Effectiveness of antipsychotic drug and associated weight gain may be predictable

T he antipsychotic drug Olanzapine (OLZ), which is prescribed for schizophrenia, can cause weight gain and insulin resistance in certain patients. In his thesis, Simon Evers demonstrates that Olanzapine is more likely to cause weight gain in people with a low level of thyroid-stimulating hormone (TSH) in their blood. ‘On the basis of my research and existing information about schizophrenia, I think that TSH could help us to predict the effectiveness of Olanzapine.’ Evers also shows that the anti-epileptic drug Topiramate can counter this weight gain. The PhD ceremony at the University of Groningen is on 6 March 2015.

Schizophrenia is a complex condition involving numerous neurotransmitters in the brain. Drugs prescribed for schizophrenia therefore affect numerous mechanisms in the body and side effects are inevitable. A commonly prescribed drug, Olanzapine, inhibits various receptors, including those for dopamine, serotonin, histamine, muscarine and noradrenalin. The main side effects of Olanzapine are weight gain and diabetes.

Weight gain

Evers designed a research project to find out what makes patients taking Olanzapine gain weight and whether this weight gain can be curbed. He used rats with character traits resembling schizophrenia. ‘These rats have increased activity of the dopamine system in the brain, display impulsive behaviour and are prone to developing addictions.’ He compared the rats with another group, which did not share the character traits of the first group, but were prone to obesity and insulin resistance as a result of changes in their diet.

‘The results show that the group of rats with schizophrenia character traits gained weight after being treated with Olanzapine,’ explains Evers. ‘This would seem to indicate a connection between a more sensitive dopamine system and increased sensitivity to the effects of Olanzapine. The way someone reacts to Olanzapine depends on his or her genetic features and character.’

Hormone levels predict effectiveness

Finally, Evers studied the effect of Olanzapine on healthy human male trial subjects. Men with a low level of thyroid-stimulating hormone (TSH) in their blood appear to be prone to weight gain after taking Olanzapine. ‘TSH is produced by the pituitary gland, which is in turn influenced by the dopaminergic system’, says Evers in his explanation of the results. ‘This study shows that weight gain when taking Olanzapine is probably linked to the dopaminergic system in humans too.’ Before prescribing Olanzapine, checking the level of pituitary hormones in the blood may help to predict the effectiveness of the proposed treatment.

Countering weight gain

The anti-epileptic drug Topiramate (TPM) appeared to inhibit the weight gain caused by Olanzapine in healthy men, specifically men with low levels of TSH. These results, in combination with previous research showing a link between weight gain when taking Olanzapine and a reduction in schizophrenia symptoms, lead Evers to conclude that Olanzapine is possibly an effective drug for treating schizophrenia in patients with low levels of TSH. ‘As this group is more likely to put on weight when taking Olanzapine, it would be effective to prescribe Topiramate alongside Olanzapine to counter the weight gain.

Background information

• Simon Evers conducted his research in the Research School of Behavioural and Cognitive Neurosciences (BCN) at the University of Groningen. After the PhD ceremony, he plans to start work as a postdoc researcher at the University of Michigan in the United States.
• The thesis The a-typical effects of olanzapine on body weight regulation - And the possible counter-effects of Topiramate can be downloaded.
• First supervisor of Evers is Anton Scheurink, professor of neuro-endocrinology and recently voted University of Groningen Lecturer of the Year. Scheurink specializes in the neural regulation of the body’s metabolism and the regulation of body weight, particularly in relation to the brain’s role in eating disorders such as Anorexia Nervosa and extreme obesity.