Potential Mechanisms of Action of Atypical Antipsychotic Medications in Treatment-Resistant Depression and Anxiety.

The serotonin (5-HT) and norepinephrine neurons have reciprocal interactions at the level of theircell bodies and nerve terminals. As an illustration of such connections, selective serotonin reuptakeinhibitors (SSRIs) gradually enhance serotonin transmission not only in the forebrain but also in thelocus ceruleus, thereby decreasing norepinephrine neuronal firing. In contrast, blocking 5-HT_2A receptorsin the presence of serotonin reuptake inhibition using the experimental compound YM992 enhancesboth serotonin and norepinephrine release. The latter pharmacologic effect may be a main contributorto the robust antidepressant effect of adding atypical antipsychotics in SSRI-resistant patients.In obsessive-compulsive disorder, risperidone has consistently been reported to be an effective augmentationstrategy in SSRI-resistant patients. This effect may result in part from its antagonisticactions on dopaminergic receptors and α₂-adrenoceptors on serotonin terminals.