In recent years, weight gain has increasingly gained attention as a side effect of antipsychotic therapy due to its metabolic and cardiovascular health risks and its negative effect on therapy compliance. The various antipsychotics show clear differences concerning their influence on body weight. These differences seem to be mainly due to the affinity of these substances to the histaminergic H1 receptors and due to serotonergic mechanisms. In the hypothalamus, the antihistaminergic effect of those antipsychotics which are associated with a high amount of weight gain leads to an increase of the activity of the adenosine monophosphate-activated protein kinase (AMPK). Hypothalamic AMPK activity has an integrative function regarding orexigenic and anorexigenic signals.