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Background: The identification of predictors of treatment response holds tremendous potential for the improvement of clinical outcomes in bipolar disorder (BP). The goal of this project is to evaluate the test-retest reliability of a new clinical tool, the Lithium Questionnaire (LQ), for the retrospective assessment of long-term lithium use in research participants with BP., Methods: Twenty-nine individuals with BP-I (n=27), major depression (n=1), or schizoaffective disorder (n=1) were recruited for participation. The LQ was administered to all participants at two time-points, spaced 17 months apart on average, and used to determine each subject׳s score on the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder Scale, or the Alda Scale. Scores were confirmed through a best-estimate procedure, and test-retest reliability (intra-class correlation coefficient [ICC]) of the LQ was calculated., Results: The correlation between the total Alda Scale scores at the two time-points was in the moderate range (ICC=0.60). Relevant clinical factors such as age or presence of Axis I psychiatric comorbidity did not influence the reliability., Limitations: The validity of the LQ was not examined. Inclusion of two participants with non-BP diagnoses may have affected the LQ׳s reliability, but re-analysis of our data after exclusion of these participants did not influence the reliability. The absence of measures of mood and cognition at time of LQ may be a limitation of this work., Conclusions: The LQ holds promise for the standardization of the retrospective assessment of long-term treatment in BP., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles., (Copyright © 2011 Wiley-Liss, Inc.)

YWHAH is a positional and functional candidate gene for both schizophrenia and bipolar disorder (BP). This gene has been previously shown to be associated with both disorders, and the chromosome location (22q12.3) has been repeatedly implicated in linkage studies for these disorders. It codes for the eta subtype of the 14-3-3 protein family, is expressed mainly in brain, and is involved in HPA axis regulation. We investigated the association of YWHAH with BP in a large sample, consisting of 1211 subjects from 318 nuclear families including 554 affected offspring. We tested for association with the standard BP phenotype as well as subtypes defined by psychotic and mood-incongruent features. We genotyped five tag SNPs and the (GCCTGCA)(n) polymorphic locus present in this gene. Using a family-based association test, we found that rs2246704 was associated with BP (OR 1.31, P = 0.03) and psychotic BP (OR = 1.66, P = 0.002). The polymorphic repeat and two other SNPs were also modestly associated with psychotic BP. We have provided additional evidence for association of variants in YWHAH with major mental illness. Additional association analyses of larger sample sets will be required to clarify the role of YWHAH in schizophrenia and BP. The use of clinical sub-phenotypes such as psychotic features or other potential schizophrenia/BP overlap variables including cognitive abnormalities and poor functioning might shed further light on the potential subtypes of illness most closely associated with genetic variation in YWHAH., ((c) 2009 Wiley-Liss, Inc.)

Psychotic features, defined as delusions or hallucinations, commonly occur in bipolar disorder (BP) and may be indicative of a more homogeneous form of the illness, with possible etiologic ties to schizophrenia. Several studies have shown that psychotic features aggregate in bipolar families, and increased interest in the molecular genetics of psychotic BP is emerging. Although preliminary, linkage studies of psychotic BP show replicated evidence for suggestive genome-wide linkage to chromosomes 8p and 13q, which have been implicated in prior linkage studies of schizophrenia and BP. Association studies of psychotic BP and subtypes such as mood-incongruent psychotic BP have uncovered modest positive results for several candidate schizophrenia susceptibility genes, including dysbindin, DAOA/G30, Disrupted-in-Schizophrenia-1, and neuregulin 1. These tentative results are consistent with the hypothesis that the subphenotype of psychotic BP may represent a clinical manifestation of "overlap" genes between schizophrenia and mood disorder syndromes.

Background: While some prior studies have found higher rates of psychotic depression in those with bipolar disorder or a bipolar relative, others have failed to confirm these observations. We examined the relationship of psychotic depression to polarity in several large familial samples of mood disorder., Methods: A total of 4,724 subjects with major mood disorder in three family studies on the genetics of bipolar I disorder (BPI) or recurrent major depressive disorder (MDDR) were administered semi-structured interviews by clinicians. Determination of psychotic features was based on a report of hallucinations and/or delusions during the most severe depressive episode in the Schedule for Affective Disorders and Schizophrenia-Lifetime Version or the Diagnostic Interview for Genetic Studies interview. Rates of psychotic depression were calculated by diagnostic category and comparisons were made between diagnoses within and across studies using the generalized estimating equation., Results: A diagnosis of BPI disorder was strongly predictive of psychotic features during depression compared to MDDR [odds ratio (OR) = 4.61, p < 0.0005]. Having bipolar II compared to MDDR was not predictive of psychosis (OR = 1.05, p = 0.260), nor was having a family history of BPI in MDDR subjects (OR = 1.20, p = 0.840)., Conclusions: Psychotic features during a depressive episode increased the likelihood of a BPI diagnosis. Prospective studies are needed to confirm these findings. The potential genetic underpinnings of psychotic depression warrant further study.