Dr. Wint is a staff physician at the Malcolm Randall VA Medical Center, and assistant professor in the Department of Psychiatry at the University of Florida in Gainesville.
Dr. Shapira is assistant professor in the Department of Psychiatry at the University of Florida.
Disclosure: Dr. Shapira is on the speaker’s bureau of Forest and Ortho-McNeil; receives research support from Abbott, Janssen, and Ortho-McNeil; and has received honoraria from Bristol-Myers Squibb, Eli Lilly, Forest, Janssen, and Pfizer.
Acknowledgments: The authors would like to thank Edward Weselcouch, PhD, for his assistance in the preparation of this manuscript.
Please direct all correspondence to: Dylan P. Wint, MD, Department of Psychiatry, PO Box 100256, Gainesville, FL 32610; Tel: 352-392-3681; Fax: 352-379-4170; E-mail: Dylan.Wint@med.va.gov.
• Impulsivity is found in a broad range of psychiatric syndromes and impulsive behavior can take many forms.
• Well-defined biological correlates of impulsive behavior exist.
• There are few well-studied treatments for some types of impulsivity and there is much to learn about the causes and treatments of impulsive behaviors overall.
Impulsivity is found across a broad range of psychiatric syndromes. It also encompasses many types of behavior, including aggression, eating, stealing, and gambling. Some types of impulsive behavior are associated with changes in brain activity and neurotransmitter turnover; serotonergic changes are particularly well linked to impulsive aggression. Efforts continue to discover the biological roots of impulsive behavior. Nevertheless, some effective treatments have been developed and antiepileptic drugs in particular have shown promise in ameliorating these disturbing behaviors.
Impaired impulse control, which is common in mental illness and can be life threatening, may be the most important characteristic of psychiatric disorders. Patients who do not possess reliable control of their impulses usually require hospitalization, restraints, forced treatment, or other impositions on their privacy and personal choices. In some psychiatric syndromes impulsivity is rare, while in others it is an essential feature. There are numerous theories about the causes of impulsivity and appropriate treatments for impulse dyscontrol. This review will briefly examine the pathophysiology and treatment of some of the clinically important impulsive behaviors seen in psychiatric illnesses.
Impulsive Anger and Aggression
Anger and aggression are among the most distressing symptoms of psychiatric illness. The lives of patients, families, and whole communities are severely disturbed when violence erupts.1 Unfortunately, anger and aggression are also rather frequent in a subgroup of the psychiatrically ill.2,3 In fact, potential or demonstrated aggressive behavior is one of the most common reasons for involuntary confinement.4 Unlike planned, predatory violence (not addressed in this article), impulsive aggression among psychiatric patients tends to be spontaneous and easily provoked.1 Aggression and violence may be directed at patients, those around them, or both.
Aggression Directed At Others
Outward-directed aggression is probably the best-studied manifestation of impulsivity, because it is relatively easy to observe and quantify. It presents itself in many psychiatric illnesses, with intermittent explosive disorder (IED) being the prototypical form of impulsive aggression. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text-Revision (DSM-IV-TR),5 IED is characterized by repeated failure to resist aggressive impulses that result in serious assaultive acts or destruction of property. IED?patients act with a degree of aggressiveness that is grossly out of proportion to the aggression-inducing stressor. Less prototypical, but more frequent, is the impulsive aggression seen in dementia, where verbal aggression and physical attack upon caregivers is common.6 Other illnesses with high incidences of outward-directed aggression include bipolar disorder,7 substance-use disorders, personality disorders,8 and psychotic disorders.9
The aggressive actions of psychiatric patients can be as harmless as angry stares and verbal assault, or as destructive as vandalism and physical violence. The type of illness does not necessarily predict the degree or nature of the aggressive acts, but the existing literature, conflicting as it is, suggests that young men with delusions seem to be the most at risk, while patients (both male and female) with depression are at lowest risk.1,10,11 The literature also implies, and personal observation confirms, that psychiatrically disturbed patients often act violently on the basis of a distorted, but genuine, instinct of self-preservation—their perception of threat, and their assessment of the appropriate action, are altered by their illness.
