Schizophrenia, Antipsychotics, and the Metabolic Syndrome: Is There a Silver Lining?

In this issue of the Journal , Lamberti and colleagues report on the association between clozapine and the metabolic syndrome, which is defined as a cluster of clinical and laboratory abnormalities including abdominal obesity, insulin resistance, hypertension, low levels of high-density lipoprotein cholesterol, and high levels of triglycerides. The metabolic syndrome is not without its own controversy. Guidelines differ on diagnostic criteria, and there is debate as to whether the syndrome represents anything more than the risk associated with its individual components (1) . That said, it is hard to overlook the fact that those with the syndrome have a two- to threefold increase in cardiovascular mortality and a twofold increase in all-cause mortality (2) .

It is no surprise that the second-generation antipsychotics are associated with an elevated risk of metabolic syndrome, given the body of evidence linking them to weight gain, hyperglycemia, and lipid abnormalities (3) . Lamberti and colleagues have now confirmed this link, noting that the prevalence of the metabolic syndrome exceeds 50% in their clozapine-treated sample—more than twice the rate reported for an epidemiological normal comparison group from the National Health and Nutrition Examination Survey (NHANES).

The authors acknowledge the limitations of their study: a cross-sectional approach, the lack of a nonmedicated control group and random assignment, and the concomitant use of other medications that can influence weight. Yet, the prevalence figures they report are in line with other studies of the metabolic syndrome in patients with schizophrenia (4) .

Whether the risk of metabolic syndrome varies among the different second-generation antipsychotics remains unclear. Surprisingly, Lamberti et al.’s report is the first to evaluate the risk of metabolic syndrome with clozapine. Among second-generation antipsychotics, clozapine is believed to carry the greatest liability for weight gain (5) , and it remains to be established what the individual risks are for other agents in this drug class. A differential risk among these agents, perhaps reflected by their individual weight gain risks, has been implicated but not verified (6) .

Also unclear is the relative contribution of second-generation antipsychotics to the metabolic syndrome in patients with schizophrenia. Several studies have failed to detect differences in the prevalence of the syndrome between patients taking second-generation antipsychotics and those taking conventional antipsychotics (7 , 8) . It may be that we have underestimated the effect of conventional antipsychotics on metabolic symptoms. Support for this possibility comes from a recent study (9) that compared olanzapine and haloperidol in patients with first-episode psychosis—a sample comparatively free of previous treatment and symptom chronicity. After 2 years, patients taking olanzapine had gained an average of 33.9 lb, and those taking haloperidol, 16.5 lb—itself a considerable weight gain. In addition, since most studies comparing antipsychotics have been carried out with chronically ill populations, it is possible that any differential weight gain liability between antipsychotics is lost or “masked” by prolonged exposure to the environmental and lifestyle adversities that characterize the lives of many people with schizophrenia.

Finally, the illness itself may contribute. While body mass index is not greater among people who go on to develop schizophrenia (10) , data suggest that those with schizophrenia have higher rates of diabetes, independent of medications taken (11) . Pilot work at our center suggests the same thing, showing insulin resistance and susceptibility to type 2 diabetes in medication-free patients in the earliest stages of schizophrenia (12) .

What does all this mean for clinicians? For the many of us who have tried to maintain a clear separation between psychiatric and medical care, a change in how we perceive our role may be necessary. Psychiatrists can no longer eschew responsibility for their patients’ medical care, assuming it will be taken up by others. As Lamberti et al. bluntly remind us in their article, “Many adults with schizophrenia receive little or no medical care.” Thus, it is up to psychiatrists treating patients in this population to ensure that their medical care does not fall through the cracks.

Creativity and the development of new programs may be required to achieve such a goal. In most settings, it will require fundamental changes in how we and our health care partners deliver care, but the ball is in our court. We have not ignored the problem; indeed, numerous guidelines have been issued to help us, and recent data confirm that clinicians are informed on the issues. Unfortunately, this knowledge has not yet been translated into clinical practice (13) .

Lamberti and colleagues conclude that “regular monitoring may be especially critical for clozapine patients, given the high prevalence of metabolic abnormalities reported in this study and others.” Their point is well taken. But I would argue that regular monitoring is critical for all patients; current evidence related to issues of illness and lifestyle suggests that monitoring not be confined to those taking clozapine, or even to those taking second-generation antipsychotics. We also cannot rely on weight gain as the clinical marker that defines individuals who may have underlying metabolic disturbances. The increased risk of diabetes in those treated with second-generation antipsychotics is not just a product of weight gain, as reflected by the subgroup of patients who present with ketoacidosis but no significant increase in weight.

So what is the silver lining to this cloud? It has long been known that schizophrenia is associated with morbidity and mortality rates that far exceed those of the general population (14) . The recent data on the association of weight gain and the metabolic syndrome with second-generation antipsychotics provide both the impetus and the portal to address important questions of medical care in this population. It would be shortsighted to consider these findings relevant only to second-generation antipsychotics or to debate on the relative merits of the different antipsychotic drugs. Likewise, in monitoring the physical health of our patients, it would be shortsighted to confine our attention to the side effects of the medications we prescribe. The silver lining to this cloud is that, as these issues come to the fore, an opportunity arises for us to take decisive steps toward establishing a comprehensive model of care in which psychiatrists play an integral role in the overall health, physical and mental, of patients with schizophrenia.