Antidepressants, Serotonin Specificity and Neuromodulation

Vernon M Neppe MD, PhD

Educational Objectives

  1. The development of a broader understanding of why antidepressants succeed and fail when they do and what to do about it.
  2. To educate in the area of serotonin in the context of clinical psychiatry.
  3. To evaluate the serotonin 2 receptor with regard to management options and problems.
  4. To elucidate a role for norepinephrine in relation to serotonin and depression.
  5. To establish alternatives for lowering antidepressant side effects.
  6. To develop a profile of the ideal antidepressant compound based on a pharmacologic model.


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 and then looks at new single drug approaches.

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 in depression. The numerous antidepressant compounds are evaluated for side-effect profile with emphasis on serotonin excess symptoms. Serotonin modulates many basic functions at a large number of levels allowing explanations of why its influences are so diverse. In fact, it impacts at physiologic (circadian rhythms, hypothalamic pitutiuary function, temperature), behavioral (aggression, weight, sex, sleep) and psychological (anxiety, depression, obsessionality, stress, memory, lability) levels. The numerous serotonin receptor subtypes and specificity is critical to appreciating why drugs work and fail and why such paradoxic reactions as anxiety or anti-anxiety effects may occur with the same drug in different patients.

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. The azapirone class generally has 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. The only marketed 5HT-1A selective drug is the azapirone, buspirone (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.

The classic bathtub example relates to the serotonin re-uptake inhibitor drugs with their in general unopposed effect of raising serotonin levels: this is useful in treating a biological depression with ostensible serotonin deficiency. The model is simplistic because there are numerous receptor subtypes. Serotonin 2A receptor subtype is relevant as blockade appears to be linked with anti-depressant effects. The links of sexual libidinal and other side-effects, nausea, akathisia, anxiety, agitation, insomnia and headache may potentially be modulated by the serotonin excess induced by the SSRI drugs. Potentially drugs which have more moderate effects on serotonin re-uptake could diminish these effects, particularly if they have some serotonin blockade at relevant receptors such as 2A.

The unopposed action of serotonin without norepinephric effects in depression as in the classical SSRI model has major limitations. Alternatives such as venlafaxine involves both receptors and moreover in general does not demonstrate the enormous potency of the SSRIs requiring a modulation of dosage and a far more physiologic approach. Venlafaxine currently may be the drug of choice in the retarded depression. Similarly, the development of another antidepressant, nefazodone, theoretically is an exciting advance as modulation not bathtub filling can occur at both these receptor levels but predominantly at the serotonergic level. This should produce theoretically efficacy with less "overfilling" side-effects. Its marked bathplug effects such as substantial serotonin 2 A blockade produce the potential towards anti-anxiety action in the context of depression as well as some sedation implying applicability for the agitated depressed patient. Dose limitations may occur as a consequence or because of the alpha adrenergic hypotensive side-effects. Strategies for dosing and using the various antidepressants are discussed.



© Copyright 1997 Pacific Neuropsychiatric Institute.