NIH

Mood booster.
Tamoxifen eased symptoms of mania in a small clinical trial.

Breast Cancer Drug Effective Against Mania

Tamoxifen, a drug commonly used to prevent recurrence of breast cancer, is also effective against the manic stage of bipolar disorder, new research suggests.

Bipolar disorder--formerly known as manic depression--afflicts about 1% of the population. As its outmoded moniker suggests, patients experience periods of both deep depression and mania, an extremely hyperactive state that can lead to wild spending, risk-taking, and extreme sexual activity. When mixed with depression, mania also leads to suicide.

Lithium has been the mainstay of bipolar treatment for more than 50 years, but about 40% of patients don't respond to it, says psychiatrist Husseini Manji of the National Institute of Mental Health (NIMH) in Bethesda, Maryland. In recent years, both antiseizure and antipsychotic drugs have been found effective for mania, but they can take weeks to kick in. Now, it looks as though a fast-acting alternative may be on the horizon.

Tamoxifen protects against breast cancer by blocking receptors for the hormone estrogen, on which some tumors depend. But the drug has another function: It inhibits an enzyme called protein kinase C (PKC), which regulates the excitability of brain cells. Studies have found increased PKC activity in the brains of people with bipolar illness, and a recent whole-genome study found that the gene with the strongest association with the disease is one that regulates PKC. It just so happens that tamoxifen is the only direct PKC-inhibiting compound approved for human use that can cross from the bloodstream into the brain.

So over several years, an NIMH group headed by psychiatrist Carlos Zarate conducted a controlled study with 16 patients hospitalized for mania. Over a 3-week period, each individual was given either tamoxifen or a placebo. In a paper appearing online today in the journal Bipolar Disorders, the team reports that the tamoxifen-treated patients started improving by the 5th day, and five of the eight showed a 50% or more reduction of symptoms on a mania-rating scale--compared with only one of the eight in the placebo group.

"This is potentially a major development if replicated," says psychiatrist Paul Keck of the University of Cincinnati in Ohio. "It potentially opens up a whole new avenue of targeted treatments."

Manji, a co-author of the study, says physicians have supplied a lot of anecdotal evidence that bipolar breast cancer patients on tamoxifen did not have as much trouble with mania. He says the fact that there were no sex differences in response to the drug in the NIMH trial shows the effect is not related to estrogen receptors. Now, he notes, the job is to test potential drugs that don't mess with estrogen and are "pure PKC inhibitors."

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