Multiple lines of research indicate that the frontal and temporal lobes play pivotal roles in the mediation of aggressive impulses. The most basic model posits that the orbitofrontal and prefrontal regions of the brain inhibit the aggressive impulses that are generated by the temporal lobe’s limbic structures. Head-injured veterans who have suffered damage to the orbitofrontal regions are more likely to have post injury aggression than those with nonfrontal brain lesions.12 In patients with dementia, frontal hypoperfusion as measured by positron emission tomography (PET) is associated with violent behavior.13 Another PET study showed that personality-disordered patients with decreased orbitofrontal metabolism are, by their own reports, more aggressive.14 In yet another PET study, decreased frontal metabolism distinguished convicted prisoners who committed crimes of passion (one type of impulsive aggression) from those who had planned their violent crimes.15 Magnetic resonance imaging diffusion tensor imaging of schizophrenic subjects suggests that atypicality of frontal white matter is associated with impulsivity and aggression.16
Temporal lobe dysfunction also results in impulsive aggression. Trauma to the temporal lobe has been associated with post injury violence17 and patients with temporal lobe epilepsy may also show aggressive behavior, especially when anterior temporal atrophy is present.18 Thus, impulsive aggression seems to result from an unfavorable balance of inhibitory influences from the prefrontal/ventromedial frontal lobe and pro-aggressive activity from the anterior temporal lobe.19
Knowledge about the relationships between impulsive aggression and neurotransmitters is evolving. The field’s best studied and most robust finding is the negative correlation between impulsive violence and markers of serotonin turnover in the brain. Linnoila and colleagues20 discovered that impulsivity was associated with low cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid, a serotonin metabolite, in aggressive convicts. This relationship between impulsivity and serotonin has been replicated in other studies of humans21,22 and nonhuman primates.23-25 This is particularly interesting in light of the prefrontal area’s high concentration of serotonin receptors.26 Serotonergic deficiency seems to be a trait phenomenon—consistently present regardless of the individual’s state of mind.27
Other studies have indicated that dopamine turnover in the brain correlates positively with aggression.28 Homozygosity for a low-activity variant of the dopamine-catabolizing enzyme catechol-O-methyltransferase predicts serious aggressive behavior in schizophrenics.29 Some evidence suggests, however, that the increased dopamine metabolism in aggressive subjects merely reflects decreased serotonergic inhibition of dopaminergic tone.30 Because of its association with stress responses, norepinephrine has also been implicated in the pathophysiology of impulsivity although its role is less clear. Alteration of norepinephrine metabolism may be a state phenomenon—occurring around the time of an impulsive action, rather than as a persistent abnormality.31 Acetylcholine may also play a role, as nicotine appears to reduce aggressive behavior.32
Given the multifactorial etiology of impulsive aggression, it is not surprising that the most commonly used treatments are not specific to any particular brain region or neurotransmitter system. The mainstays of pharmacologic treatment for impulsive aggression have been the antiepileptics (AEDs).33 Valproic acid is broadly effective in treating aggression and impulsivity.34 In the treatment of acute mania, valproate may have particular efficacy for impulsivity and irritability.35 In mostly uncontrolled studies, valproate was useful in ameliorating impulsive aggression associated with dementia,36 traumatic brain injury,37 and cluster B personality disorders.38 Carbamazepine may also effectively treat impulsive aggression. Among rehabilitation specialists, it is the preferred drug for patients who have suffered traumatic brain injury39 and it has demonstrated efficacy in aggression associated with dementia40 and epilepsy.41 Gabapentin, one of the “new generation” AEDs, was used successfully in a retrospective study of dementia-related aggression.42 Finally, an open-label reported that topiramate improved behavioral disturbances in patients with Alzheimer’s disease.43 Clinical effectiveness was evident during the first week of therapy and was sustained for at least
4 weeks with doses of 25–100 mg/day.
Although the role of antipsychotics has yet to be fully determined, their influence on dopamine- and serotonin-related neurotransmission has stimulated interest in studying their clinical effects. In a controlled study of 206 subjects with Alzheimer’s dementia, olanzapine 5–10 mg was significantly superior to placebo in controlling psychosis and aggression.44 A similar study with 337 subjects demonstrated the efficacy of risperidone in reducing aggressive behavior.45 Interpreting these results is somewhat difficult, because antipsychotics may improve thought content and processes, rather than impulsive aggression per se.
Other medications that may ameliorate impulsive aggression are lithium,33 propranolol,46 and the antidepressants.37 Lithium has a particularly long history of use for impulsive aggression,47 but recent controlled studies have used only conduct-disordered children as subjects.48-50 Unfortunately, because of the necessity of serum monitoring, multiple drug interactions, and a variety of dangerous side effects, lithium is poorly suited to treating many impulsive patients.51,52 The use of propranolol in patients with aggression due to organic brain disease is supported by a blinded crossover study of 10 otherwise refractory patients. Treatment with propranolol may be limited by bradycardia and hypotension.53 In a well-controlled study of 40 patients with personality disorders, fluoxetine reduced irritability and aggression.54 Although many of the medications used to treat impulsive aggression have sedating qualities, it should be noted that sedation is usually neither necessary nor sufficient to achieve control of aggression.
Environmental, behavioral, and cognitive treatments should also be used in impulsive aggression. Misinterpretation of the intentions of hospital staff can induce violence in psychiatric patients.55,56 Giving patients positive reinforcement of appropriate behavior and social skills training may dramatically reduce verbal and physical aggression.57 Training of those who interact with disturbed patients may also be of benefit.58
Suicide attempts and self-mutilation are common precipitants to psychiatric hospitalization and treatment. In the United States, the suicide rate averaged 12.5 per 100,000 people in the 1990s.59 Depression is responsible for 50% of completed suicides, but substance use disorders, mania, personality disorders, and adjustment disorders are also important risk factors.59
For a variety of reasons, psychiatrically disturbed patients cause themselves injury without the intent to die. Although it is casually linked to cluster B personality disorders, self-injurious behavior (SIB) occurs as a result of many psychiatric illnesses, including developmental impairment, substance abuse, mania, and depression.42 Other forms of SIB include skin picking in Prader-Willi syndrome, self-mutilation in Lesch-Nyhan syndrome, and trichotillomania. Patients suffering from psychosis may also seriously injure themselves in response to command hallucinations or delusions.
