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, 25 (4), 468-73

Decreased AKT1/mTOR Pathway mRNA Expression in Short-Term Bipolar Disorder

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Decreased AKT1/mTOR Pathway mRNA Expression in Short-Term Bipolar Disorder

Rodrigo Machado-Vieira et al. Eur Neuropsychopharmacol.

Abstract

Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.

Keywords: AKT; Bipolar disorder; Depression; Lithium; Treatment; mTOR.

Conflict of interest statement

Conflict of interest

Dr Zarate is listed as a coinventor on a patent for the use of ketamine and its metabolites in major depression. Dr Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. The other authors declare no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1
AKT1 (A) and mTOR (B) expression in unmedicated, short-term bipolar disorder during acute depressive episode (BD Depression), after 6-weeks of lithium treatment (BD Lithium) and healthy subjects (Controls); *p≤0.001, **p≤0.01.
Figure 2
Figure 2
Association between changes in AKT-1 and Bcl-2 with improvement in depression symptoms with lithium.

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