Psychiatric News June 18, 2004
Volume 39 Number 12
© 2004 American Psychiatric Association
p. 23
Seizure Drug Combats Antipsychotic Side Effects
Jim Rosack
An old-line medication may be beneficial in the fight against metabolic
complications associated with some second-generation antipsychotics.
The metabolic complications sometimes associated with the use of some
second-generation antipsychotics (SGAs)—changes in weight, serum lipids,
triglycerides, and glucose—have become increasingly worrisome to
clinicians managing patients with serious mental illness. Now, physicians and
patients may have an unexpected ally in the fight against these potentially
serious effects.
New research presented at APA's annual meeting last month confirms earlier
reports that divalproex sodium (Depakote) blocks the increases in serum
cholesterol often seen with two of the most often prescribed SGAs, olanzapine
(Zyprexa) and risperidone (Risperdal). Those changes in cholesterol have been
strongly associated with cardiovascular disease. Studies now show that
cardiovascular disease is a leading cause of death among patients with
schizophrenia.
"This really involves a recalculation—a recalibration of
psychiatrists' way of practicing," Daniel Casey, M.D., told
Psychiatric News. "We must learn to think below the neck
again—we did it in medical school, and we must do it in practice. We
need to understand metabolic syndrome and its consequences so that we can
safely manage our patients."
Casey is a professor of psychiatry and neurology and associate director for
the Mental Illness Research, Education, and Clinical Center at Oregon Health
and Sciences University in Portland.
Casey's research was presented as a poster at the annual meeting. The
research was funded by Abbott Laboratories, maker of the Depakote brand of
divalproex, approved 20 years ago as an antiepileptic. The drug is considered
first-line therapy (along with lithium) for mania in the APA Practice
Guideline for the Treatment of Patients With Bipolar Disorder, having gained
an indication for the treatment of acute manic episodes associated with
bipolar disorder in 1996. (Divalproex is also approved for the prevention of
migraine.)
"Our patients are at high risk for metabolic disorders—both
from a possible increased predisposition that could be genetically based, but
also largely as a consequence of the medications we prescribe," Casey
noted. "It is inherently important for psychiatrists to do necessary
primary care follow-up. Our patients are usually more in contact with us than
with any other physician."
All physicians play a part in spotting the risk of potentially fatal
metabolic syndrome in their patients, Casey added. "Some will serve as
identifiers, some as evaluators, and some as treating physicians. All
psychiatrists must at least be an identifier."
The meaning of the term "metabolic syndrome" varies from one
source to another, but most commonly describes a clinical picture that begins
with weight gain associated with elevations in serum cholesterol and
triglycerides and is accompanied over time with an increase in resistance to
insulin. If insulin resistance goes untreated, patients may develop diabetes,
in addition to cardiovascular disease. The origins and mechanisms of metabolic
syndrome are not yet understood, but it is clear that morbidity and mortality
are markedly increased.
Casey noted that psychiatry is certainly making progress in dealing with
the syndrome, having released the joint APA/American Diabetes Association
consensus guidelines on appropriate monitoring of patients on antipsychotics
(Psychiatric News, March 5). APA's Office of Research and Council on
Research are also formulating formal APA guidelines on the issue.
"You have to have some sort of consensus on what really is the
problem and how to deal with it," Casey said. He noted that it is hard
to get insurance coverage for metabolic monitoring and testing of psychiatric
patients, but he thinks that will soon change.
"Once you have formal guidelines, people start looking at liability
and risk management. They will look at the consequences and the associated
costs of managing [these problems] against those of not monitoring."
Casey's study was a post hoc analysis of a double-blind, randomized,
multicenter trial that assessed the efficacy and safety of divalproex when
combined with either risperidone or olanzapine as adjunctive therapy for
schizophrenia.
The study randomly assigned 249 patients to olanzapine monotherapy,
olanzapine plus divalproex, risperidone monotherapy, or risperidone plus
divalproex.
Patients in the olanzapine monotherapy group had the highest rate of shift
from a normal total cholesterol (less than 200 mg/dl) to a high total
cholesterol (above 200 mg/dl). Nearly 55 percent of patients taking olanzapine
alone shifted from normal to high cholesterol, with an average increase in
cholesterol of 27 mg/dl. Of those patients taking olanzapine and divalproex,
only 27 percent saw an increase to a total cholesterol over 200 mg/dl, and the
average increase was much smaller, less than 1 mg/dl.
Those patients randomly assigned to risperidone alone had a moderate rate
of shifting from normal to high cholesterol as well, although not as high as
that of the patients taking olanzapine. Twenty seven percent of patients
shifted, with an average increase of about 10 mg/dl. Patients taking both
risperidone and divalproex saw dramatically different changes. While about 5
percent of these patients shifted from normal to high cholesterol levels, the
majority of the group experienced an average decrease in total cholesterol of
13.5 mg/dl.
Interestingly, no significant correlations were seen between baseline
weight, body-mass index, and total cholesterol. Also, serum levels of
olanzapine and risperidone were not affected by the addition of divalproex,
and there were no significant differences in glucose levels in the four
groups.
"Across the categories, in this study and in the previous
research," Casey emphasized, "there has been a fairly consistent
25 percent reduction of cholesterol in patients taking the combination
compared with the antipsychotic monotherapy." These data, he noted, are
consistent with data on patients with bipolar disorder and patients with
epilepsy given divalproex.
Casey is not sure of the mechanism by which divalproex lowers serum
cholesterol; however, he and other researchers suspect that the drug is
altering the liver's metabolism of cholesterol.
The results are peculiarly interesting because divalproex's effects on the
liver are well known. For years the drug has been associated with very rare
cases of drug-emergent liver failure, sometimes requiring transplant or
resulting in death. In addition, the drug has been associated with rare
reports of pancreatitis. In this study, Casey noted, divalproex ameliorated
the increase in liver enzymes that were observed in the olanzapine and
risperidone monotherapy groups, suggesting an interactive protective effect on
the liver. Pancreatic enzymes were not monitored in this study.
"As psychiatrists, we have a high-risk population, and our choice of
medication can profoundly affect someone's chance of converting from
borderline to clearly abnormal [metabolic indicators]," Casey
stressed.
Studies of the general population have shown that a 10 percent reduction in
cholesterol can result in a 20 percent to 30 percent reduction in the risk of
cardiovascular disease, Casey noted. He hopes attenuating increases in
cholesterol tied to SGAs by prescribing divalproex will lead to the same
benefit. 
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