[NYAPRS Enews] MNT: Study Pinpoints How Antipsychotic Meds Cause Obesity, Diabetes

[Harvey Rosenthal]

Metabolic Side Effects Such As Obesity And Diabetes Caused By
Antipsychotic Medications

Medical News Today   February 3, 2012   

In 2008, roughly 14.3 million Americans were taking antipsychotics -
typically prescribed for bipolar disorder, schizophrenia, or a number of
other behavioral disorders - making them among the most prescribed drugs
in the U.S. Almost all of these medications are known to cause the
metabolic side effects of obesity and diabetes, leaving patients with a
difficult choice between improving their mental health and damaging
their physical health. In a paper published January 31 in the journal
Molecular Psychiatry, researchers at Sanford-Burnham Medical Research
Institute (Sanford-Burnham) reveal how antipsychotic drugs interfere
with normal metabolism by activating a protein called SMAD3, an
important part of the transforming growth factor beta (TGFbeta) pathway.


The TGFbeta pathway is a cellular mechanism that regulates many
biological processes, including cell growth, inflammation, and insulin
signaling. In this study, all antipsychotics that cause metabolic side
effects activated SMAD3, while antipsychotics free from these side
effects did not. What's more, SMAD3 activation by antipsychotics was
completely independent from their neurological effects, raising the
possibility that antipsychotics could be designed that retain beneficial
therapeutic effects in the brain, but lack the negative metabolic side
effects. 

"We now believe that many antipsychotics cause obesity and diabetes
because they trigger the TGFbeta pathway. Of all the drugs we tested,
the only two that didn't activate the pathway were the ones that are
known not to cause metabolic side effects," said Fred Levine, M.D.,
Ph.D., director of the Sanford Children's Health Research Center at
Sanford-Burnham and senior author of the study. 

In a previous study aimed at developing new insights into diabetes, Dr.
Levine and his team used Sanford-Burnham's high-throughput screening
capabilities to search a collection of known drugs for those that alter
the body's ability to generate insulin, the pancreatic hormone that
helps regulate glucose. That's when they first noticed that many
antipsychotics alter the activity of the insulin gene. In this current
study, the researchers set out to connect the dots between
antipsychotics and insulin. In doing so, experiments in laboratory
cell-lines showed that antipsychotics known to cause metabolic side
effects also activated the TGFbeta pathway - a mechanism that controls
many cellular functions, including the production of insulin - while the
drugs without these side effects did not. 

Wondering whether their initial laboratory observations were relevant to
the human experience, the researchers reanalyzed previously published
gene expression patterns in brain tissue from schizophrenic patients
treated with antipsychotics. What they found supported their earlier
findings - TGFbeta signaling was activated only in those patients
receiving antipsychotic treatment. Looking further, they found that the
extent to which each antipsychotic drug activated the TGFbeta pathway in
human brains correlated very closely with the extent to which those same
drugs activated SMAD3 and affected the insulin promoter in their cell
culture experiments. 

The TGFbeta pathway also plays an important role in metabolic disease in
people who don't take antipsychotic medications. "It's known that people
who have elevated TGFbeta levels are more prone to diabetes. So having a
dysregulated TGFbeta pathway - whether caused by antipsychotics or
through some other mechanism - is clearly a very bad thing," said Dr.
Levine. "The fact that antipsychotics activate this pathway should be a
big concern to pharmaceutical companies. We hope this new information
will lead to the development of improved drugs."

________________________________

References:
This study was funded by a gift from Mr. T. Denny Sanford to the Sanford
Children's Health Research Center at Sanford-Burnham. Co-authors include
Thomas Cohen, Sanford-Burnham and University of California, San Diego;
S. Sundaresh, NextBio; and Fred Levine, Sanford-Burnham.
Sanford-Burnham Medical Research Institute
<http://www.burnham-inst.org/> 

________________________________

Sanford-Burnham Medical Research Institute. (2012, February 3).
"Metabolic Side Effects Such As Obesity And Diabetes Caused By
Antipsychotic Medications."Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/241084.php.

 

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