Pindolol and the acceleration of the antidepressant response

Background: It has been suggested that treatment with selective serotonin reuptake inhibitors (SSRIs) in combination with pindolol, a partial agonist at the 5-HT1A receptor, may produce a fast antidepressant response. However, inconsistent results have been obtained in clinical studies with combination of the two drugs. Some studies, most using paroxetine, show an acceleration of the antidepressant response, whereas studies with other SSRIs find no marked latency reduction. Methods: The free SSRI concentration in patients either receiving the first dose, or in steady state treatment with the five different SSRIs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline was estimated using pharmacokinetic data for the individual drugs. Results: Due to differences between the drugs regarding protein binding, distribution volume and affinity for the 5-HT transporter (5-HTT), the 5-HT uptake inhibition obtained with clinically relevant doses differs markedly among the SSRIs. Conclusions: A nearly complete blockade of the 5-HTT is obtained already after the first dose only with paroxetine, explaining why the latency reducing effect of pindolol preferentially is seen when pindolol is combined with paroxetine.