Genotype, drugs and other modifiable factors, such as smoking, appear to interact to increase the risk of obesity and metabolic syndrome in patients with schizophrenia, according to a study presented at the 20th Congress of the European College of Neuropsychopharmacology (ECNP) in Vienna last week.

The study identified two genetic polymorphisms that explain about 30% of the variance in weight gain in people with schizophrenia. The findings could lead to a new test that predicts a patient’s liability to develop metabolic disease following antipsychotic treatment.

The study enrolled 130 patients with schizophrenia or schizoaffective psychosis. Of these, 121 received antipsychotics, including clozapine, olanzapine and risperidone. Most were obese: 74% had waist circumferences _94 cm for males or _80 cm in females (central obesity), and 41% showed BMI>30.

Six per cent of the patients showed diabetes or impaired glucose tolerance, while 38% met the definition for metabolic syndrome. Smoking did not reduce the risk of obesity. However, 44% of smokers in the study met the criteria for metabolic syndrome compared with 26% of non-smokers.

Leptin disruption

Lead author Gavin Reynolds, from the Division of Psychiatry and Neuroscience, Queen's University Belfast, notes that antipsychotics disrupt leptin signalling. Leptin is a hormone released from adipose tissue that reduces food intake and increases metabolism. Some serotonin receptors (such as 5-HT2C) modulate leptin’s effect on the brain, particularly the hypothalamus. Therefore, some antipsychotics may disrupt leptin’s signalling in the hypothalamus.

“The disruption means that people taking some antipsychotics eat more, which may result in the ‘metabolic syndrome’ and an increased risk of cardiovascular disease and diabetes,” Professor Reynolds says.

Nevertheless, he notes, there is "substantial inter-individual variability between patients in the extent of weight gain and emergence of metabolic syndrome. Genetic risk factors – such as common functional polymorphisms in the 5-HT2C receptor and leptin genes - may underlie some of this variability."

Presenting their research in Vienna, Professor Reynolds’ group showed that polymorphisms in the 5-HT2C and leptin genes interacted strongly to influence waist circumference and body mass index (BMI) in people with schizophrenia.

For example, among patients expressing a common polymorphism in the 5-HT2C receptor (759CC), those carrying the leptin G allele (AG or GG) exhibited significantly higher BMI, larger waist circumference and lower risk of metabolic syndrome than those with the AA leptin genotype. BMI was approximately 26 kg/m2 and waist circumference almost 94 cm in those with the AA genotype. This compared with 30 kg/m2 and 104 cm respectively in those carrying the leptin G allele.

“In our studies of patients taking antipsychotics for the first time, our two genetic polymorphisms explain about 30% of the variance in weight gain,” Professor Reynolds told PharmaTimes. "That’s not bad for something that is inevitably dependent on other factors, such as is there a Coke dispenser nearby, do they prefer salad to chips and how much exercise they take."

Genetic test?

In the future, Professor Reynolds suggests, these genetic risk factors may lead to a test that predicts a patient's liability to metabolic disease following antipsychotic drug treatment and could help doctors to choose the most appropriate treatment for each patient. However, he adds, further work is needed to translate the research into a clinical test. For example, other genes may contribute to the risk.

Nevertheless, Professor Reynolds believes a kit could be developed. Indeed, marketed tests already predict the response to, and side-effects from, clozapine.

“As well as expanding our current sample, we plan to investigate prospectively the impact of genetic information about patients’ propensity to gain weight and, eventually, develop the metabolic syndrome on antipsychotic prescribing,” he comments. "This would indicate the value of such a genetic test."