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Histone Deacetylases Appear to Have Pathophysiologic Role in Bipolar Disorder

Key findings

  • Genetic, pharmacological and pathological studies have suggested roles for histone deacetylases (HDACs) in bipolar disorder (BD)
  • This study measured HDAC expression in 11 participants with BD and 11 age- and sex-matched healthy controls using an HDAC-specific radiotracer during simultaneous magnetic resonance–positron emission tomography neuroimaging
  • HDAC expression was significantly lower in the BD group than the control group in the right amygdala and a broader fronto-limbic distribution including the thalamus, orbitofrontal cortex and hippocampus
  • In the BD group, HDAC expression was associated with emotion regulation in the frontal and perisylvian regions and with attention in the temporal and fronto-parietal regions
  • These results suggest a potential role for HDACs in the fundamental pathophysiology of BD as well as in two of its hallmark clinical features

The heritability of bipolar disorder (BD) is estimated to be 60%–80%, and environmental factors such as childhood trauma and life events add to the risk. Some research suggests the link between genetic and environmental factors could be explained by epigenetic mechanisms, including those regulated by histone deacetylases (HDACs). What's more, HDACs have been shown to have roles in both emotion and attention.

Researchers at Massachusetts General Hospital recently became the first to demonstrate a potential role for HDACs in the fundamental pathophysiology of BD as well as two of its hallmark clinical features. Chieh-En J. Tseng, PhD, Nicole R. Zürcher, PhD, and Jacob M. Hooker, PhD, of the Athinoula A. Martinos Center for Biomedical Imaging, and colleagues report their findings in Translational Psychiatry.

Study Methods

11 participants with BD (six with BD type 1, five with BD type 2) and 11 age- and sex-matched controls without neuropsychiatric illness underwent simultaneous magnetic resonance–positron emission tomography neuroimaging with an HDAC-specific radiotracer. Participants also completed the Measurement and Treatment Research to Improve Cognition in Schizophrenia(MATRICS) consensus cognitive battery (MCCB).

Region of Interest Analyses

Uptake of an HDAC-specific radiotracer was lower in the right amygdala of the BD group compared with controls (average difference, 7%; P = 0.03). The amygdala is involved in mood and emotion regulation.

In exploratory whole-brain analyses, the BD group also showed lower HDAC expression in the bilateral thalamus, orbitofrontal cortex and right hippocampus (Pcluster< 0.05). No area studied showed higherHDAC expression in the BD group.

Effects of Medication

No participants with BD were currently taking valproic acid, a well-known HDAC inhibitor, but six were taking lithium or lamotrigine, which have shown inhibitory effects on HDACs in vitro. Uptake of the radiotracer in the right amygdala of participants with BD was not related to lithium or lamotrigine use.

Emotion Regulation and Attention

There were no significant differences between the BD and control group in MCCB emotion regulation or attention scores. Neither was there any association between the scores in the BD group and uptake of the radiotracer in the right amygdala.

Exploratory whole-brain analyses demonstrated the following in the BD group:

  • Higher uptake of the radiotracer in the right prefrontal white matter and left perisylvian region was associated with higher (better) emotion regulation scores
  • Lower uptake in the right middle frontal gyrus was associated with higher emotion regulation scores
  • Higher uptake in temporal regions and lower uptake in fronto-parietal regions were associated with higher attention scores


In a previous study reported in the Journal of Clinical Investigation, Mass General researchers found that HDAC expression in the amygdala did not differ between individuals with schizophrenia and controls. Lower HDAC expression in the right amygdala may be a specific etiological feature of BD.

Emotion dysregulation and disturbances of attention can be present during not only manic and depressive episodes but also periods of euthymia, greatly adding to the burden of BD. For many patients, current medications do not adequately improve these processes. This study suggests that novel molecular strategies may someday be possible.

Learn more about the Martinos Center for Biomedical Imaging

Learn more about research in the Department of Psychiatry

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