Clinical Implications of Serotonin 1A Neuromodulation

Vernon M Neppe MD, PhD

Educational Objectives

To educate in the area of serotonin and particularly the serotonin 1A receptor subtype in the context of clinical psychiatry.
To discuss the clinical implications of the serotonin 1A receptor with regard to management options and problems.
The development of a broader theory of innovative psychopharmacotherapy and the understanding of concepts such as neuromodulation and partial agonism.

Abstract

The serotonin receptors modulate a variety of basic functions at a large number of levels. These functions reflect serotonin 1A neuromodulators as well. The clinical application is broad because drug action at the serotonin 1A receptor subtype involves low toxicity, lack of dependency and no sedation. Moreover, some serotonin 1A related compounds act selectively at that receptor. This combined with the uniqueness of the 1A subtype in acting at the autoreceptor in the raphe nucleus and post-synaptically in areas of the brain of strategic relevance to psychopathology makes their potential application in psychiatry and medicine substantial. Finally, the availability of post-synaptic partial agonists at the receptor level makes the application potentially enormous.

Serotonin 1A receptor action can be measured relatively specifically by the azapirones. These act as partial agonists postsynaptically and full agonists at the autoreceptor. Non-specifically, beta 2 -adrenergic receptor blockers (like propranolol) produce overall serotonin 1A receptor antagonist effects. The benzodioxines, an experimental group, which includes eltoprazine, act as partial agonists postsynaptically on both 5HT 1A and 1B receptors. Lithium has very non-specific effects but technically is a serotonin 1A agonist. It is marketed for manic-depressive illness prophylaxis and treatment of mania (e.g. 450-1500 mg per day with serum levels such as 0.4 to 0.7 to 1.0 meq / L). Similar doses have been used in open cases for aggression (not approved).

The literature on beta-blockers and the role of serotonin 1A in this regard is reviewed. The perspectives in somatic anxiety, akathisia and aggression particularly may be relevant. Low doses of beta-blocker (e.g. 10 mg tid of nadolol or propranolol) may act peripherally on the beta-adrenergic receptor. Anti-akathisic effects require lipid solubility and beta-2 drugs implying 5HT 1A effects (e.g. 20mg tid of propranolol). Higher doses of lipid soluble beta-2-blocker such as propranolol in enormous doses (e.g. 240mg q.i.d. of propranolol monitored carefully because of safety considerations) have been occasionally used in aggression and probably are serotonin related.

Specific serotonin modulators are evaluated using the azapirones as the pharmacologic probe. Buspirone as the only marketed azapirone is 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.

Low doses of buspirone (5-20mg ) probably act at the autoreceptor as agonists effectively producing post-synaptic antagonism across all serotonin receptor subtypes. These doses are provisionally excellent anti-aggressive agents using animal and human models. They may have adjunctive use in attention deficit disorder. Speculatively, they help SSRI induced akathisia: This effect may be post-synaptic partial agonism with the antagonist effect being uppermost (dosing 15-30mg per day). Medium doses act post-synaptically modulating the prophylaxis of anxiety (30-45mg /day). Higher doses are weak agonists and may correspond with weak antidepressant effects (45-60 mg / day). Serotonin 1A partial agonism may imply adjunctive use of buspirone or other azapirones in instances when SSRI compounds stop facilitating depression. Higher doses may also imply some modulation of obsessionality (60mg / day), disputably post-traumatic stress disorder (60-75 mg / day) and even possible effects on the irritability of the manic (60-90 mg / day). Such doses also may induce mild akathisia: this may imply a serotonin 1A modulating role, but this is complex as serotonin re-uptake blockers like fluoxetine which act broadly also induce akathisia; moreover this can be blocked by buspirone. Finally extremely high doses of buspirone appear very promising anti-tardive dyskinesia agents (120-240 mg per day): as these effects may be tentatively blocked by cyproheptadine, this too may be via serotonin 1A neuromodulation of the known partial dopamine agonist effects of buspirone in conventionally supratherapeutic doses. The scanty literature is discussed.