Treatment Is Delicate Balance Between Efficacy, Side Effects

A woman with schizophrenia in her late 40s at an upstate New York hospital is successfully treated with clozapine, but gains significant weight and begins to develop lipid abnormalities.

She is switched to ziprasidone and put on a regimen of exercise and reduced food portions; in time, she loses the weight she had gained, but her clinical status deteriorates.

“We raised the dose but ultimately had to give up on the ziprasidone,” reported treating psychiatrist Sanjay Gupta, M.D.“ But she didn't want to take another drug that would raise her weight.”

Finally, the patient was placed on a first-generation antipsychotic.

Another case almost identical in detail, from the Menninger Clinic:“ A patient I worked with was very treatment resistant and ended up on clozapine,” said Joyce Davidson, M.D., medical director of the OCD Clinic at Menninger; she treated patients with schizophrenia when the clinic was located in Topeka, Kan. “She did quite well but gained 20 to 25 pounds. Because clozapine is an end-of-the-line treatment, there weren't any good options. But we worked very closely with her and ended up using a personal trainer and nutritional counseling. I don't think she lost all the weight, but she was able to lose enough.”

Both cases illustrate in microcosm the phenomenon of metabolic syndrome—a cluster of symptoms including increased abdominal girth, hyperglycemia, decreased HDL cholesterol, hypertension, and elevated triglycerides—in patients with schizophrenia. Experts say the problem is a public health issue of epidemic proportions.

The cases underscore a clinical dilemma for psychiatrists and their patients: while weight gain and symptoms of metabolic syndrome appear to arise from a host of confounding factors—diet, lifestyle, and a genetic predisposition that comes with the disease—they are exacerbated by the very drugs that may best resolve symptoms.

Evidence of the role of drugs in metabolic syndrome from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and elsewhere is troubling, especially but not exclusively regarding olanzapine and clozapine (see article on facing page). And a 2004 statement from the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes concluded that clozapine and olanzapine are associated with the greatest weight gain and highest occurrence of diabetes and dyslipidemia.

(That statement was developed by representatives from APA, American Diabetes Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity.)

Yet the consensus statement also noted that “even for those medications associated with an increased risk of metabolic side effects, the benefits to specific patients could outweigh the potential risks.” The latter may be especially the case for clozapine, according to the statement.

“That's the real challenge in day-to-day practice,” Gupta told Psychiatric News. “How do you decide the best drug—on the basis of efficacy or side effects?”

Gupta added that advertisements by attorneys soliciting patients seeking damages for injury related to metabolic syndrome have begun to appear, and some patients have stopped treatment. “On the one hand, you have metabolic syndrome, but on the other hand, you have the danger of decompensation and suicide if patients stop taking medication,” he said.

He is chair of the department of psychiatry at Olean General Hospital in Olean, N.Y., and a clinical professor of psychiatry at the University of Buffalo and SUNY Upstate Medical University in Syracuse, N.Y.

Numbers from the CATIE study tell the story of schizophrenia and symptoms of metabolic syndrome: 11 percent of the 1,460 enrolled patients had diabetes type I or II, 14 percent had hyperlipidemia, and 20 percent had hypertension.

Together those numbers suggest that patients with schizophrenia are at twice the risk of the general population for metabolic syndrome. And though rare, deaths from diabetic ketoacidosis and pancreatitis associated with use of antipsychotic medication have been reported.

“We believe this is a crisis,” said Wayne Fenton, M.D., director of adult translational research and treatment development at the National Institute of Mental Health (NIMH). “We need to acknowledge that this is really an epidemic. Chlorpromazine was introduced in 1954, and it wasn't until the mid-70s that tardive dyskinesia became recognized as a major issue in terms of side effects. But the problem of metabolic syndrome symptoms among patients with schizophrenia is going to be bigger than tardive dyskinesia, and we can't afford to wait any longer to address it.”

Multiple Factors Involved

Recently NIMH convened a conference of research scientists around the issue of metabolic syndrome, schizophrenia, and antipsychotic use at Washington University School of Medicine in St. Louis.

Fenton said NIMH has created a new program within the Division of Adult Translational Research focused on medication side effects. The program will fund research to predict who is at risk for metabolic syndrome and to test treatment and prevention strategies, he said.

APA's Council on Research has also convened a work group to review existing knowledge about the problem. Work group chair John Newcomer, M.D., told Psychiatric News that the group aims to publish a white paper on the subject later this year in the American Journal of Psychiatry.

Clinicians and researchers familiar with the problem say much remains to be learned about the relationship between metabolic syndrome and the role of antipsychotic medication, as well as the confounding influence of lifestyle and dietary factors in patients who are typically poor, may consume large amounts of fast food, and do very little exercise.

“All factors are involved—diet, lifestyle, and medication—and they are not mutually exclusive,” said William Carpenter, M.D., director of the Maryland Psychiatric Research Center.“ There is also fairly good reason to believe the disease itself involves a vulnerability to diabetes. This makes it especially important to avoid iatrogenic contribution to risk for diabetes and cardiovascular disease.”

Many Patients Untreated for Syndrome

When it comes to treatment of symptoms of metabolic syndrome, a closer analysis of the CATIE data reveals even more disturbing patterns.

Newcomer noted that 89 percent of the people in the study who at baseline met diagnostic criteria for dyslipidemia were not being treated with cholesterol-lowering statin drugs—or with anything else. “They weren't being undertreated,” he said. “They were getting no treatment at all.”

He is a professor of medicine at Washington University School of Medicine in St. Louis.

In this way, a mounting public health epidemic that is largely below the radar of most policymakers intersects with the problems of a public health safety net already overburdened with the costs of an ever-expanding medical and pharmaceutical capacity.

“Let's say we could wave a magic wand and have primary care doctors writing prescriptions for statins for every patient with schizophrenia who needs them,” Newcomer said. “We would break the bank of Medicaid overnight.”

What's to be done?

There is widespread agreement that psychiatrists need to be more actively involved in the monitoring patients' weight and symptoms of metabolic syndrome. Newcomer cited the recent Institute of Medicine report titled“ Improving the Quality of Health Care for Mental and Substance Use Conditions: Quality Chasm Series,” which calls on psychiatrists to anticipate medical comorbidity and perform routine screening in collaboration with primary care.

“Psychiatric stability of the patient is the cornerstone of a comprehensive management plan, as these individuals will not follow through with treatment for metabolic and other medical issues if not psychiatrically stable,” said Gupta, of SUNY Upstate. “It is important for psychiatrists to screen patients for metabolic problems just as we screen patients on lithium for renal and thyroid problems.”

Yet experts also agreed that optimal treatment of medical comorbidity—including symptoms of metabolic syndrome—in patients with schizophrenia requires a reconfiguration of the mental health system.

“Community mental health centers, where most of the psychiatric care is provided, are physically separate from primary care and quite often don't have primary care specialists on site,” said Newcomer.

Fenton agreed. “We need services research to understand how to best integrate medical and psychiatric care at the community mental health center,” he said. “What we are seeing now is analogous to substance abuse dual diagnosis 20 years ago when there were two separate systems of care. The psychiatrist is liable to believe that the internist is looking after metabolic issues, while the internist defers all patients with schizophrenia to the psychiatrist.

“Meanwhile, the patient is falling between the cracks,” he continued. “This crisis calls for fundamentally new ways of integrating medical and psychiatric care.” ▪