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Food for Thought—Weight Gain and Mortality in the Mentally Ill

14 February 2007. Is medication spoiling your Valentine’s Day? Many people on prescription medication find that they are heavier on the bathroom scales, a major dilemma when tempted by designer truffles. But more importantly, weight gain can be a significant health risk and, as exemplified by two new studies, may be particularly dangerous for people who suffer from major mental illness.

Writing in the February Archives of General Psychiatry, David Osborn and colleagues at the Royal Free and University College Medical School, London, report that people with severe mental illness have increased risk of dying from coronary heart disease and stroke. In some cases that risk is threefold higher than normal. In this week’s PNAS online, Solomon Snyder and colleagues at The Johns Hopkins University School of Medicine, Baltimore, Maryland, reveal how certain antipsychotic medications can lead to weight gain, a major risk factor for cardiovascular disease. The researchers report that some second-generation “atypical” antipsychotic medications upset metabolic balance by acting like an antihistamine in the hypothalamus, the region of the brain that controls food intake. The finding suggests ways to develop newer “low calorie” antipsychotics.

Perhaps these results will also help spur more research like that reported by Suzanne Archie of McMaster University in Hamilton, Ontario, Canada, and colleagues in the February issue of Psychiatric Services. Archie and colleagues report on successful efforts to help some patients with schizophrenia lose weight, specifically those identified by the "transtheoretical model" as being ready to make lifestyle changes (Archie et al., 2007).

Weight gain and antipsychotics
When atypical antipsychotic drugs (AAPDs) were introduced, they were considered a vast improvement on the older “typical” antipsychotics, which had some severe side effects, including Parkinson-like symptoms. Even though the recent CATIE study has cast some doubt on the efficacy of AAPDs (see SRF related news story), they are still widely prescribed to people with schizophrenia or other psychoses, despite the propensity for piling on the pounds. Correcting this side effect would not only make these drugs more tolerable, but it might also make them safer.

To address the reason for this side effect, Solomon and colleagues turned their attention to the hypothalamus and to AMP kinase (AMPK) in particular. This enzyme plays a major role in lipid metabolism in the periphery, but in the hypothalamus it appears to play a key role in regulating food intake. Agents that induce anorexia, such as the hormone leptin, activate hypothalamic AMPK, while orexigenic agents, which induce weight gain, have the opposite effect, inhibiting the enzyme.

First author Sangwon Kim and colleagues found that the orexigenic AAPDs, including clozapine, olanzapine, and to a lesser extent quetiapine, lower levels of active AMPK in mouse hypothalamus tissue, while the non-orexigenic AAPDs did not. In the case of clozapine and olanzapine, the effect was quite potent, with EC50s (the amount that gives a 50 percent response) of about 10 nM. The researchers also found that the AAPDs could offset the anorexic effects of leptin—in live mice, clozapine could prevent leptin-induced activation of AMPK.

These findings might make one wonder if AAPDs interfere with leptin signaling. Kim and colleagues tested this idea and found that the antipsychotics have no affinity for leptin receptors or for those that bind neuropeptide Y or α-MSH, two other hormones that regulate metabolism. Instead, the authors discovered that the major metabolic effect of AAPDs relates to their affinities for histamine H1 receptors. When Kim and colleagues tested the orexigenic AAPDs in mice with no H1 receptors, there was no change in AMPK activity. The finding helps explain why the orexigenic activity of AAPDs correlates with their affinity for these receptors (see Wirshing et al., 1999) and why using antihistamines, such as those found in cold and allergy medicines, can lead to weight gain.

In an accompanying commentary, Herbert Meltzer, Vanderbilt University School of Medicine, notes that we have now “come full circle,” because the original antipsychotic drugs were developed in the search of a better antihistamine. “Thus, identification of the H1R as an important target for minimizing weight gain raises the possibility of using this information to guide therapeutic attempts to alleviate the metabolic side effects and to develop novel AAPDs, lacking H1R antagonism, which should cause fewer metabolic side effects,” Meltzer writes.

The cardiovascular consequences
The second study shows why such new and improved drugs may be valuable. While AAPDs are not the sole reason for increased mortality among people with severe mental illness (SMI), Osborn and colleagues report that they do slightly increase the risk for coronary heart disease and stroke in that population. However, it is important to note that patients not taking these medications also have greater risk for cardiovascular disease than the general population. The authors also looked at cancer cases but found no correlation between cancer deaths and severe mental illness.

Osborn and colleagues used the United Kingdom’s general practice research database to obtain mortality rates among more than 46,000 people with severe mental illness. They compared this data with figures from over 300,000 controls. They found that mortality due to coronary heart disease in 18-49-year-old SMI patients was 3.2-fold higher than in controls. This risk decreased with age—for those aged 50-75 and those over 75, the relative risk compared to controls was 1.86 and 1.05, respectively. Stroke data showed a similar age-dependent pattern, though the increased risks were not as high.

When antipsychotic medications were taken into account, the results became quite complex. At the lowest doses it seems that these medications may be slightly protective, though patients with severe mental illness were still at higher risk than controls. At the highest doses, however, antipsychotics do seem to slightly elevate the risk of dying from both coronary heart disease (CHD) and stroke. But when the authors looked at atypical antipsychotics alone, they did not find any association with mortality. The authors note that this is counterintuitive, given the metabolic effects of these drugs.

There were limitations in the study, as acknowledged by the authors. They did not compare antipsychotics that do and do not lead to weight gain, for example, and in fact, they did not address the issue of weight at all except to emphasize that those who are overweight may not be prescribed atypical antipsychotics. They did comment that “CHD lifestyle factors, such as poor diet and exercise, which are more prevalent in people with SMI, provide another important focus for intervention.”

While this study highlights the importance of monitoring cardiovascular disease in the severely mentally ill, more work needs to be done to understand the relationship. One major factor that is worth keeping an eye on is the relatively recent trend toward prescribing atypical antipsychotics: “…it is possible that any effect on CHD mortality may not have occurred within the period of our study,” write the authors.

As for tumors, data from this large dataset suggests that mentally ill patients are neither more nor less likely to die from cancer. Some previous studies have suggested that patients with schizophrenia may have reduced incidence of cancer (see Grinshpoon et al., 2005); however, there are also conflicting reports (see Dalton et al., 2005; Dalton et al., 2004). The relationship between cancer and mental illness may also be worthy of further study.—Tom Fagan.

Reference:
Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. PNAS early edition.

Osborn DPJ, Levy G, Nazareth I, Petersen I, Islam A, King MB. Relative risk of Cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s general practice research database.

 
Comments on News and Primary Papers
Comment by:  Mary Reid
Submitted 12 March 2007 Posted 14 March 2007

Atmaca and colleagues report that atypical antipsychotic-, especially clozapine- and olanzapine-induced weight gain is related to increased levels of leptin. How does this tie in with the study by Sangwon Kim and colleagues, who found that clozapine and olanzapine lower levels of active AMPK in mouse hypothalamus tissue while leptin activates hypothalamic AMPK?

Wannamethee et al. conclude, "Plasma leptin is associated with insulin resistance, inflammation, and disturbances in homeostasis independent of waist circumference, suggesting possible pathways by which leptin may influence risk of cardiovascular disease." They also report that leptin is lowered in cigarette smokers.

It is of interest that De Rosa and colleagues report reduced activation of FOXP3 by leptin. Is this a positive or a negative in schizophrenia? Is there a...  Read more


View all comments by Mary Reid
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