Toward Constructing an Endophenotype Strategy for Bipolar Disorders

Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland, USA.
Biological Psychiatry (Impact Factor: 10.26). 08/2006; 60(2):93-105. DOI: 10.1016/j.biopsych.2005.11.006
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Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients' sensitivity to sleep deprivation, psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged.

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Available from: Gregor Hasler, Oct 10, 2015
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    • "In conclusion, this association study of ER in a sample of patients with BD identified four SNPs accounting for 24.5% of the variance of AIM score. These results are illustrative of the proposal that focusing on a quantitative phenotype of the disorder (here affect intensity), possibly involving a smaller number of genes with a higher effect size, might help reducing the underlying genetic heterogeneity, thus favoring the identification of susceptibility genes (Hasler et al., 2006; Schulze 2010; Schulze and McMahon 2004). Further studies are required to confirm the involvement of the candidate genes identified here in their involvement in the regulation of affective states. "
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    ABSTRACT: Background: Emotional reactivity has been proposed as a relevant intermediate phenotype of bipolar disorder (BD). Our goal was to identify genetic factors underlying emotional reactivity in a sample of bipolar patients. Methods: Affect intensity (a proxy measure of emotional reactivity) was measured in a sample of 281 euthymic patients meeting DSM-IV criteria for BD. We use a validated dimensional tool, the 40-item self-report Affect Intensity Measure scale developed by Larsen and Diener. Patients with BD were genotyped for 475. 740 SNPs (using Illumina HumanHap550 Beadchips or HumanHap610 Quad chip). Association was investigated with a general mixed regression model of the continuous trait against genotypes, including gender as covariate. Results: Four regions (1p31.3, 3q13.11, 11p15.1 and 11q14.4) with a p-value lower or equal to 5×10(-6) were identified. In these regions, the joint effect of the four variants accounted for 24.5% of the variance of AIM score. Epistasis analysis did not detect interaction between these variants. In the 11p15.1 region, the rs10766743 located in the intron of the NELL1 gene remained significant after correction for multiple testing (p=2×10(-7)). Conclusions: These findings illustrate that focusing on quantitative intermediate phenotypes can facilitate the identification of genetic susceptibility variants in BD.
    Journal of Affective Disorders 09/2015; 188:101-106. DOI:10.1016/j.jad.2015.08.037 · 3.38 Impact Factor
    • "The concordance rates for monozygotic twins are only 40—70% (Craddock and Jones, 2001). Among predictive or predisposing factors at the time of the disease onset (Hasler et al., 2006), a link between bipolar disorder and alterations in thyroid function, specifically in thyroid autoimmunity , has been suggested (Chakrabarti, 2011). However, the precise nature of this link remains unclear and some important implications, such as the familial aggregation of the abnormalities, are not well known. "
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    ABSTRACT: Background: Among the biological factors associated with the development and outcomes in Bipolar Disorder Type I (BD-I), previous studies have highlighted the involvement of both thyroid function and/or auto-immunity, proposing a thyroid endophenotype. The objective of this study was to determine the presence of thyroid alterations in BD-I and their first-degree relatives (FDR). Methodology: Unselected, cross-sectional case-control study with parallel analysis of individuals affected by BD-I (239), their FD-R (131), and 108 healthy controls. Thyroidal functional abnormalities (TSH and free T4) and thyroidal antibodies (thyroglobulin and thyroperoxidase antibodies) were studied. Assessments were carried out in parallel. The sample was described using arithmetic means, standard deviations, percentages and ranges. Chi-square, Student-t tests, ANOVA and Pearson correlation coefficients were used when indicated. Results: BD-I on actual and/or ever treated with lithium showed significant thyroidal functional abnormalities as compared to their FD-R and healthy controls. This BD-I subgroup showed a significant greater proportion of subjects suffering from subclinical hypothyroidism (22%). The role of gender/lithium interactions was relevant. The groups did not show differences in terms of positivization of thyroidal antibodies. Limitations: The crosssectional design and the lack of determination of dietary iodine deficiencies and/or thyroidal ecographical controls may be a drawback. Conclusions: The present study supports previous findings on the effect of lithium treatment on thyroidal functional, but did not support previous findings related to a familial association or endophenotype. In addition, the present study did not support a familial aggregation of thyroidal antibodies positivization in pedegrees of BD-I.
    Psychoneuroendocrinology 01/2015; 51. DOI:10.1016/j.psyneuen.2014.09.032 · 4.94 Impact Factor
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    • "However, identification of individual risk genes is still unsuccessful. This is striking since risk genes have been found for complex genetic diseases with lower heritability than bipolar disorder, such as diabetes mellitus, Alzheimer's disease, and breast cancer (Hasler et al., 2006). "
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    ABSTRACT: In bipolar disorders, there are unclear diagnostic boundaries with unipolar depression and schizophrenia, inconsistency of treatment guidelines, relatively long trial-and-error phases of treatment optimization, and increasing use of complex combination therapies lacking empirical evidence. These suggest that the current definition of bipolar disorders based on clinical symptoms reflects a clinically and etiologically heterogeneous entity. Stratification of treatments for bipolar disorders based on biomarkers and improved clinical markers are greatly needed to increase the efficacy of currently available treatments and improve the chances of developing novel therapeutic approaches. This review provides a theoretical framework to identify biomarkers and summarizes the most promising markers for stratification regarding beneficial and adverse treatment effects. State and stage specifiers, neuropsychological tests, neuroimaging, and genetic and epigenetic biomarkers will be discussed with respect to their ability to predict the response to specific pharmacological and psychosocial psychotherapies for bipolar disorders. To date, the most reliable markers are derived from psychopathology and history-taking, while no biomarker has been found that reliably predicts individual treatment responses. This review underlines both the importance of clinical diagnostic skills and the need for biological research to identify markers that will allow the targeting of treatment specifically to sub-populations of bipolar patients who are more likely to benefit from a specific treatment and less likely to develop adverse reactions. Copyright © 2015. Published by Elsevier B.V.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 01/2015; 58(3). DOI:10.1016/j.euroneuro.2014.12.006 · 4.37 Impact Factor
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