(Great Neck, NY - September 25, 2007) -- The medication tamoxifen, best known as a treatment for breast cancer, can dramatically reduce symptoms of the manic phase of bipolar disorder (BPD), and do so more quickly than many standard medications for the illness, a study conducted by a NARSAD researcher and colleagues at the National Institute of Mental Health has shown.

The researchers, led by Husseini K. Manji, M.D., a member of NARSAD’s Scientific Council, and Carlos A. Zarate Jr., M.D., a NARSAD Independent Investigator, published their results in the September issue of Bipolar Disorders. In their paper they explained how tamoxifen blocks an enzyme called protein kinase C (PKC) that regulates activities in brain cells. The enzyme is thought to be overactive during the manic phase of bipolar disorder.

By pointing to PKC as a target for new medications, the study raises the possibility of developing faster-acting treatments for the manic phase of BPD. Current medications for the manic phase generally take more than a week to begin working, and not everyone responds to them.

Tamoxifen is one of a class of drugs called SERMs, or selective estrogen receptor modulators. It is currently used for the treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopausal women. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease.

Tamoxifen was used experimentally in the bipolar study because it blocks PKC and is able to enter the brain. But it might not become a treatment of choice for BPD precisely because it blocks estrogen – the property that makes it useful as a treatment for breast cancer – and because it may cause endometrial cancer if taken over long periods of time.

Almost 6 million American adults have bipolar disorder, whose symptoms can be disabling. They include profound mood swings, from depression to soaring elation, often accompanied by severe irritability. Children also can develop the illness.

During the manic phase of bipolar disorder, patients are in “overdrive” and may throw themselves intensely into harmful behaviors they might not otherwise engage in. They might, for instance, indulge in risky pleasure-seeking behaviors with potentially serious health consequences, or lavish spending sprees they can’t afford. The symptoms sometimes are severe enough to require hospitalization.

“People think of the depressive phase of this brain disorder as the time of risk, but the manic phase has its own dangers,” said NIMH Director Thomas R. Insel, M.D., a former member of NARSAD’s Scientific Council. “Being able to treat the manic phase more quickly would be a great asset to patients, not just for restoring balance in mood, but also because it could help stop harmful behaviors before they start or get out of control.”

The three-week study of Drs. Manji and Zarate included eight patients who were given tamoxifen and eight who were given a placebo; all were adults and all were having a manic episode at the time of the study. Neither the patients nor the researchers knew which of the substances the patients were getting.

By the end of the study, 63 percent of the patients taking tamoxifen had reduced manic symptoms, compared with only 13 percent of those taking a placebo. Patients taking tamoxifen responded by the fifth day – which corresponds with the amount of time needed to build up enough tamoxifen in the brain to dampen PKC activity.

The researchers decided to test tamoxifen’s effects on the manic phase of bipolar disorder because standard medications used to treat this phase, specifically, are known to lower PKC activity, but do so via a roundabout biochemical route that takes time. Tamoxifen in contrast is known to block PKC directly. As the researchers suspected would happen, tamoxifen’s direct actions on PKC resulted in much faster relief of manic symptoms, compared with some of the standard medications available today.

“Mania isn’t just your average mood swing, where any of us might feel upbeat in response to something that happens. It’s part of a brain disorder whose behavioral manifestations can severely undermine people’s jobs, relationships, and health,” said Dr. Zarate. “The sooner we can help patients get back on an even keel, the more we can help them avoid major disruptions to their lives and the lives of people around them.”

Dr. Zarate is chief of the Mood and Anxiety Disorders Research Unit and Associate Clinical Director of the Laboratory of Molecular Pathophysiology at NIMH. He was named a NARSAD Independent Investigator in 2005.

Findings from another recent NIMH study strengthen the results. This previous study showed that the risk of developing bipolar disorder is influenced by a variation in a gene called DGKH. The gene makes a PKC-regulating protein known to be active in the biochemical pathway through which standard medications for bipolar disorder exert their effects – another sign that PKC is a promising direct target at which to aim new medications for the illness.

“We now have proof of principle. Our results show that targeting PKC directly, rather than through the trickle-down mechanisms of current medications, is a feasible strategy for developing faster-acting medications for mania,” said Dr. Manji, a NARSAD Scientific Council member and chief of the Laboratory of Molecular Pathophysiology at NIMH. “This is a major step toward developing new kinds of medications," he said.