Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects.

OBJECTIVE: Various measures of neurocognitive function show mean differences among individuals with schizophrenia (SZ), their relatives, and population controls. We use eigenvector transformations that maximize heritability of multiple neurocognitive measures, namely principal components of heritability (PCH), and evaluate how they distribute in SZ families and controls. METHODS: African-Americans with SZ or schizoaffective disorder (SZA) (n = 514), their relatives (n = 1092), and adult controls (n = 300) completed diagnostic interviews and computerized neurocognitive tests. PCH were estimated from 9 neurocognitive domains. Three PCH, PCH1-PCH3, were modeled to determine if status (SZ, relative, and control), other psychiatric covariates, and education were significant predictors of mean values. A small-scale linkage analysis was also conducted in a subset of the sample. RESULTS: PCH1, PCH2, and PCH3 account for 72% of the genetic variance. PCH1 represents 8 of 9 neurocognitive domains, is most highly correlated with spatial processing and emotion recognition, and has unadjusted heritability of 68%. The means for PCH1 differ significantly among SZ, their relatives, and controls. PCH2, orthogonal to PCH1, is most closely correlated with working memory and has an unadjusted heritability of 45%. Mean PCH2 is different only between SZ families and controls. PCH3 apparently represents a heritable component of neurocognition similar across the 3 diagnostic groups. No significant linkage evidence to PCH1-PCH3 or individual neurocognitive measures was discovered. CONCLUSIONS: PCH1 is highly heritable and genetically correlated with SZ. It should prove useful in future genetic analyses. Mean PCH2 differentiates SZ families and controls but not SZ and unaffected family members.

Evaluation of HLA polymorphisms in relation to schizophrenia risk and infectious exposure.

BACKGROUND: Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. METHOD: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. RESULTS: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. CONCLUSIONS: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.

Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.

OBJECTIVE: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. METHODS: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. RESULTS: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). CONCLUSIONS: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): evidence for impairment and heritability of neurocognitive functioning in families of schizophrenia patients.

OBJECTIVE: Neurocognitive impairments in schizophrenia are well replicated and widely regarded as candidate endophenotypes that may facilitate understanding of schizophrenia genetics and pathophysiology. The Project Among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) aims to identify genes underlying liability to schizophrenia. The unprecedented size of its study group (N=1,872), made possible through use of a computerized neurocognitive battery, can help further investigation of the genetics of neurocognition. The current analysis evaluated two characteristics not fully addressed in prior research: 1) heritability of neurocognition in African American families and 2) relationship between neurocognition and psychopathology in families of African American probands with schizophrenia or schizoaffective disorder. METHOD: Across eight data collection sites, patients with schizophrenia or schizoaffective disorder (N=610), their biological relatives (N=928), and community comparison subjects (N=334) completed a standardized diagnostic evaluation and the computerized neurocognitive battery. Performance accuracy and response time (speed) were measured separately for 10 neurocognitive domains. RESULTS: The patients with schizophrenia or schizoaffective disorder exhibited less accuracy and speed in most neurocognitive domains than their relatives both with and without other psychiatric disorders, who in turn were more impaired than comparison subjects in most domains. Estimated trait heritability after inclusion of the mean effect of diagnostic status, age, and sex revealed significant heritabilities for most neurocognitive domains, with the highest for accuracy of abstraction/flexibility, verbal memory, face memory, spatial processing, and emotion processing and for speed of attention. CONCLUSION: Neurocognitive functions in African American families are heritable and associated with schizophrenia. They show potential for gene-mapping studies.

Trends in CNS prescribing following the economic slowdown.

We investigated total prescription and new prescription trends before and after the economic slowdown beginning in September 2008. Over the July to November timeframe, both total prescriptions and new prescriptions for sleep aids, benzodiazepines, and antidepressants increased. There appears to be a small spike in the number of total and new prescriptions following September 2008, although this increase was not enough to cause a statistically significant change in the overall rate of increase of prescriptions over time. Discussion of data is provided.

Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples.

Recessive mutations in the phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH "tag" SNPs and three exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414). The samples included two US Caucasian cohorts (260 trios, 230 independent cases, 474 controls), Bulgarian families (659 trios), and an African-American sample (464 families, 401 controls). Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele (G) of rs1522305 from case-control analyses (z = 2.99, P = 0.006). This SNP was independently replicated in the Bulgarian cohort (z = 2.39, P = 0.015). A non-significant trend was also observed among African-American families (z = 1.39, P = 0.165), and combined analyses of all four samples were significant (rs1522305: chi(2) = 23.28, 8 d.f., P = 0.003). Results for rs1522305 met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case-control results in African-Americans detected an association with L321L (P = 0.047, OR = 1.46). Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted.

