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 their cell bodies and nerve terminals. As an illustration of such connections, selective serotonin reuptake inhibitors (SSRIs) gradually enhance serotonin transmission not only in the forebrain but also in the locus ceruleus, thereby decreasing norepinephrine neuronal firing. In contrast, blocking 5-HT2A receptors in the presence of serotonin reuptake inhibition using the experimental compound YM992 enhances both serotonin and norepinephrine release. The latter pharmacologic effect may be a main contributor to 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 augmentation strategy in SSRI-resistant patients. This effect may result in part from its antagonistic actions on dopaminergic receptors and alpha2-adrenoceptors on serotonin terminals.