Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists

At clinically relevant doses, selective serotonin (5-HT) reuptake inhibitors (SSRIs) and MAO inhibitors (MAOIs) increase the extracellular concentration of 5-HT in the midbrain raphe nuclei, thereby activating inhibitory somatodendritic 5-HTIA autoreceptors, Consequently, the firing activity of 5-HT neurons is reduced and the enhancement of extracellular 5-HT concentration in forebrain is dampened, Overriding this feedback by using antagonists of 5-HTIA autoreceptors permits SSRIs to produce a marked increase of extracellular 5-HT in the forebrain. Hence, combined treatment with an SSRI and a 5-HTIA antagonist increases the extracellular concentration of 5-HT more so than the former drug alone, The treatment of patients with major depression using an SSRI and pindolol, a 5-HTIA/beta-adrenoceptor antagonist, markedly reduced the latency of the antidepressant response in previously untreated patients and induced a rapid improvement in treatment-resistant patients.