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods.

The Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) is a multi-site, NIMH-funded study that seeks to identify genetic polymorphisms that confer susceptibility to schizophrenia among African-Americans by linkage mapping and targeted association analyses. Because deficits in certain dimensions of cognitive ability are thought to underlie liability to schizophrenia, the project also examines cognitive abilities in individuals affected by schizophrenia and their extended family members. This article describes PAARTNERS study design, ascertainment methods and preliminary sample characteristics. We aim to recruit a sample of 1260 African-American families, all of whom have at least one proband with schizophrenia or schizoaffective disorder. The data collection protocol includes a structured Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, focused neurocognitive assessment, medical records review, and the collection of blood or buccal cells for genetic analyses. We have currently completed study procedures for 106 affected sib-pair, 457 case-parent trio and 23 multiplex families. A total of 289 probands have completed the best estimate final diagnosis process and 1153 probands and family members have been administered the computerized neuropsychological battery. This project lays the foundation for future analysis of cognitive and behavioral endophenotypes. This novel integration of diagnostic, neurocognitive and genetic data will also generate valuable information for future phenotypic and genetic studies of schizophrenia.

Treatment enhances ultradian rhythms of CSF monoamine metabolites in patients with major depressive episodes.

Unipolar and bipolar depressions show abnormal behavioral manifestations of ultradian (less than 24 h) rhythms, but abnormal rhythms of the central neurotransmitters thought to be important for depression pathophysiology (eg dopamine (DA) and serotonin (5-HT)) have not been shown in this time frame. Since antidepressant treatments normalize disrupted rhythms in depression (eg rapid-eye-movement sleep and hormonal rhythms), we hypothesized that depression-related changes in ultradian oscillations of DA and 5-HT might be revealed during antidepressant treatment. Cerebrospinal fluid (CSF) samples collected q10 min for 24 h in 13 patients experiencing major depressive episodes (MDE) before and after treatment for 5 weeks with sertraline or bupropion were assayed for levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), and their ratio was calculated. Data were analyzed in the frequency domain using Fourier transforms and multivariate permutation testing. Antidepressant treatments were associated with decreased variance for 5-HIAA, increased variance for HVA, and markedly increased variance for the HVA : 5-HIAA ratio (p<0.05, p<0.02, and p<0.003, respectively). With treatment, the correlations between 5-HIAA and HVA weakened (p=0.06). Power spectral density (PSD-the Fourier magnitude squared) of the 5-HIAA signals at periods of 1.75 and 3.7 h (both p<0.05) decreased, while circadian cycling of HVA levels (p<0.05) and of the ratio (p<0.005) increased after treatment. The PSD of the full-length HVA : 5-HIAA ratio series after treatment increased in rapid variability (20-103 min periods, p<0.05). Spectrographic windowing demonstrated a focal span of enhanced HVA : 5-HIAA ratio variability following antidepressant treatment, in an approximately 84-min period through the evening (p<0.05). Periodic neurotransmitter relationships in depressed patients were altered by treatment in this analysis of a small data set. This may represent a baseline abnormality in the regulation of periodic functions involved in the depression pathophysiology, but it could also be due to an unrelated antidepressant effect. Further studies including comparisons with healthy subject data are in progress.

Association of a critical CSF tryptophan threshold level with depressive relapse.

This work studies association between relapse during acute tryptophan depletion (ATD) and CSF level of tryptophan (TRP) in remitted depressives treated with sertraline or bupropion. Eight medication-responding depressives ingested an ATD amino acid mixture during 48-h continuous CSF sampling before and after treatment. Mood rating scores were compared with nadir levels of TRP in CSF. CSF TRP nadirs averaged 8.7% of am baselines in remitted patients. Mood relapsed whenever the CSF nadir was below 40 nmol/l TRP in remitted patients, and never when above (Fisher's exact test, P=0.029). Relapsing medication responders also showed very low preantidepressant ATD-induced nadirs. ATD-induced relapses were associated with low CSF TRP levels. Individual susceptibility to depletion may be independent of antidepressant treatment, mood state, or treatment status. Resistance to relapse may invoke an undefined, protective CNS mechanism against extremely low CSF levels of TRP during ATD.