|Manic Phase of Bipolar Disorder Benefits from
Breast Cancer Medication
Tamoxifen Treats Mania Faster than Some Standard Medications
The medication tamoxifen, best known as a treatment for breast
cancer, dramatically reduces symptoms of the manic phase of bipolar
disorder more quickly than many standard medications for the mental
illness, a new study shows. Researchers at the National Institutes
of Health's National Institute of Mental Health (NIMH) who conducted
the study also explained how: Tamoxifen blocks an enzyme called
protein kinase C (PKC) that regulates activities in brain cells.
The enzyme is thought to be over-active 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 the illness. Current medications for the manic
phase generally take more than a week to begin working, and not
everyone responds to them. Tamoxifen itself might not become a
treatment of choice, though, because it also 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. Currently, tamoxifen is approved by the Food and Drug
Administration for treatment of some kinds of cancer and infertility,
for example. It was used experimentally in this study because it
both blocks PKC and is able to enter the brain.
Results of the study were published online in the September issue
of Bipolar Disorders by Husseini K. Manji, MD, Carlos A. Zarate
Jr., MD, and colleagues.
Almost 6 million American adults have bipolar disorder, whose
symptoms can be disabling. They include profound mood swings, from
depression to vastly overblown excitement, energy, and elation,
often accompanied by severe irritability. Children also can develop
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 indulge in risky pleasure-seeking
behaviors with potentially serious health consequences, for example,
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, MD. "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 included eight patients who were given tamoxifen
and eight who were given a placebo (a sugar pill); 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
they do it through a roundabout biochemical route that takes time.
Tamoxifen is known instead 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.
"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 Manji. "This is a major
step toward developing new kinds of medications."
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.
"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
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."
For more information about bipolar disorder, visit the NIMH website
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH website: http://www.nimh.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.