Combination Serotonin Antidepressant Therapy

Vernon M Neppe MD, PhD

Educational Objectives

The development of a broader theory of innovative psychopharmacotherapy and the understanding of concepts such as neuromodulation and partial agonism.
To educate in the area of serotonin and particularly partial agonism in the context of clinical psychiatry.
To discuss the clinical and theoretical frameworks for enhancing the effects of SSRIs in cases of clinical refractoriness and side-effects.

Abstract

Three clinical scenarios relate to patients who fail treatment after receiving selective serotonin re-uptake inhibitor drugs. Acutely, they may experience the "I'm climbing out of my skin" feeling; more chronically over several weeks the "It's not working anymore" complaint; and over many months an "It worked so well before" amazement. This paper examines theoretical and practical options using combination serotonin antidepressant therapy.

A broader theory of management of such patients can be developed with the understanding of concepts such as neuromodulation, partial agonism and the serotonin bathtub analogy. Moreover, serotonin modulates many basic functions at a large number of levels allowing explanations of such conundrums as the delayed effects of antidepressants. Finally receptor specificity is critical to appreciating why drugs work and fail. Drug action at the serotonin 1A receptor subtype is particularly important. It involves post-synaptic effects in areas of the brain of strategic relevance to psychopathology. Drugs such as the azapirones generally have apparent low toxicity, lack of dependency and sedation and selectivity at the Serotonin 1 A receptor with partial agonism making their potential application in psychiatry substantial.

Buspirone is the only marketed azapirone (approved for use only in anxiety and mixed anxiety depressive states). However, clinical experience in several other areas is interesting but still at various early research stages. Serotonin re-uptake inhibitors like fluoxetine induce a serotonergic akathisia which can be blocked by buspirone. When SSRI compounds stop working with re-exacerbation of depression, adjunctive use of azapirones may theoretically extend their action. High therapeutic azapirone doses may also imply some modulation of obsessionality and weak antidepressant effects.