PSYCHOPHARMACOLOGIC TREATMENT OF PATHOLOGIC AGGRESSION

Pathologic aggression and anger are extremely heterogeneous phenomena present in a variety of psychiatric and neurologic disorders, ranging from brain injury to schizophrenia and major depressive disorder. Several researchers have attempted to link certain forms of pathologic aggression with specific neuropsychiatric conditions. For example, whereas repetitive unprovoked assaultive behaviors have been associated with brain injury,¹⁰² recurrent inappropriate verbal or physical responses to external stimuli have been considered to be characteristic of mood disorders accompanied by marked irritability (Fava, 1993). Pathologic aggression, however, is influenced heavily by many psychological, developmental, and environmental factors in addition to the underlying medical condition, so that its manifestations within subjects with the same neuropsychiatric disorder are quite variable and somewhat unpredictable.

A number of neurochemical systems, including those involving GABAergic, serotonergic, noradrenergic, dopaminergic, and glutaminergic neurotransmission, have been implicated in the modulation of aggressive behavior in animal models.14, 36, 57, 94, 134 Similarly, as described in the article by Kavoussi et al elsewhere in this issue, neurochemical studies in human beings have supported the modulating role in pathologic aggression of several systems of neurotransmitters, in particular serotonin. It is, therefore, not surprising that investigators have studied the effects of psychotropic drugs both in animal models and human subjects. The effects of specific psychotropic agents, however, do vary across different animal models of affective aggression,³² and, in human beings, the same drug (i.e., methylphenidate) can show antiaggressive effects in certain populations (i.e., adolescents with attention deficit hyperactivity disorder) and precipitate aggressive responses in others (i.e., bipolar patients).

The systematic study of the effects of treatment on pathologic aggression also is complicated by the fact that this is typically an intermittent phenomenon whose occurrence and intensity are often unpredictable. An alternative approach to the clinical trial in affected populations would be that of studying the effects of a particular drug in individuals undergoing pharmacologic challenges that recreate in the laboratory setting aggressive responses. Although researchers have developed pharmacologic challenges (e.g., yohimbine and lactate) to induce fear or panic in the laboratory among patients with a history of panic attacks, there is no comparable test to study anger attacks or rage in patients with a history of pathologic aggression. A possible tool for such investigation is m-chlorophenylpiperazine (m-CPP), which was found to induce an anger response in patients with generalized anxiety disorder, although not in patients with other disorders.⁵⁶

Despite the lack of approval by Food and Drug Administration (FDA) of any drug specifically for the treatment of aggression, a number of currently available drugs are used for this purpose. The FDA (P David, personal communication), however, does recognize that pathologic aggression may be an aspect of certain disorders (e.g., bipolar disorder and schizophrenia) for which specific drug treatments have been approved. In addition, no pharmaceutical company has yet applied for approval of a drug indicated for the treatment of pathologic aggression (P David, personal communication), suggesting that the lack of FDA-approved uses of certain drugs in the management of aggressive patients may stem from a relative lack of market interest in this field and, perhaps, by the medicolegal risk related to the process leading to such approval. It is not difficult to imagine the degree of concern on the part of the legal departments of pharmaceutical companies conducting placebo-controlled clinical trials in subjects with pathologic aggression. In spite of these limitations, a number of studies and anecdotal reports have been guiding physicians' decisions concerning the drug treatment of pathologic aggression. The aim of this article is, therefore, to review the drug treatment of pathologic aggression. In addition, some of the most frequently used instruments for the assessment of pathologic aggression and anger are reviewed, as the characteristics of the instruments used in the clinical trials may affect outcome.