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Letters to the Editor
January 2000

A Preliminary Investigation of a Protein Kinase C Inhibitor in the Treatment of Acute Mania

Arch Gen Psychiatry. 2000;57(1):95-97. doi:

The discovery of lithium's carbonate efficacy as an antimanic agent revolutionized the treatment of patients with bipolar disorder, but despite its remarkable effect on the lives of millions,1 the biochemical basis for its antimanic effects remains to be elucidated.2 In recent years, considerable progress has been made in the identification of signal transduction pathways as targets for the action of long-term lithium use.2,3 Regulation of signal transduction affects the intracellular signal generated by multiple neurotransmitter systems. These affects are attractive candidates as mediators of lithium's therapeutic effects, since the behavioral and physiological manifestations of mania are complex, including a disruption of sleep and motor, cognitive, and psychological function, and are likely mediated by a network of interconnected neurotransmitter pathways. It is particularly noteworthy that when administered long-term (days to weeks), the 2 clinically efficacious46 (but structurally dissimilar) antimanic agents, lithium and valproate, bring about similar isozyme-selective reductions in the levels of protein kinase C (PKC) α and ϵ.3,7,8 The pivotal role of the PKC signaling pathway in regulation of neuronal excitability, neurotransmitter release, and long-term synaptic events,9,10 has led us to postulate that the attenuation of PKC activity may play a major role in the antimanic effects of lithium and valproate. Thus, there is a clear need to investigate the efficacy of directly acting PKC inhibitors in the treatment of mania; such a strategy is arguably 1 of the more hypothesis-driven endeavors in bipolar research in recent years.

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