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Novel Drug Target Proposed for Bipolar Disorder

Key findings

  • Dysregulation of brain energy metabolism may contribute to the psychopathology of bipolar disorder
  • PGC-1a, a protein that regulates inflammation and total body energy, represents a novel class of potential targets for bipolar disorder
  • In preliminary trials, antidiabetic drugs that target PGC-1a have shown promise in treating depressive symptoms
  • Researchers are conducting a proof-of-concept trial of bezafibrate for treatment of bipolar depression

The role of neural metabolism and inflammation in psychiatric illness is of great interest because proteins in those pathways might prove to be new drug targets. A key protein with profound and broad effects on metabolism and inflammation is peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α).

In Biological Psychiatry, Andrew A. Nierenberg, MD, director of Mass General's Dauten Family Center for Bipolar Innovation, and colleagues review why they believe PGC-1α may be a novel target for bipolar disorder and perhaps other psychiatric disorders, and how they are testing their hypothesis in a clinical trial.

PGC-1α regulates inflammation and total body energy, including the high metabolic energy of neurons and astrocytes. It also plays a part in regulating mitochondrial density. It does so by activating nuclear receptors, especially peroxisome proliferator-activated receptors (PPARs).

The authors note that Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis have been associated with dysregulated mitochondrial and brain energy metabolism, just as bipolar disorder has. In laboratory studies, lack of PGC-1α has been linked to each of the three neurodegenerative diseases, and there have been suggestions of a link between lack of PGC-1α and bipolar disorder.

In the neurodegenerative diseases, preliminary studies failed to show any efficacy of targeting PGC-1α with either of two antidiabetic PPAR agonists: pioglitazone or bezafibrate. The use of PPAR agonists to treat depression has been more promising. In a seminal case report published in 2009, psychiatrists described a woman with severe treatment-resistant major depression and metabolic syndrome for whom adjunctive pioglitazone therapy was associated with a marked and durable antidepressant response.

Since then, other research groups have observed similar results in seven clinical trials of pioglitazone or rosiglitazone for unipolar and/or bipolar depression. Some of the trials of pioglitazone showed that reduction of depressive symptoms was independent of its effects on insulin resistance.

Dr. Nierenberg's team is currently conducting a proof-of-concept trial of bezafibrate for treatment of patients with bipolar I disorder who are experiencing a current episode of major depression. Bezafibrate reverses some of the mitochondrial and cellular abnormalities in animal models of Huntington's disease and Parkinson's disease, and it has antioxidant and anti-inflammatory effects that may be neuroprotective.

Moreover, unlike pioglitazone and rosiglitazone, which are selective PPAR-gamma agonists, bezafibrate stimulates the full spectrum of PPARs (alpha, delta and gamma). Therefore, it carries much less risk of certain adverse effects that are serious for patients with bipolar disorder, including weight gain and increased cardiovascular risk.

If the proof-of-concept trial supports the efficacy of bezafibrate for bipolar depression, the researchers plan to investigate additional medications that target PGC-1α and PPARs. Also, they will continue to study the mechanisms of such agents in psychiatric disease.

Learn more about the Dauten Family Center for Bipolar Treatment Innovation

Learn more about the Bezafibrate Study for Bipolar Disorder

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