Cracking the bell jar

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Science Translational Medicine  22 Apr 2015:
Vol. 7, Issue 284, pp. 284ec65
DOI: 10.1126/scitranslmed.aab3128

“I didn’t know why I was going to cry, but I knew that if anybody spoke to me or looked at me too closely the tears would fly out of my eyes and the sobs would fly out of my throat and I’d cry for a week. I could feel the tears brimming and sloshing in me like water in a glass that is unsteady and too full.”― Sylvia Plath

Everyone occasionally feels sad, but sometimes depression can affect day-to-day life. Clinical depression is one of the most common mental illnesses, affecting more than 19 million Americans each year. Depression is thought to result from a combination of genetic and environmental factors, and antidepressant responsiveness may be modulated by our genetics. Lithium is one of the most commonly prescribed treatments for bipolar disorder, but it is also used to supplement treatment in major depression. Lithium directly inhibits glycogen synthase kinase 3 beta (GSK3β) activity, but the mechanism by which GSK3β inhibition improves depressive symptoms is unknown, as GSK3β plays a variety of roles in the brain.

In a characterization of both FKBP1-knockout mice and patient clinical samples, Gassen et al. provide compelling evidence of the ability of lithium and the antidepressant paroxetine to inhibit GSK3β through FKBP51, which binds GSK3β and promotes its phosphorylation at serine 9 (pGSK3βS9). In vitro, lithium and paroxetine increase pGSK3βS9 in wild-type but not in FKBP51-KO cells. Moreover, FKBP51-KO mice treated with paroxetine have an attenuated increase in pGSK3βS9 and reduced amelioration of depression-like behavior relative to wild-type animals. In blood cells obtained from 21 healthy subjects, the effect of lithium and paroxetine on pGSK3βS9 showed a significant positive correlation with FKBP51 expression. There was also a significant correlation of pGSK3βS9 activity in blood samples taken at the time of hospital admission from 55 depression patients with their subsequent clinical improvement. When blood samples from these patients were treated ex vivo with lithium or paroxetine, the cellular response of pGSK3βS9 even more highly correlated with clinical improvement.

The reported effect of antidepressants on pGSK3βS9 in patient blood samples suggests that this may serve as an indicator of patient pharmacological responsiveness, and also indicates that FKBP1 should be pursued as a target for therapeutic intervention in depression or bipolar disorder.

N. C. Gassen et al., FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications. Mol. Psychiatry 10.1038/mp.2015.38 (2015). [Abstract]

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