FEATURE REVIEW Neurobiological trait abnormalities in bipolar disorder C Langan and C McDonald Department of Psychiatry, Clinical Science Institute, National University of Ireland Galway, Galway, Ireland Dissecting trait neurobiological abnormalities in bipolar disorder (BD) from those characteriz- ing episodes of mood disturbance will help elucidate the aetiopathogenesis of the illness. This selective review highlights the immunological, neuroendocrinological, molecular biological and neuroimaging abnormalities characteristic of BD, with a focus on those likely to reflect trait abnormalities by virtue of their presence in euthymic patients or in unaffected relatives of patients at high genetic liability for illness. Trait neurobiological abnormalities of BD include heightened pro-inflammatory function and hypothalamic–pituitary–adrenal axis dysfunction. Dysfunction in the intracellular signal transduction pathway is indicated by elevated protein kinase A activity and altered intracellular calcium signalling. Consistent neuroimaging abnormalities include the presence of ventricular enlargement and white matter abnormalities in patients with BD, which may represent intermediate phenotypes of illness. In addition, spectroscopy studies indicate reduced prefrontal cerebral N-acetylaspartate and phospho- monoester concentrations. Functional neuroimaging studies of euthymic patients implicate inherently impaired neural networks subserving emotional regulation, including anterior limbic, ventral and dorsal prefrontal regions. Despite heterogeneous samples and conflicting findings pervading the literature, there is accumulating evidence for the existence of neurobiological trait abnormalities in BD at various scales of investigation. The aetiopatho- genesis of BD will be better elucidated by future clinical research studies, which investigate larger and more homogenous samples and employ a longitudinal design to dissect neurobiological abnormalities that are underlying traits of the illness from those related to episodes of mood exacerbation or pharmacological treatment. Molecular Psychiatry (2009) 14, 833–846; doi:10.1038/mp.2009.39; published online 19 May 2009 Keywords: bipolar disorder; neurobiology; neurotrophins; magnetic resonance imaging; positron emission tomography Introduction Bipolar disorder (BD) is an illness of high heritability characterized by recurrent episodes of elation and depression, with interspersed periods of relatively normal mood. There has been a wide array of research studies into neurobiological abnormalities associated with BD in recent years incorporating diverse levels of scale and investigative techniques from intracel- lular signalling processes through to neuroimaging of neural networks. These have revealed marked hetero- geneity of many neurobiological abnormalities de- scribed to date. This is most likely contributed to by the varying mood state of patients when assessed, the use of cross-sectional study designs and the examina- tion of relatively small samples of patients. In an effort to distil out those neurobiological abnormal- ities, which are likely to be underlying trait features of the disorder, some research groups have specifically examined samples of patients during euthymia or remission. An allied research design that seeks to identify those trait abnormalities related to under- lying susceptibility genes for the illness (that is, intermediate phenotypes) is to assess unaffected individuals genetically liable for BD, such as first- degree relatives of patients or co-twins. Any such abnormalities cannot be because of the effects of medication or illness course, which might contribute to neurobiological abnormalities identified in euthy- mic patients. Identifying intermediate phenotypes could assist in elucidating the pathways from geno- typic variation to the clinical syndrome of BD. 1 Alternatively, the identification of neurobiological abnormalities, which vary with mood state, best identified through longitudinal study designs, may help clarify the pathophysiology of affective episodes and serve as markers to assess the impact of therapeutic interventions. This selective review provides an overview of the neurobiological trait abnormalities characteristic of BD in the fields of immunology, neuroendocrinology, molecular biology and neuroimaging. The review focuses on research that has sought to identify the fundamental trait-related abnormalities as indicated by their detection in adult patients with confirmed Received 18 December 2007; revised 8 January 2009; accepted 16 April 2009; published online 19 May 2009 Correspondence: Dr C Langan, Department of Psychiatry, Clinical Science Institute, National University of Ireland, Galway, Ireland. E-mail: camilla.langan@nuigalway.ie Molecular Psychiatry (2009) 14, 833–846 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp