Psychiatr News January 5, 2007
Volume 42, Number 1, page 17
© 2007 American Psychiatric Association
Diabetes Drug Reverses SGA-Related Weight Gain
Jim Rosack
Experts are debating the addition of a second medication to counteract a
significant side effect of antipsychotic therapy. The question is: When is
"reactive polypharmacy" appropriate?
A new study has come to the same conclusion as two earlier reports: a
common diabetes medication, metformin (Glucophage), appears to be effective at
blocking the sometimes significant weight gain associated with
second-generation antipsychotic medications (SGAs). What was new in the latest
report was the age of the patients in the study: children and adolescents aged
10 to 17.
The report by David klein, M.D., Ph.D., an associate professor of medicine
and pediatric endocrinology at the Cincinnati Children's Hospital Medical
Center, and colleagues appeared in the December 2006 American Journal of
Psychiatry. Their work was supported in part by an investigator-initiated
award from Eli Lilly and Co.
Eli Lilly markets the SGA olanzapine (Zyprexa) and has ties to other
companies that market antidiabetic drugs. The Glucophage brand of metformin is
marketed by Bristol-Myers Squibb, which also markets the SGA aripiprazole
(Abilify). Two coauthors of the report hold patents relating to the use of
metformin to counteract weight gain with psychotropic medications.
Klein and his colleagues conducted a protocol known as an "add-on,
parallel-design trial" in which they enrolled 39 patients aged 10 to 17
who had been taking one of three SGAs—olanzapine, quetiapine (Seroquel),
or risperidone (Risperdal)—for up to one year and had gained more than
10 percent of their pretreatment body weight while on the SGA. No diagnostic
criteria were reported to indicate why these child and adolescent patients
were taking an SGA.
Metformin is an antihyperglycemic agent that improves glucose tolerance in
patients with type 2 diabetes. It decreases hepatic glucose production,
decreases intestinal absorption of glucose, and improves insulin sensitivity
by increasing peripheral glucose uptake and utilization.
At the beginning of the study, each of the 39 patients was randomly
assigned to having either metformin or a matched placebo added to their SGA
regimen for 16 weeks. In addition, all patients and their participating
families received the same three sessions of generic dietary counseling. At
baseline, and at weeks 4, 8, 12, and 16, several measures were examined
including height, weight, waist circumference, a series of laboratory tests,
and screening for adverse events.
At study completion those who were randomly assigned to placebo had gained
an average of 8.8 pounds and had an average increase in body mass index (BMI)
of 2.4 pounds/m2 (see graph top right). Those who took metformin along with
their SGA, on average, lost 0.26 pounds and had an average decline of 0.9
pounds/m2 in their BMI. In addition, measures of insulin resistance—a
potential precursor to diabetes—increased significantly in those on
placebo while remaining stable in those taking metformin (see graph below
right).
Since it is rare that a medication trial reports such an indisputable
result, those with expertise in the field took note.
"I'm not at all surprised that you could take children, or adults for
that matter, with the kind of metabolic profiles that these subjects appeared
to have and see significant beneficial effects with a medication like
metformin," said John Newcomer, M.D., a professor of psychiatry at
Washington University in St. Louis. Newcomer chairs the APA Council on
Research's Workgroup on Antipsychotics and Metabolic Risk. "I think the
real issue is, Where does metformin fit into treatment considerations for
people taking antipsychotic medications, and especially, where does it fit for
children?"
In an editorial accompanying the report, Kenneth Towbin, M.D., chief of
clinical child and adolescent psychiatry in the Intramural Research Program at
the National Institute of Mental Health, described the report as
"extremely timely," noting that the "prescription rate of
atypical antipsychotics in children is following a familiar
cycle—initial gradual use followed by accelerating, widespread practice.
Awareness of cardiovascular and metabolic risks has yet to cool clinicians'
enthusiasm."
"The results are notable," Towbin said, "for the clear
differences between treatment groups in average weight gain, absolute BMI...
[and] there were impressive changes in measures of insulin
resistance."
While Towbin called the report "a welcome investigation addressing a
serious problem," and stated that the "findings are good
news," he qualified his comments by noting that "any zeal should
be tempered." The study does not address the long-term safety of
metformin, for example, or whether the weight loss is sustained.
"What concerned me about this paper, and the commentary, is that
there wasn't as much discussion as I would have hoped for, as far as removing
the offending agent prior to... adding a second drug to treat the adverse
effects," added Newcomer. There was no discussion of re-evaluating the
antipsychotic therapy and perhaps switching patients to a medication
associated with less weight gain liability, he noted.
P. Murali Doraiswamy, M.D., an associate professor of psychiatry and chief
of the Division of Biological Psychiatry at Duke University School of
Medicine, told Psychiatric News, "This is a terrific pilot
study and a much needed one."
Yet Doraiswamy, who is an expert on the association between SGAs and
metabolic adverse effects, added, "Before we debate whether or not to
add metformin to minimize metabolic side effects, our first priority should be
large clinical trials to prove the [SGAs] are effective in children.
Otherwise, we will be putting the cart before the horse."
"A Randomized, Double-Blind, Placebo-Controlled Trial of
Metformin Treatment of Weight Gain Associated With Initiation of Atypical
Antipsychotic Therapy in Children and Adolescents" is posted at
<http://ajp.psychiatryonline.org/cgi/content/abstract/163/12/2072>.
The editorial "Gaining: Pediatric Patients and Use of Atypical
Antipsychotics" is posted at
<http://ajp.psychiatryonline.org/cgi/content/full/163/12/2034>.
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