FIG1 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
Wayne Fenton, M.D.: "This crisis calls for fundamentally new ways
of integrating medical and psychiatric care."
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
"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
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
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
"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
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
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."
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
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
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." ▪