Innovations in the Pharmacologic Management of Anxiety From the Serotonergic Perspective

Vernon M Neppe MD, PhD, FRCPC, FFPsych, MMed
Director, Pacific Neuropsychiatric Institute, Seattle WA
Adjunct Professor, St. Louis University Dept. of Psychiatry

Educational Objectives

To educate in the area of anxiety and briefly frustration irritability.
To discuss the clinical implications with regard to management options and problems.
To examine pharmacologic mechanisms and explain these clinically.

Abstract

The current classification of anxiety of a separation of panic and generalized anxiety disorder has historical and epidemiologic limitations with new terms being developed for old concepts and a statistical interface between the two conditions. An alternative perspectives is viewing anxiety along the normal - abnormal continuum, as well as the frameworks of somatic and psychic anxiety. Similarly, subdivisions into adjustment disorder, anxiety states, mixed anxiety / depression and organic anxiety disorder lead to a more fruitful approach as to the patientās pharmacologic needs. The frustration spectrum with irritability is an important components. We do not have a classification of irritability: At times, anger and related affects are closely linked with frustration and anxiety but such symptoms may exist separately too.

Future innovative approaches to anxiety paradoxically imply a re-evaluation of management over the last century to eliminate side-effects and develop customized treatment. Alcohol, bromides, barbiturates and meprobamate have all had their problems. The benzodiazepines, an apparent major advance, have turned out to have benefits with selected but limited indications. This is so because of their significant problems.

The rare electrical mechanisms may explain responsiveness to anticonvulsants such as carbamazepine in certain episodic - atypical panic - anxieties. The adrenergic, GABA / chloride ionophore receptor and serotonergic bathtub theories of pharmacologic mechanism are important frameworks for usage of such drugs as the beta-adrenergic blockers, benzodiazepines and selective serotonin re-uptake inhibitors (with their paradoxic side-effects of anxiety and agitation). Serotonin 1 A agonism and 2 A blockade introduce mechanisms for azapirones and such drugs as trazodone, risperidone, phenothiazines and nefazodone.

Legitimate alternatives such as antidepressant, beta-adrenergic blockers and azapirones are examined. Specialized groups such as addicts, medically ill and geriatric patients, have their own particular problems. Psychopharmacology is rapidly approaching the age of specialized receptorology and serotonin subtypes play a major role in management of both anxiety and depression. The advent of the azapirones has been a significant advance and may exemplify the neuromodulating roles played by varying doses of drug impinging on a specific receptor, in this instance serotonin 1A.

Animal models of aggression suggest the azapirones are potent anti-aggressive agents. This should be via components of their specific serotonin 1A partial agonist effects. Irritability is an early target symptom of response with buspirone in generalized anxiety disorder possibly implying persistent low-dose effects. Early preliminary open experience by the author suggests low doses of buspirone (15-25 mg per day) were effective after a few days in alleviating irritability, anger and hostility without associated significant anxiety in inpatients and outpatients plus a series of children and adolescents with similar results. Strangely, higher doses such as 60-90 mg per day almost immediately greatly relieved manic irritability, agitation, restlessness and mood lability in ten subjects. This data requires adequate controlled studies. If real, these two effects can be explained in a unified serotonin theory.