Noradrenergic augmentation of escitalopram response by risperidone: electrophysiologic studies in the rat brain.
BACKGROUND
Atypical antipsychotic drugs have been used in depressed patients not responding adequately to the selective serotonin reuptake inhibitors (SSRIs). The aim of the current study was to investigate putative mechanisms of the beneficial effect of atypical antipsychotic drugs during their co-administration with SSRIs. In previous electrophysiological studies, it was found that SSRIs decrease, while atypical antipsychotics increase, norepinephrine neuronal firing. Thus, the resistance to SSRIs could be explained, at least in part, by the SSRI-induced decrease of norepinephrine neuronal firing activity, and the beneficial effect of atypical antipsychotic drugs could be explained by the reversal of the above-mentioned suppression of firing.


METHODS
Rats were administered the SSRI escitalopram and the atypical antipsychotic drug risperidone. Norepinephrine neuronal activity was determined using in vivo electrophysiology.


RESULTS
Subacute and long-term escitalopram decreased, while risperidone co-administered with escitalopram increased, norepinephrine neuronal firing. Attempts at reversing the escitalopram-induced decrease of firing with various selective antagonists revealed that the serotonin-2A receptor antagonistic property of risperidone may mediate the pronoradrenergic action of atypical antipsychotics in the presence of serotonin reuptake inhibition.


CONCLUSIONS
Risperidone reverses escitalopram-induced inhibition of norepinephrine neuronal activity by a mechanism involving serotonin-2A receptors. This reversal may explain the beneficial effect of atypical antipsychotics in treatment-resistant depression.
Dremencov
Eliyahu
E
University of Ottawa Institute of Mental Health Research, Ottawa, Canada.
El Mansari
Mostafa
M
Blier
Pierre
P
D000200:Action Potentials / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology*; D004357:Drug Synergism; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology*
D014150:Antipsychotic Agents; D015283:Citalopram; D018967:Risperidone; D009638:Norepinephrine