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: 10.25). 08/2006; 60(2):93-105. DOI: 10.1016/j.biopsych.2005.11.006
Source: PubMed

ABSTRACT 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, Aug 29, 2015
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    • "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: Our data represent a strong non-confirmative association between the relevance of thyroid function and thyroid autoimmunity in bipolar disorders.•The sample size and the parallel design are the main strengths of the study.•The study underscores the relevance of pharmacological treatments in the metabolism of thyroidal hormones, especially lithium.•The study did not support a familial aggregation (or endophenotype) of thyroidal antibodies positivization in pedegrees of bipolar I disorder.
    Psychoneuroendocrinology 01/2015; 51. DOI:10.1016/j.psyneuen.2014.09.032 · 5.59 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 · 5.40 Impact Factor
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    • "Conversely, the behavioral activation and manic symptoms caused by methylphenidate were antagonized by physostigmine (Janowsky et al., 1973a), supporting an adrenergic–cholinergic balance hypothesis. Moreover, methylphenidate as well as other psychostimulants such as amphetamine can induce symptoms relevant to mania in healthy persons (Peet and Peters, 1995) or exacerbate symptoms of mania in patients with bipolar disorder (Meyendorff et al., 1985; Hasler et al., 2006). Therefore, mania was thought to involve an underlying pathophysiology of hypocholinergia and increased adrenergic signaling in contrast to depression , which was thought to have the converse. "
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    ABSTRACT: Bipolar disorder is a unique illness characterized by fluctuations between mood states of depression and mania. Originally, an adrenergic-cholinergic balance hypothesis was postulated to underlie these different affective states. In this review, we update this hypothesis with recent findings from human and animal studies, suggesting that a catecholaminergic-cholinergic hypothesis may be more relevant. Evidence from neuroimaging studies, neuropharmacological interventions, and genetic associations support the notion that increased cholinergic functioning underlies depression, whereas increased activations of the catecholamines (dopamine and norepinephrine) underlie mania. Elevated functional acetylcholine during depression may affect both muscarinic and nicotinic acetylcholine receptors in a compensatory fashion. Increased functional dopamine and norepinephrine during mania on the other hand may affect receptor expression and functioning of dopamine reuptake transporters. Despite increasing evidence supporting this hypothesis, a relationship between these two neurotransmitter systems that could explain cycling between states of depression and mania is missing. Future studies should focus on the influence of environmental stimuli and genetic susceptibilities that may affect the catecholaminergic-cholinergic balance underlying cycling between the affective states. Overall, observations from recent studies add important data to this revised balance theory of bipolar disorder, renewing interest in this field of research.
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