Pharmacologic Management of Aggression and Irritability
Vernon M Neppe MD, PhD
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.
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
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.