Weight Gain Still Confounds Therapy With Psychotropics

Carl Sherman, Contributing Writer

[Clinical Psychiatry News 28(3):1,5, 2000. © 2000 International Medical News Group.]

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 exercise changes.

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," he said.

Generally, quick intervention -- switching to drugs such as risperidone or quetiapine that have less weight gain potential -- is a better approach.

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 was added.

Over 10 months, they lost a mean of 20.75 pounds [Clin. Drug Invest. 18 [2]: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 quetiapine (Seroquel).

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 symptoms.

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 said.

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 problem.

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.