Preclinical evidence indicates that repeated treatment with antidepressant drugs (serotonin [5-HT] reuptake or monoamine oxidase [MAO] inhibitors) potentiates the ascending brain serotonergic pathways.1,2 Also, clinical data show that the inhibition of 5-HT synthesis results in a marked worsening of patients recovering from depression who are treated with these drugs.3-5 These findings suggest that the antidepressant effects of uptake and MAO inhibitors emerge when serotonergic activity increases.
Using intracerebral microdialysis in the awake, freely moving rat, a single treatment with 5-HT uptake blockers, such as clomipramine6 or fluvoxamine,7 was reported to cause little or no increase of 5-HT concentration in frontal cortex at doses comparable with or higher than those used clinically. In contrast, extracellular 5-HT concentration is dramatically augmented by the same doses in the vicinity of cell bodies of serotonergic neurons, in the midbrain raphe nuclei, a preferential increase also observed after a single treatment
Artigas F, Perez V, Alvarez E. Pindolol Induces a Rapid Improvement of Depressed Patients Treated With Serotonin Reuptake Inhibitors. Arch Gen Psychiatry. 1994;51(3):248-251. doi:10.1001/archpsyc.1994.03950030084009