disorders, and gastrointestinal abnormalities. There is, however, a lack of detailed longitudinal case studies describing 3q29 deletion syndrome in adults with psychosis. In this case report, we describe the lifetime clinical portrait of a 57-year-old woman with 3q29 deletion syndrome, treatment-resistant psychotic symptoms, multiple medical comorbidities, and a previously unreported co-occurrence of early-onset dementia.

Treatment-resistant psychotic symptoms and the 15q11.2 BP1-BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature.

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.

Successful Treatment of Severe Tardive Dyskinesia with Valbenazine, Including a Patient's Perspective.

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.

Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia. METHOD: In a randomized, double-blind, placebo-controlled 12-week trial, 40 patients unresponsive or partially responsive to clozapine monotherapy received a steady dose of clozapine combined with either placebo (N=20) or up to 6 mg/day of risperidone (N=20). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS), among other measures. Movement disorders were assessed with the Simpson-Angus Rating Scale. RESULTS: From baseline to week 6 and week 12, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine/placebo. The adverse event profile for clozapine/risperidone treatment was similar to that for clozapine/placebo. Simpson-Angus Rating Scale scores were lower with clozapine/risperidone treatment throughout the trial but increased to approach those of clozapine/placebo treatment at week 12. Clozapine/risperidone treatment did not induce additional weight gain, agranulocytosis, or seizures compared with clozapine/placebo treatment. CONCLUSIONS: In patients with a suboptimal response to clozapine, the addition of risperidone improved overall symptoms and positive and negative symptoms of schizophrenia. The combination appears to be safe and well tolerated. Augmentation of clozapine with risperidone may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.

Psychomotor deficits associated with hyponatremia: a retrospective analysis.

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.

Vaptans: a potential new approach for treating chronic hyponatremia in psychotic patients.

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.

Tolvaptan: a new tool for the effective treatment of hyponatremia in psychotic disorders.

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.

Early intervention with second-generation antipsychotics in first-episode psychosis: results of an 8-week naturalistic study.

OBJECTIVE: The objective was to compare short-term effectiveness of aripiprazole with three other second-generation antipsychotics (SGAs) in the treatment of first-episode psychosis. METHOD: In a naturalistic, 'single-blind' design, 60 subjects experiencing their first psychotic episode were treated for 8 weeks with aripiprazole (n = 19), risperidone (n = 16), olanzapine (n = 14) or quetiapine (n = 11). Medication and dosing decisions were made by treating psychiatrists, constrained to once-a-day dosing, low initial doses and no clozapine. Weekly ratings were obtained using the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Rating Scale and Barnes Akathasia Rating Scale. Weight and vital signs were also collected weekly. RESULTS: The group presented with severe psychotic symptoms (mean baseline PANSS total score of 105.2), which were reduced rapidly (P < 0.0005). The between-group and group by time interaction terms were non-significant. Similar reductions were seen across all PANSS sub-scales. At Week 1 the mean PANSS Activation Scale score was reduced more with olanzapine than in the other groups (P < 0.002). Few instances of extrapyramidal symptoms occurred; all were sporadic and did not require treatment. Group body weight increased by 7.3% over the study. Vital signs remained unchanged. CONCLUSIONS: Early intervention with low doses of four SGAs led to rapid symptom reduction in first-episode psychotic patients with severe psychopathology. Although no clear medication advantages were observed in the short term, longer duration studies with larger samples will be required for determining efficacy, rates of compliance, relapse prevention and diminished incidence of extrapyramidal signs and symptoms.

Double-blind, placebo-controlled, multicenter trial of a vasopressin V2-receptor antagonist in patients with schizophrenia and hyponatremia.

OBJECTIVES: Hyponatremia (serum sodium [Na+] concentration <136 mmol/L) is a prevalent and potentially life-threatening medical comorbidity for schizophrenic patients. No definitive pharmacological treatments have been established. Tolvaptan (OPC-41061), an oral non-peptide V2-receptor antagonist, was recently shown to correct hyponatremia in a diverse population of 448 hyponatremic patients. Efficacy in a sub-set of 19 schizophrenic patients with idiopathic hyponatremia included in that sample is specifically examined. METHODS: Nineteen subjects were randomly assigned to receive placebo (n = 12) or tolvaptan (n = 7) once daily for 30 days. Dosage adjustment was based on serum Na+ changes, initially 15 mg, titratable to 30 or 60 mg. The average daily area under the curve (AUC) changes in serum Na+ from baseline to Day 4 and Day 30 were co-primary end points. RESULTS: Increases in serum Na+ concentrations were significantly greater with tolvaptan than placebo at Day 4 (p = .0055) and at Day 30 (p < .0001). Two subjects receiving tolvaptan (28.6%) became dehydrated and experienced hypotension, and five subjects receiving placebo (41.7%) experienced symptoms associated with dilutional hyponatremia. CONCLUSIONS: These results suggest that tolvaptan effectively normalizes idiopathic hyponatremia in schizophrenic patients. Clinicians are advised to carefully monitor fluid status especially at the beginning of treatment to prevent dehydration.