Clinical and Research News
Clinicians Urged To Better Monitor Drug-Related Side Effects
Psychiatric News
Volume 41 Number 13 page 1-34

Patients with schizophrenia and bipolar disorder lose as much as 20 years off their average life expectancy compared with similar individuals in the general population without serious mental illness. According to a report from the Centers for Disease Control and Prevention released in April, the leading cause of death contributing to that shortened lifespan is not the patients' mental illness, but rather something largely preventable: cardiovascular disease.

These statistics and others were cited by an expert panel as indirect evidence that the fi eld of psychiatry is earning a failing grade when it comes to managing medical comorbidity in patients with schizophrenia and bipolar disorder—especially those patients who are taking second-generation antipsychotics (SGAs). This class of drugs is generally considered to be linked closely with increased risk of metabolic syndrome, a leading risk factor for cardiovascular disease.

The panel of experts, chaired by John Newcomer, M.D., a professor of psychiatry, psychology, and medicine at Washington University School of Medicine in St. Louis, held a press briefing at APA's 2006 annual meeting in May to issue the "Call to Action: Raising the Standard of Care in the Treatment of Schizophrenia and Bipolar Disorder."

"The good news about this is that we know a lot about the prevention of cardiovascular disease," said Newcomer, who also chairs APA's Subcommittee on Antipsychotics and Metabolic Risk. "The bad news is that the risk factors—the well-established risk factors for cardiovascular disease in this population—are generally occurring at very high levels. These risk factors are not being monitored and are not being attended to in this population."

Newcomer's point was supported by a series of nearly 50 new research presentations on the issue of metabolic syndrome and serious mental illness during the annual meeting. Among those presentations was an analysis of baseline data from the National Institute of Mental Health's CATIE trial (Clinical Antipsychotic Trials of Intervention Effectiveness). That analysis revealed that large percentages of patients who enrolled in the 18-month comparative treatment study already had comorbid disorders that significantly increased their risk for cardiovascular disease, even before receiving any study medications. (The average patient in CATIE had been diagnosed 14 years before entering the study and had taken numerous antipsychotics previously.)

"I think this is probably the single most important finding in the CATIE study," noted Henry Nasrallah, M.D., a professor of psychiatry, neurology, and neuroscience at the University of Cincinnati College of Medicine and a CATIE investigator. CATIE allowed investigators to determine" to what degree patients were at high risk when they entered CATIE, and what happened to them when they received certain antipsychotics within the CATIE [protocol]."

Results from CATIE largely confirmed what other studies have reported over the last five to seven years, Nasrallah said. "Some antipsychotics worsened the [patients'] metabolic condition, and other [medications] helped them by lowering their weight, lowering [blood glucose levels], and lowering their lipids."

Somewhat surprising, Nasrallah said, was the finding that 42 percent of the 1,460 patients initially enrolled in CATIE met criteria for metabolic syndrome. Metabolic syndrome is a constellation of signs and symptoms that taken together signal a significantly increased risk of death by cardiovascular disease (see box).

However, Nasrallah reported at the press briefing and in a new research poster presentation that these were the truly troubling findings: 45.3 percent of the patients who had diabetes when they initially enrolled in CATIE were not receiving any treatment to help control their blood glucose levels; 89.4 percent of the patients who had hyperlipidemia at baseline were not taking a statin medication to lower blood lipid levels; and 62.4 percent of the patients who met criteria for hypertension at baseline were not receiving antihypertensive pharmacotherapy.


Similar data were presented at APA's annual meeting by John Kane, M.D., chief of psychiatry at Zucker Hillside Hospital/Long Island Jewish Medical Center. Kane is participating in a large international study, funded by Pfizer, that is examining the cardiovascular safety profile of Pfizer's Geodon brand of ziprasidone, compared with olanzapine (Eli Lilly and Co.'s Zyprexa). The study, the "Ziprasidone Observational Study of Cardiac Outcomes," is being led by Brian Strom, M.D., M.P.H., the director of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine. The study has enrolled more than 17,000 patients with schizophrenia who have been randomly assigned to receive either ziprasidone or olanzapine. Multiple cardiovascular outcomes will be assessed to determine whether or not the cardiovascular safety profiles of the two medications differ.

At baseline, 19 percent of zODIAC patients had hypertension, and 16 percent met criteria for hyperlipidemia, yet less than 3 percent were taking any antihypertensive or statin medications. Nearly two-thirds of the patients met criteria for obesity, and 8.3 percent had diabetes.

"Clearly," Nasrallah said at the press briefing, "our patients with schizophrenia are subject to double jeopardy, as I like to call it. On the one hand, they have a high risk of metabolic disorders that shorten their lives and cause early heart disease. On the other hand, they are not getting appropriate and necessary treatment" for these problems.


Nasrallah believes the most significant factor underlying the lack of treatment for cardiovascular risk factors in patients with serious mental illness is clinicians' failure to identify and monitor metabolic adverse effects.

"Are psychiatrists actually checking their patients at baseline?" Nasrallah asked. "Do they measure and follow their patients' obesity, their hypertension, their hyperglycemia and hyperlipidemia?"

In February 2004, APA joined with the American Diabetes Association in issuing a consensus statement calling for standardized monitoring of metabolic adverse effects associated with the use of SGAs (Psychiatric News, March 5, 2004). It was also endorsed by the American Association of Clinical Endocrinologists and the North American Association for the Study of Obesity.

The statement included a summary review of evidence showing that not all six of the SGAs appeared to be equally associated with metabolic adverse events and recommended specific laboratory tests that should start at baseline, prior to the patients' first dose of antipsychotic medication, and continue at regular intervals through the first five years of antipsychotic therapy.

Based on data from several studies presented at APA's annual meeting, it appears that less than 10 percent of patients on the medications are being monitored using the APA/ADA consensus protocol.

New research presented at APA's 2006 annual meeting by Brian Cuffel, Ph.D., and Antony Loebel, M.D., of Pfizer revealed that after release of the APA/ADA consensus statement, only 6 percent to 8 percent of patients in their study taking SGAs completed the recommended baseline evaluation of serum lipid levels along with follow-up measurement three months after initiation of antipsychotic therapy. Similarly, only 16 percent to 23 percent of patients underwent recommended baseline and follow-up serum glucose testing.

To see whether baseline monitoring and follow-up of patients improved after the release of the consensus statement, Cuffel and Loebel compared data on 21,848 patients before the statement's release and 8,166 patients six months afterward. The researchers were surprised to find little improvement. While baseline monitoring was more common than follow-up, monitoring rates actually declined after antipsychotic treatment was initiated.

The obvious disconnect between recommended monitoring of serious adverse events and what actually occurs with patients taking antipsychotics is of" growing concern," Newcomer said.

"The good news is, there are efforts now under way" to educate doctors about the importance of monitoring, he added. "And there's a sort of groundswell of interest" in making sure recommended monitoring is performed appropriately.

The APA Subcommittee on Antipsychotics and Metabolic Risk, Newcomer added, will soon issue a white paper summarizing SGAs' differential metabolic risk and the monitoring protocols that should help to prevent or reduce serious adverse events. In addition, the National Association of State Mental Health Program Directors recently held a policy meeting and will issue a report soon.

Finally, Nasrallah noted, increasing evidence indicates that initial impressions of differential adverse effects among the SGAs exist. "There are antipsychotics that are completely metabolically weight-neutral, lipid-neutral, and glucose-neutral. There are other antipsychotics that significantly increase [all three]. We need to match the patient with the drug and get the safest medication for patients who are at the highest risk"

Newcomer agreed. "This is a variable that psychiatrists are potentially in a position to control." ▪

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