Influence of ZNF804a on brain structure volumes and symptom severity in individuals with schizophrenia.

CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F = 3.98, P = .02; F = 4.95, P = .007; and F = 3.08, P = .05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F = 3.93, P = .02) and frontal WM volumes (F = 7.16, P < .001) and on psychotic symptom severity (F = 6.07, P = .003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F = 4.61, P = .03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.

Informed consent in medication-free schizophrenia research.

OBJECTIVE: The authors' goal was to determine whether people with schizophrenia experience changes in decisional capacity when their antipsychotic regimens are discontinued for research purposes. METHOD: Capacity for informed consent for research, neuropsychological performance, and psychiatric symptoms were assessed before and after discontinuation of antipsychotic medication in 10 individuals with schizophrenia. RESULTS: Overall, participants showed minimal change on most measures during the medication-free interval, although their reasoning ability declined significantly. All participants who demonstrated adequate understanding of study procedures at enrollment retained this capacity throughout the study. CONCLUSIONS: Participants in medication-free schizophrenia research do not show a major decline in decisional capacity. However, the apparent decline in reasoning ability found in this study is of concern and underscores the need for both additional research on this topic and the development of remediational interventions aimed at enhancing this aspect of decisional capacity.

Weight gain associated with the -759C/T polymorphism of the 5HT2C receptor and olanzapine.

BACKGROUND: Weight gain from atypical antipsychotic use has become a significant problem. Recent reports have liked the -759 polymorphism of the 5HT2C receptor and obesity as well as weight gain from chlorpromazine, risperidone, and clozapine. AIM: To determine associations between weight gain during olanzapine treatment and the -759C/T polymorphism of the 5HT2C receptor gene. METHODS: This study included 42 acutely ill patients with schizophrenia (DSM-IV). Weekly assessments included Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Negative Symptoms (SANS), and weight measurements. Olanzapine was titrated to a fixed dose (7.5-20 mg/day) for 2-6 weeks. A 24 hr plasma level was obtained at the endpoint visit. Genomic DNA was isolated from a whole blood sample and analyzed for the -759C/T polymorphism of the 5HT2C receptor. RESULTS: A chi-square analysis was conducted comparing the distribution of T and C alleles in subjects grouped as gaining more or less than 5, 7, and 10% of their baseline weight during treatment with olanzapine. A threshold of 10% was found to be significant. The distribution of T alleles was higher in subjects not gaining 10% of more of their body weight compared who did gain significant weight (11/27 (40.7%) vs. 0/15 (100%), chi2 = 11.805, P = 0.0035). CONCLUSIONS: Subjects with a T allele of the 5HT2C receptor -759C/T polymorphism may have a lower incidence of weight gain from olanzapine over a 6 week period compared to those with the C allele. These results need to be replicated.

5-HT2A receptor promoter polymorphism, -1438G/A and negative symptom response to olanzapine in schizophrenia.

The 5-HT2A receptor promoter -1438G/A polymorphism, which is in complete linkage disequilibrium with the 5-HT2A 102T/C polymorphism, may be related to antipsychotic response. The aim of this paper is to determine relationships between the -1438G/A polymorphism and olanzapine negative symptom response. DNA from 41 subjects with schizophrenia (as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was analyzed for the -1438G/A polymorphism. Olanzapine (7.5-20 mg/day) was given for 6 weeks and response was assessed using the Scale for Assessment of Negative Symptoms (SANS). A linear regression used a dependent variable of percent change in SANS. Independent variables included 5-HT2A polymorphisms and interactions. The -1438G/A polymorphism and percent change in SANS showed a significant trend (P=.0542). The A/A genotype group had a 45% reduction in SANS compared with 19% in the other groups. We conclude that the A/A genotype may be associated with olanzapine negative symptom response, seen as a 2-fold greater percent reduction in SANS, and may be clinically relevant.

Insomnia as a predictor for symptom worsening following antipsychotic withdrawal in schizophrenia.

Sleep disturbances have been associated with schizophrenia, and are an especially prominent feature during the prodrome preceding psychotic relapse. In this study, we examined the changes in sleep quality following withdrawal of antipsychotic treatment, as well as the predictive value of sleep disturbances on symptom exacerbation. One hundred twenty-two patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder underwent a 3-week medication wash-out prior to neuroimaging studies. Sleep quality was rated using items on the Hamilton Rating Scale for Depression (HAM-D), while symptom severity was measured using the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS). Sleep quality deteriorated progressively following antipsychotic discontinuation. Total insomnia score prior to antipsychotic withdrawal had a significant effect on the severity of psychotic symptoms at the last weekly assessment, while baseline terminal insomnia had a significant effect on disorganized symptoms at the end of the medication-free period. These findings were independent of baseline symptom severity. Our findings suggest that schizophrenia patients with sleep disturbances are at a greater risk for worsening of positive symptoms after antipsychotic discontinuation. The implications of these findings in research and clinical settings are discussed.

Capacity to provide informed consent for participation in schizophrenia and HIV research.

OBJECTIVE: The degree to which people with psychiatric symptoms and cognitive dysfunction can provide informed consent to participate in research is a controversial issue. This study was designed to examine the capacity of subjects with schizophrenia and subjects with HIV to provide informed consent for research participation and to determine the relationships among cognitive dysfunction, psychiatric symptoms, and decisional capacity. METHOD: Twenty-five men and women with a DSM-IV diagnosis of schizophrenia and 25 men and women with HIV were recruited. The groups were compared in terms of neuropsychological functioning, psychiatric symptoms, and ability to provide informed consent to a hypothetical drug trial. RESULTS: Eighty percent of the subjects with schizophrenia and 96% of the HIV-positive subjects demonstrated adequate capacity to consent to the hypothetical drug trial, but subjects in the schizophrenia group had significantly lower scores on two of the four aspects of decisional capacity. For the subjects with schizophrenia, neuropsychological functioning and psychiatric symptoms (e.g., apathy and avolition), but not psychotic symptoms (e.g., hallucinations and delusions), were significantly associated with decisional capacity. CONCLUSIONS: The majority of subjects who are recruited and willing to participate in schizophrenia or HIV research will have adequate capacity to provide consent. Cognitive dysfunction and the symptoms shown to be associated with impaired decisional capacity are not unique to schizophrenia and may occur with many other forms of illness. These findings underscore the importance of considering how decisional capacity will be assessed in all types of research, regardless of the specific condition being studied.