Clinical Psychiatry News
Weight Gain Still Confounds Therapy With Psychotropics
Carl Sherman, Contributing Writer
Psychiatry News 28(3):1,5, 2000. © 2000 International Medical News
Weight gain is an adverse drug response that observes few class
distinctions: It can complicate treatment with antipsychotics,
antidepressants, and mood stabilizers old and new.
As striking as the problem's ubiquity is the paucity of published
research on solutions.
"Nobody at this point has really studied interventions for
psychotropic-induced weight gain," said Dr. David Ginsberg, director
of outpatient psychiatry at Tisch Hospital in New York. "Given the
prevalence, it's amazing how few data there are."
Renewed attention to the issue has been paid, however, in the
context of newer antipsychotics and antidepressants whose otherwise
favorable side effect profiles are a selling point.
"Extrapyramidal side effects [EPS] aren't a problem any more," Dr.
Tony Cohn of the Centre for Addiction and Mental Health in Toronto
said of the atypical antipsychotics that have largely supplanted
conventional neuroleptics for schizophrenia. "What's emerging is
concern about weight gain and its health complications."
The issue is most pressing with clozapine and olanzapine, which are
also the atypicals with least EPS potential and -- in the case of
clozapine -- greatest efficacy in treatment-resistant patients. "The
drugs that cause [the] most weight gain are those we prescribe most,"
Dr. Cohn said.
Clozapine is associated with a mean 10% increase from baseline
weight; 20% of patients may gain up to 30% over baseline. "Olanzapine
isn't far behind," he said.
Cardiovascular risk in this population lends urgency to dealing
with the problem of weight gain, Dr. Cohn observed. Schizophrenic
patients tend to be extremely sedentary, and many -- an estimated
70%-90% -- are heavy smokers. In addition, the same drugs may increase
triglyceride levels and promote the development of diabetes.
Dr. Cohn described a behavioral program he developed for Whitby
(Ont.) Mental Health Centre that educates schizophrenic inpatients
about weight-control strategies and fosters effective diet and
Originally targeted to patients in their teens and 20s with
refractory psychosis -- who, the literature suggests, are at highest
risk of weight gain -- it includes a reward system for participation
and increased physical activity.
While no formal study of the program has been published, Dr. Cohn
reported that there was less weight gain over a 3-month period in a
small sample of participants than in other patients on the same drugs.
His experience also suggests that patients at risk of significant
weight problems can be identified early in treatment. "Those who
aren't gaining in the first few weeks probably won't [do so] later,"
Generally, quick intervention -- switching to drugs such as
risperidone or quetiapine that have less weight gain potential -- is a
As with other populations, "once weight gain is established, it's
difficult to reverse," Dr. Cohn said.
But Dr. Michael J. Reinstein, research director at Riveredge
Hospital in Oak Park, Ill., reported success with 65 schizophrenic
patients who had already gained a mean of 14.3 pounds during 6 months
on clozapine. They were switched to a combination regimen in which
clozapine was reduced by 25%, and an equivalent amount of quetiapine
Over 10 months, they lost a mean of 20.75 pounds [Clin. Drug
Invest. 18 :99-104, 1999].
Improvements also occurred in glycemic status. Thirteen of the 65
patients had developed diabetes during clozapine therapy. In three of
these patients, blood glucose normalized on the combined regimen in
this study supported by a grant from Zeneca Pharmaceuticals, maker of
In his clinical practice, Dr. Reinstein has switched many patients
previously on clozapine alone to the combination regimen, in most
cases reducing clozapine by half, he said.
"Quetiapine [seems] to buffer the bad things that clozapine does,"
he said. Urinary control, tachycardia, drooling, and constipation as
well as weight have improved, with no worsening in schizophrenia
The situation with the newer antidepressants is more ambiguous.
Although early weight gain has been reported with several of them --
mirtazapine and citalopram, for example -- most selective serotonin
reuptake inhibitors (SSRIs) were first associated with weight loss.
With their continued use, however, have come clinical reports and
open series suggesting significant weight gain among 8%-87% of
patients on SSRIs as a late-emergent side effect. Controlled trials,
however, have found little difference in terms of weight gain between
SSRIs and placebo, Dr. Ginsberg said.
In his experience, patients vary widely in this area. "Most won't
gain weight on [SSRIs], but a minority will," he said.
As with the atypical antipsychotics, early intervention is best.
"For someone at risk for gaining weight [because of medical
comorbidity such as cardiovascular disease or diabetes], I'd recommend
diet and exercise counseling before they start these medications. It
may go a long way to minimizing the [weight] increase," he said.
When clinical parameters allow, agents with less weight gain
potential -- bupropion and nefazadone -- should be considered in these
cases, he said.
After weight gain has occurred, nonpharmacologic options should be
the first line of defense, with a drug switch to be considered when
this approach is ineffective.
Adjunctive treatment is another possibility, Dr. Ginsberg said.
The addition of the anticonvulsant topiramate to the mood
stabilizers lithium or divalproate has led to substantial weight loss
in several open studies, and its cautious use may be considered for
patients on antidepressants as well.
Bupropion is a more logical adjunct to SSRI therapy. "The drugs
combine quite nicely," he said. This strategy is often used for SSRI-linked
sexual dysfunction. Although there are no data on the combination
regarding psychotropic-associated weight gain, some research suggests
bupropion has independent efficacy as a weight-loss agent.
As for the weight-loss agents approved by the Food and Drug
Administration, a trial of orlistat (Xenical), which blocks the
absorption of fat by inhibiting lipase secretion, would be reasonable,
although experience is limited in this population. Sibutramine (Meridia),
which inhibits reuptake of serotonin and norepinephrine, should not be
added to SSRIs because of the risk of serotonin syndrome, Dr. Ginsberg
Dietary control is part of any weight-loss program.
According to Judith Wurtman, Ph.D., manipulation of carbohydrate
intake is a vital component when psychotropic effects are part of the
Patients who have gained weight on atypical antipsychotics and
SSRIs, in particular, "come in with carbohydrate craving ... an
appetite for sweet, starchy foods they can't control," said Dr.
Wurtman, director of the Triad Weight Management Center at McLean
Hospital in Belmont, Mass.
Consumption of carbohydrate-rich, protein-poor foods increases
brain tryptophan levels and serotonin synthesis, which in turn reduces
the craving, she commented.
Toward this end, Dr. Wurtman gives patients a proprietary drink
that contains 40 g of simple and complex carbohydrates two to three
times a day on an empty stomach. She also counsels them to have a
high-carbohydrate, low-fat, low-protein meal in the evening, when
cravings are typically worst.
About 200 people -- 60% of whom were taking one or more
psychotropic drugs -- have completed a 14-week program that includes
the carbohydrate drink, diet, and an exercise regimen.
The average weight loss was 20 pounds, she said.