Treatment with an anti-psychotic drug found to cause changes in metabolism earlier than expected

Schizophrenia is a complex type of psychotic mental illness characterized by thoughts that are uncoupled from reality.

Huge gains in the effective treatment of individuals with the disease began in the 1950s with the development of the first generation of antipsychotic drugs. The medications allowed physicians to treat the “positive” effects of the illness (delusions and hallucinations) and, to a lesser extent, the “negative” symptoms (apathy). The second generation of antipsychotics – known as atypical antipsychotics (AAP) – began in 1990. These newer medicines have proven as effective in treating the positive aspects of the disease and more effective in combating the negative ones.

As is the case with nearly all medications, antipsychotics have side affects, including weight gain and some other risk factors of metabolic syndrome, which puts an individual at greater risk of heart disease and type 2 diabetes. Physicians are concerned that these side effects will cause their patients to stop taking their medications.

A team of French researchers has now found in an animal model that consuming at least one of the AAPs exhibit some of the risks related to metabolic syndrome that are similar to those found in patients. This model allows researchers to explore the sequence of early metabolic events that result from AAP treatment.

Montserrat Victoriano, Gilles Fromentin, Jean-Francois Huneau, and Dominique Hermier of the Department of Human Nutrition, INRA, Paris, France; and Renaud de Beaurepaire, Department of Psychopharmacology, Hospital Paul Guiraud, Villejuif, France, conducted the study. It is entitled Energy Metabolism Disturbances Induced by Antipsychotic Treatment in a Rat Model. Dr. Hermier will present the team's findings at the 121st annual meeting of the American Physiological Society (APS; www.the-APS.org/press), part of the Experimental Biology 2008 scientific conference.

The researchers had previously developed a model for antipsychotic-induced weight gain in the male rat, which allowed them to clearly distinguish between those antipsychotic drugs that produce some weight gain, moderate weight gain or no gain at all. These distinctions corresponded to the response in humans. Their latest study is built on these findings.

In the latest study they used 18 male rats which were randomly assigned to one of three groups: (1) those receiving the conventional antipsychotic drug haloperidol (HA); (2) those receiving the atypical antipsychotic drug olanzapine (OL); or (3) the control (CO) group which did not receive either drug. The medicines were given in food for a period of six weeks. Female rats were excluded to eliminate bias in the study since antipsychotic-induced weight gain in female rodents is likely related to an interaction of the drugs with estrogens.

Testing after four weeks found that the concentration of blood sugar (as glucose) was higher in OL rats (0.87 g/l) than in CO rats (0.75 g/l) and the levels increased more rapidly after a glucose meal. Testing six weeks later found fasting blood sugar levels continued to rise in OL rats (1.46 g/l vs. 1.25 g/l in CO rats) while the level of lipids (fats) in the blood was similar for both groups. Although there was no difference in body weight gain or food intake, the proportion of fat stored in the abdominal cavity was higher in OL rats (1.63%) vs. CO rats (1.44%).

The HA rats did not vary in any way with the control group at any time. They exhibited a lower blood sugar level after a glucose meal and a lower proportion of intraabdominal fat store (1.44%) than OL rats.

Senior study author Dominique Hermier said, “Based on these findings we concluded that male rats treated with olanzapine experienced an early disruption of energy metabolism. This was a result of the fat tissue we observed and the impairment in blood sugar regulation which are both associated with metabolic syndrome and subsequent risk of diabetes.”

She added, “Atypical medications like olanzapine are of tremendous value in treating individuals with certain kinds of mental illness. Our hope is that through discoveries such as this one, such life-enhancing medicines can be further optimized.”