Pharmacologic Management of Aggression and Irritability

Vernon M Neppe MD, PhD

EDUCATIONAL OBJECTIVES:

To educate in the area of aggression in the context of anxiety and depression and to discuss the clinical implications with regard to management options and problems.

ABSTRACT

Exploration of aggression spectrum concepts such as anger, aggression, hostility, dyscontrol, rage, irritability and impulsivity are compromised by the absence of an adequate diagnostic and therapeutic classification, the general equivalent use of these terms, their measuring difficulties and their lack of research. Without a current diagnostic framework for aggression in the Diagnostic and Statistical Manual III revision or DSM-IV, there are no FDA approved drugs for aggression.

Drugs such as carbamazepine have enormous potential in the management of episodic disorders particularly those linked with hostility. Preliminary research suggests its use is particularly apposite in "Paroxysmal Neurobehavioral Disorders" as a prototype organic illness with epilepsy like phenomena. While this aggression may occur incidentally in the context of anxiety and depression, this is not necessarily more frequent than other conditions.

Probably more important for anxiety and depression is the frustration aggression context linked with adrenergic and serotonergic elements.

Evidence exists for serotonin receptor involvement in the aggression spectrum using animal models and human clinical and post-mortem studies.

Beta-adrenergic blockers are useful but to a limited degree because of side-effects in high doses in organic populations. Biphasic effects are seen with the lipid soluble propranolol - low doses probably relate to simple alleviation of frustration, but, high doses seem to have a central, possibly non-beta effect. Their action may have links with serotonin 1A or 1B, and so may a new unmarketed group, the Benzodioxines. Additionally, lithium cation is commonly used in similar populations for affective illness and aggression has serotonin 1A agonist effects.

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 suggests a biphasic dose effect for buspirone: 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 nine successive patients (p< 0.001, but many inpatients improve with milieu). 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.