Enhanced Cortical Androgen Action Noted in Bipolar Disorder

Patients with bipolar disorder may experience elevated cortical androgen activity compared with individuals without bipolar disorder.

The relationship between low testosterone and greater negative symptoms in men with schizophrenia, and a greater prevalence of anxiety and depressive disorders in men, prompted researchers to hypothesize that androgens may contribute to brain pathophysiology in mental illnesses. To this end, patients with bipolar disorder may experience elevated cortical androgen activity compared with healthy individuals, according to study data published in Psychiatry Research. No such results were seen for individuals with schizophrenia or major depressive disorder.

Investigators assessed androgen receptor (AR) messenger RNA (mRNA) levels in postmortem dorsolateral prefrontal cortex samples from the Stanley Medical Research Institute Array collection. Samples were available for 35 individuals each with either schizophrenia or bipolar disorder, as well as for 35 healthy control individuals. AR polymorphic trinucleotide (CAG) repeat length was determined from genomic DNA sequencing; quantitative polymerase chain reaction was performed to measure AR and 5α-reductase mRNA expression. Layer-specific AR mRNA expression was determined with in situ hybridization performed for 15 individuals each with either schizophrenia, bipolar disorder, or major depressive disorder, and for 15 control individuals without a psychiatric diagnosis.

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AR mRNA levels were found to be increased by 15.5% in bipolar disorder cases relative to controls (P =.05) and by 18.1% relative to schizophrenia cases (P =.02). AR mRNA levels were not significantly different between individuals with schizophrenia and control individuals. There were no significant differences in 5α-reductase mRNA levels between diagnostic groups. AR mRNA and 5α-reductase mRNA levels were significantly positively correlated in bipolar disorder cases (P =.02), nominally positively correlated in control cases (P =.07), and not correlated in schizophrenia cases (P =.49).

CAG repeat length in the sample ranged from 14 to 30 repeats, with 58% of cases having 20 to 23 repeats. CAG repeat length was found to be significantly lower in bipolar disorder relative to schizophrenia cases (P =.02), although no significant difference was detected between control individuals and either schizophrenia (P =.26) or bipolar disorder cases (P =.22). No significant correlation was observed between CAG repeat length and AR mRNA expression either in the total cohort or in specific diagnostic groups. Per hybridization analyses, a significant main effect of cortical layer was observed on AR mRNA expression levels (P <.001). Although layer-specific AR mRNA levels did not differ between diagnostic groups, AR mRNA expression was highest in cortical layers IV and V.

The investigators noted the limitations associated with postmortem studies, including the potential confounding effects of chronic disease. Larger group sizes are also necessary to confirm the genetic association between AR CAG repeat length and psychiatric diagnosis.

These data present 3 distinct forms of evidence supporting enhanced androgen activity in the brains of patients with bipolar disorder: enhanced AR mRNA expression, positive correlation between AR and 5α-reductase mRNA, and lower CAG repeat length compared with schizophrenia cases. These results support the use of “sex steroid modulating therapies… [to] moderate androgen action in people with bipolar disorder,” investigators wrote.

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Owens SJ, Purves-Tyson TD, Webster MJ, Shannon Weickert C. Evidence for enhanced androgen action in the prefrontal cortex of people with bipolar disorder but not schizophrenia or major depressive disorder. Psychiatry Res. 2019;280:112503.