Evaluating endophenotypes for bipolar disorder.

Area of Science:

• Neuroscience
• Psychiatry
• Genetics

Background:

• Phenotypic heterogeneity complicates understanding bipolar disorder's neurobiology and genetics.
• Endophenotypes, as direct expressions of gene effects, can reduce this heterogeneity.
• This review examines clinical, epidemiological, neurobiological, and genetic findings to identify candidate endophenotypes for bipolar disorder.

Purpose of the Study:

• To review and evaluate candidate endophenotypes for bipolar disorder.
• To improve the definition of bipolar disorder phenotypes in genetic studies.
• To aid in dissecting psychiatric macro-phenotypes into biologically valid components for improved diagnostics.

Main Methods:

• Review of recent literature on clinical, epidemiological, neurobiological, and genetic findings.
• Evaluation of candidate endophenotypes based on specificity, temporal stability, heritability, familiarity, and plausibility.
• Discussion of associations among psychopathological and biological endophenotypes.

Main Results:

• Numerous findings indicate altered brain function, structure, neuropsychology, and neurochemical pathways in bipolar disorder patients and relatives.
• Candidate endophenotypes are present in early stages of the disorder and in at-risk subjects, suggesting a developmental origin.
• Stronger candidate endophenotypes include circadian rhythm instability, emotion/reward dysmodulation, neuroimmune alterations, attention/executive dysfunctions, anterior cingulate cortex thickness, and early white matter abnormalities.

Conclusions:

• Early white matter abnormalities may indicate a vulnerable brain, exacerbated by stressors, leading to bipolar disorder onset.
• Candidate endophenotypes suggest a developmental pathway to bipolar disorder.
• Further investigation into molecular and imaging endophenotypes can elucidate pathways to a vulnerable brain.