A press release in January 2007 generated excitement among Chicago researchers and clinicians studying and treating bipolar disorder.
Dr. Alan Kozikowski and his group in the Department of Medicinal Chemistry and Pharmacognosy at the University of Illinois in Chicago were awarded a three-year, $2.1 million grant from the National Institute of Mental Health (NIMH). The grant was awarded for research toward the development a new drug, a safe and selective glycogen synthase kinase-3 (GSK-3) inhibitor, to treat bipolar disorder.
Glycogen synthase kinase was initially identified as a key enzyme involved in glycogen metabolism. Later, GSK was implicated in a variety of cell functions. When GSK-3 is active, it rapidly destroys downstream transcription factors that are essential for cell survival. A survey of current medical literature shows that GSK-3 inhibition is a hot topic in many fields. Investigators are looking into new drugs for treating type II diabetes, cancer, inflammation, and shock.
Interest in GSK-3 in psychiatry started in late 1990’s and early 2000’s. Researchers found that the therapeutic effects of lithium and valproic acid on bipolar disorder were mediated through pathways involving GSK-3. Lithium is identified as a specific inhibitor of GSK-3 beta, among its other functions.
Drs. Husseini Manji and Todd Gould at NIMH are the leading investigators on GSK-3 beta and bipolar disorder. Their work suggests that GSK-3 beta plays an important role in regulating synaptic plasticity, cell survival, and circadian rhythms in the CNS. The neuroprotective effect of inhibiting GSK-3 beta is also being tested for other neurological diseases such as Alzheimer, Parkinson, Huntington, and stroke.
Dr. Kozikowski and his colleagues, using a mouse model for mania, are testing new chemicals that specifically inhibit GSK-3 beta. By mimicking the therapeutic action of mood stabilizers, designer drugs may be developed for treating patients with bipolar disorder and other neurodegenerative disorders. However, it will take years for a new product to be brought into clinical trials. Whether newly-developed synthetic agents will have any clinical superiority over lithium and existing mood stabilizers is not known. In the mean time, we are all eagerly anticipating the outcome.