A double-blind placebo-controlled crossover study of phenytoin in individuals with impulsive aggression
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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2011, Neurologic ClinicsCitation Excerpt :Subjects with a known history of seizures were excluded from the study, suggesting that effects of anticonvulsants on aggression are independent of effects on seizures. A second study by Stanford and colleagues83 supported the earlier results of Barratt and colleagues82 of reduced impulsive aggression in patients treated with phenytoin, and a third study showed that effects of phenytoin on impulsive aggression were similar to effects of valproate.84 Phenytoin was well tolerated at the dose used in these studies, which produced blood levels that were, on average, lower than those used to treat epilepsy.