Olanzapine

Olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos). ^[1]

Olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors. ^[1] Olanzapine combined with fluoxetine produces robust, sustained increases of extracellular levels of dopamine ([DA](ex)) and norepinephrine ([NE](ex)) up to 361% and 272% of the baseline in rat prefrontal cortex, respectively, which are significantly greater than either drug alone. ^[2] Olanzapine at 0.5 mg/kg, 3 mg/kg and 10 mg/kg (s.c.) dose-dependently increases the extracellular dopamine (DA) and norepinephrine (NE) levels in rat prefrontal cortex, nucleus accumbens and striatum. Olanzapine also increases extracellular levels of a DA metabolite, DOPAC, and tissue concentrations of a released DA metabolite, 3-methoxytyramine. ^[3] Olanzapine results in an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in macaque monkeys. ^[4] Olanzapine results in substantial increases in adiposity: increased total body fat reflecting marked increases in subcutaneous and visceral adipose stores. Olanzapine results in marked hepatic insulin resistance. ^[5]