Elsevier

Psychiatry Research

Volume 103, Issues 2–3, 20 September 2001, Pages 193-203
Psychiatry Research

A double-blind placebo-controlled crossover study of phenytoin in individuals with impulsive aggression

https://doi.org/10.1016/S0165-1781(01)00287-6Get rights and content

Abstract

The present study examines the behavioral and psychophysiological effects of phenytoin (PHT) in individuals who display impulsive-aggressive outbursts. In a double-blind placebo-controlled crossover design, individuals meeting previously established criteria for impulsive aggression were administered PHT and placebo during separate 6-week conditions. The efficacy measures used were the Overt Aggression Scale (OAS) and the Profile of Mood States (POMS). Psychophysiological measures (evoked potentials) were taken at baseline and at the end of each 6-week condition. Photic stimulation was used to evoke the mid-latency P1–N1–P2 waveform complex. Analysis indicated a significant decrease in the frequency of impulsive-aggressive outbursts during PHT administration compared to baseline and placebo. Analysis of the psychophysiological data showed significantly increased P1 amplitude and significantly longer N1 latency during PHT administration. In addition, a reduction in N1 amplitude during PHT administration was also suggested. These findings indicate reparation of physiological abnormalities previously observed in impulsive-aggressive individuals and imply more efficient sensory processing and effective orienting of attention. Taken together, these results provide insight as to the physiological mechanisms by which PHT serves to ameliorate impulsive-aggressive behavior.

Introduction

Within the research literature, aggressive behavior has traditionally been classified into two distinct subtypes (Feshbach, 1964, Dodge and Coie, 1987, Vitiello et al., 1990, Barratt, 1991, Barratt et al., 1997b, Barratt et al., 1999): (1) an emotionally charged, uncontrolled type of aggressive display (impulsive, unintentional, affective, reactive) or (2) a planned, controlled, unemotional aggressive act (premeditated, intentional, predatory, proactive). Research suggests that this first subtype, impulsive aggression, may have biological underpinnings related to deficits in physiological arousal (Barratt et al., 1997a, Barratt et al., 1997b). Psychophysiological measures in these individuals have indicated a low level of arousal during resting conditions (Fishbein et al., 1989, Convit et al., 1991, Barratt et al., 1997b, Mathias and Stanford, 1999). It has been hypothesized that this low arousal leads to sensation-seeking and impulsive behaviors as well as a reduction in the efficiency of executive functioning (Eysenck and Eysenck, 1985, p. 249). In addition, impulsive-aggressive individuals show greater physiological reactivity as compared to controls (Mathias and Stanford, 1997). It has been suggested that sudden surges in arousal induce an agitated state that the impulsive-aggressive individual is unable to control.

Previous studies using evoked and event-related potential techniques have begun to shed some light on the psychophysiological substrates that underlie this problem behavior. Research utilizing photic stimulation has demonstrated an increase in P1-N1 amplitude in response to increasing stimulus intensity (augmenting) in impulsive-aggressive subjects (Houston and Stanford, 2001). In conjunction with this increased augmenting, P1 amplitude is smaller, N1 amplitude is generally larger and PI-NI-P2 latency is shorter in impulsive aggressors (Houston and Stanford, 2001). Specifically, the reduced P1 amplitude exhibited in this sample is hypothesized to reflect a deficiency in sensory gating (Rosenstein et al., 1994, Houston and Stanford, 2001). This deficit is further reflected in the greater physiological reactivity that characterizes impulsive-aggressive individuals (Barratt, 1963, Mathias and Stanford, 1997). Furthermore, inefficient sensory gating may also contribute to the deficient cognitive processing seen in impulsive-aggressive individuals during event-related potential paradigms (i.e. P3; Barratt et al., 1997b, Mathias and Stanford, 1999). The N1 amplitude, usually thought to indicate orienting or attention, has also provided insight into the physiological abberations demonstrated in impulsive-aggressive samples. The larger N1 amplitude in these individuals indicates a different response to evoking stimuli. This response is thought to be indicative of the impulse aggressor's constant search for stimulation in an effort to boost arousal to a more optimal level. In addition, the shorter evoked potential (EP) latencies demonstrated by impulsive-aggressive individuals are also thought to reflect this constant search for stimulation. Furthermore, larger NI amplitudes in response to increasing stimulus intensities, as compared to controls, lend support to the notion of greater physiological reactivity in this sample. Taken together, these psychophysiological results provide further evidence of arousal modulation deficits underlying impulsive-aggressive behavior.

