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Protein Kinase C Inhibitors

Rationale for Use and Potential in the Treatment of Bipolar Disorder

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Abstract

Bipolar disorder is one of the most severely debilitating of all medical illnesses. For a large number of patients, outcomes are quite poor. The illness results in tremendous suffering for patients and their families and commonly impairs functioning and workplace productivity. Risks of increased morbidity and mortality, unfortunately, are frequent occurrences as well.

Until recently, little has been known about the specific molecular and cellular underpinnings of bipolar disorder. Such knowledge is crucial for the prospect of developing specific targeted therapies that are more effective and that have a more rapid onset of action than currently available treatments. Exciting recent data suggest that regulation of certain signalling pathways may be involved in the aetiology of bipolar disorder and that these pathways may be profitably targeted to treat the disorder. In particular, mania is associated with overactive protein kinase C (PKC) intracellular signalling, and recent genome-wide association studies of bipolar disorder have implicated an enzyme that reduces the activation of PKC. Importantly, the current mainstays in the treatment of mania, lithium (a monovalent cation) and valproate (a small fatty acid) indirectly inhibit PKC. In addition, recent clinical studies with the relatively selective PKC inhibitor tamoxifen add support to the relevance of the PKC target in bipolar disorder.

Overall, a growing body of work both on a preclinical and clinical level indicates that PKC signalling may play an important role in the pathophysiology and treatment of bipolar disorder. The development of CNS-penetrant PKC inhibitors may have considerable benefit for this devastating illness.

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Acknowledgements

We would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Heath, the Stanley Medical Research Institute. The authors have no conflicts of interest that are directly relevant to the content of this review. Husseini K. Manji is currently employed by Johnson & Johnson Pharmaceuticals Research and Development.

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  1. Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Bethesda, Maryland, USA

    Carlos A. Zarate & Husseini K. Manji

  2. Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Bethesda, Maryland, USA

    Carlos A. Zarate & Husseini K. Manji

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Correspondence to Carlos A. Zarate.

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Zarate, C.A., Manji, H.K. Protein Kinase C Inhibitors. CNS Drugs 23, 569–582 (2009). https://doi.org/10.2165/00023210-200923070-00003

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