Cited by 122Bipolar Disorder and TreatmentTreatment of Major DepressionSchizophrenia research and treatment

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Protein Kinase C Inhibitors: Rationale for Use and Potential in the Treatment of Bipolar Disorder

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Zarate, Carlos A., Manji, Husseini K.·2009·CNS Drugs

DOI 10.2165/00023210-200923070-00003PMC PMC2802274

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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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Authors: Zarate, C. A., & Manji, H. K.
Affiliations: National Institutes of Health (US)
National Institute of Mental Health (US)
Corresponding author: Zarate, Carlos A.
ORCID: Zarate, Carlos A.
Manji, Husseini K.
Venue: CNS Drugs
Publisher: Springer Science and Business Media LLC
Published: 2009-07
Volume: 23
Issue: 7
Pages: 569-582
ISSN: 1172-7047 (ISSN-L)
DOI: 10.2165/00023210-200923070-00003
PMC: PMC2802274
OpenAlex: W2139699538
Cited by: 122
References: 80
Citations by year: 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 10 · 2018: 5 · 2017: 13 · 2016: 6 · 2015: 6 · 2014: 10 · 2013: 7 · 2012: 12
FWCI: 1.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: CNS Drugs (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute of Mental Health (Z01MH002830)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords: protein kinase C, PKC inhibitors, bipolar disorder, mania, lithium, valproic acid, tamoxifen, targeted therapy, genome-wide association study
MeSH terms: Animals, Bipolar Disorder, Clinical Trials as Topic, Humans, Models, Biological, Protein Kinase C, Antimanic Agents, Protein Kinase Inhibitors

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Protein Kinase C Inhibitors: Rationale for Use and Potential in the Treatment of Bipolar Disorder

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