In light of previous research indicating psychophysiological irregularities in impulsive aggression as well as clinical treatment of such behavior, the efficacy of various pharmacological agents has been investigated. One medication that has shown ameliorative effects specific to impulsive-aggressive behavior is the anticonvulsant phenytoin (PHT; Dilantin®, Parke-Davis). In normal subjects, administration of phenytoin results in prolonged EP latencies (P1, N1) and a reduction in N1 amplitude (Barratt et al., 1986, Yagyu et al., 1991, Akaho, 1996). These effects are contrary to those EP abnormalities (shorter P1-N1-P2 latency, higher N1 amplitude) exhibited by impulsive-aggressive subjects (Houston and Stanford, 2001). Psychiatric patients with episodic dyscontrol syndrome showed significant reductions in violent outbursts during treatment with phenytoin (Maletzky, 1973, Maletzky and Klotter, 1974). Similarly, incarcerated inmates whose aggressive behavior was classified as impulsive in nature showed significant reductions in the frequency and intensity of aggressive acts, normalization of event-related potentials (P3), and improvement in mood state measures during a 6-week double-blind trial of phenytoin when compared to placebo (Barratt et al., 1991, Barratt et al., 1997a). Inmates whose aggressive behavior was classified as premeditated showed no improvement during the same trial.

Given that phenytoin has been shown to reduce the frequency of impulsive-aggressive outbursts as well as alter mid-latency evoked potentials, the present investigation was conducted to elucidate those psychophysiological effects phenytoin might have related to arousal modulation in impulsive aggression. Consolidation of previous research from both normal and aggressive samples led to the development of the following hypothesis for the present investigation:

  • 1.

    The frequency of impulsive-aggressive outbursts should be attenuated during phenytoin administration (Barratt et al., 1991, Barratt et al., 1997a).

  • 2.

    Mood scores on the Profile of Mood States (POMS), specifically tension/anxiety, should be significantly improved during phenytoin administration (Barratt et al., 1991, Barratt et al., 1997a).

  • 3.

    P1 amplitude should be enhanced during phenytoin administration indicating some reparation of sensory gating deficiencies (Houston and Stanford, 2001).

  • 4.

    N1 amplitude should be reduced during phenytoin administration as indicated by previous work in normal samples (Barratt et al., 1986, Yagyu et al., 1991, Akaho, 1996).

  • 5.

    EP latencies should be prolonged during phenytoin administration. This effect has been demonstrated in normal samples with the N1 (Yagyu et al., 1991, Akaho, 1996).

Section snippets

Subject recruitment/screening

Impulsive-aggressive subjects were recruited via local radio advertisements that described a potential treatment for men who have problems controlling their tempers. Interested individuals were instructed to call the laboratory for a screening interview. Females were excluded from the study due to phenytoin's potential teratogenic effects. To be considered for participation in the study, the subject must have met the following criteria: (1) over the past six months, the subject identified

Subject screening

Of a potential 148 men who contacted the laboratory for screening, 46 met full criteria and were included in the study, 76 were excluded and 26 refused participation. Of the 46 subjects included in the study, 29 (63%) completed the full 16 weeks. Within the group of subjects who completed the study, four reported no outbursts throughout the 16 weeks and two had serum phenytoin levels of 0 μg/ml; these six subjects were excluded from the sample. Thus, a sample size of n=23 was used in the

Discussion

As hypothesized, the present results corroborate previous work indicating the anti-aggressive effects of phenytoin (Maletzky, 1973, Maletzky and Klotter, 1974, Barratt et al., 1991, Barratt et al., 1997a). In the present study, the frequency of impulsive-aggressive outbursts was significantly reduced during phenytoin administration compared to baseline (57%) and placebo (38%). Consistent with previous research, a placebo effect (33%) was observed (35%, Barratt et al., 1991; 25%, Barratt et al.,

Acknowledgements

This research was supported by the Dreyfus Health Foundation, The Rogosin Institute, New York Hospital-Cornell Medical Center.

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