Current understanding of antidepressant action primarily revolves around pharmacological effects regulating the Cediranib order activity of serotonin neurotransmission, although a variety of other mechanisms, mostly not inconsistent

with serotoninergic regulation, have been proposed. Certainly the antipsychotic drugs used in bipolar disorder have effects on serotonin receptors. As well as all having a high affinity at the 5-HT2A receptor, Inhibitors,research,lifescience,medical asenapine, olanzapine and clozapine have very high relative 5-HT2C receptor affinities. The 5-HT2C receptors have strong evidence supporting their potential as targets for antidepressant action [Jensen et al. 2010]. Most atypicals, namely Inhibitors,research,lifescience,medical asenapine, ziprasidone, quetiapine and aripiprazole, have a partial agonist activity at 5-HT1A receptors which may be functional at clinical doses. Further potentially valuable effects of asenapine, some of which are shared with other atypicals, include antagonism of the presynaptic 5-HT1B receptor that may lead to an increase

in serotonin release, antagonism of inhibitory alpha2 adrenoceptors found on serotonin neurons resulting in their increased activity, and actions at 5-HT6 and 5-HT7 receptors. The latter two receptors have attracted much recent research interest; both agonists and antagonists at the 5-HT6 receptor have been reported to have potential Inhibitors,research,lifescience,medical antidepressant and anxiolytic effects [Wesolowska, 2010]; this receptor is also a target for procognitive drugs. The 5-HT7 receptor too is considered a valuable target for antidepressant drugs [Hedlund, Inhibitors,research,lifescience,medical 2009]. Notably both these reviews highlight the particular potential of 5-HT6 or 5-HT7 antagonists in augmenting the effects of established antidepressant drugs, indicating the possibility of an enhanced antidepressant action Inhibitors,research,lifescience,medical associated with their antagonism in conjunction with other pharmacological mechanisms increasing synaptic serotonin by e.g. alpha2 adrenergic or 5-HT1B receptor antagonism as may occur with asenapine. However this synergism may also be true of other established antidepressant targets including the

5-HT2A [Blier and Szabo, 2005] and 5-HT2C receptors. Adverse effects Extrapyramidal side effects A consequence of dopamine D2 receptor antagonism, the main anti-manic mechanism others of the antipsychotic drugs, is an inhibition of dopaminergic function in the basal ganglia, regions of the brain controlling automatic motor function. This results in the acute extrapyramidal side effects (EPS), which include the relatively immediate effects of akathisia, dystonia and parkinsonism, as well as tardive dyskinesia (TD), a severe and occasionally irreversible problem associated with chronic antipsychotic drug treatment. The avoidance of these acute and chronic EPS has driven the development of the second generation of antipsychotic drugs.