Even less is known about self-directed aggression than is known about violence directed at others. Suicidality, like outward-directed impulsive aggression, has been repeatedly associated with low serotonin levels in the central nervous system.60 The lethality of suicide attempts is correlated with decreased frontal lobe metabolism and reduced serotonergic reactivity, two frequent findings in major depressive disorder.61,62 Serotonergic tone (probably decreased) also seems to play a role in self-mutilation. In addition, opiate and dopamine activity are thought to be involved in creating a biological reward system that promotes SIB.63
Treatment of suicidality is typically accomplished by treating the underlying disorder (eg, major depressive disorder, alcohol dependence). However, some treatments seem to be of particular benefit when applied to suicidal patients. Chronic lithium therapy seems to have a specific antisuicidal effect.64 Electroconvulsive therapy can treat acute suicidality, but seems to have no effect on long-term suicide risk.65
Clearly, more work must to be done in order to understand the causes and treatments of suicide. British authorities recently banned the prescribing of paroxetine to children because of a paradoxical increase in suicide rates among patients who were treated with the medication.66 The cause of this phenomenon is under investigation but the controversy is somewhat reminiscent of similar concerns about increased violence resulting from fluoxetine treatment; those fears have proven to be unfounded.67
Nonsuicidal SIB lends itself better to long-term psychotherapeutic and pharmacologic treatments. Linehan’s dialectical behavioral therapy is effective in decreasing parasuicidal behavior in women suffering from borderline personality disorder.68 In a study of borderline patients, carbamazepine had a beneficial effect on behavioral dyscontrol; in the same study, alprazolam exacerbated dyscontrol.69 Fluoxetine may also reduce self-injurious behavior in borderline patients.70 In open-label studies, topiramate has shown efficacy in treating the self-injurious behavior of Prader-Willi syndrome,71,72 and carbamazepine has been effective in treating Lesch-Nyhan self-mutilation.73
Impulsive Consumption and Pleasure Seeking
Bulimia nervosa is an eating disorder characterized by the DSM-IV-TR5 as binge eating and inappropriate compensatory methods to prevent weight gain occurring ≥2 times/week and persisting for ≥3 months.5 In purging-type bulimia, the subject engages in self-induced vomiting or misuse of laxatives, diuretics, or enemas. Patients with nonpurging-type bulimia compensate with other abnormal behaviors, such as fasting or excessive exercise. The prevalence is estimated at 1% to 3% in the general population and 4% to 13% in female college-age students.74 The disorder is more common in women than in men and often causes dental problems due to repeated vomiting, menstrual problems, electrolyte imbalance, and severe mood disturbances. Although not mentioned in DSM-IV-TR, impulsivity and bulimia are clearly associated.75 About 30% of bulimic patients exhibit SIB, compared to 4% to 10% in the general psychiatric population.76 Bulimia’s other common impulsive comorbidities are substance use disorders, kleptomania, and compulsive buying.77-79
Successful treatment for bulimia nervosa should be anchored by cognitive-behavioral therapy (CBT), which is the best-studied remedy for the illness. In a study of 113 women who were treated with CBT, 89% were no longer bulimic and 69% had no eating disorder diagnosis after 3 years of treatment.80 Interpersonal therapy has a similar long-term benefit.81 Many of the studies that have evaluated psychotherapy for bulimia, however, are not blinded.
Until recently, the pharmacologic treatment of bulimia nervosa consisted primarily of antidepressants, especially tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Several double-blind, placebo-controlled studies have demonstrated the efficacy of TCAs in treating bulimia.82,83 Hughes and colleagues82 reported that desipramine reduced weekly binge frequency by 91% compared to a 19% increase in those treated with placebo (P<.01). Despite the apparent success of TCAs, their use is limited by an array of side effects, including weight gain, drowsiness, and cardiac arrhythmias.84
The SSRI fluoxetine was shown to be effective in a double-blind study of
387 bulimic women.85 In this 8-week trial, fluoxetine 60 mg/day was superior to placebo in reducing the weekly frequency of binge eating and vomiting episodes. Fluoxetine is the only antidepressant approved by the Food and Drug Administration for the treatment of bulimia nervosa. Of interest is the observation that the effectiveness of the antidepressants in the treatment of bulimia appears to be distinct from their effect on depression, ie, their effect is similar in patients regardless of the presence or degree of concomitant depression.82,83
Other pharmacologic classes are being evaluated for use in bulimia nervosa. For example, ondansetron, a 5-HT3 receptor antagonist, resulted in a 50% reduction in binge-purge episodes— an effect attributed to restoring vagal afferent sensitivity and increasing the awareness of satiety.86 AEDs have also been used, although early studies demonstrated minimal benefit.87,88 Recently, topiramate has generated interest based on several case reports and a single clinical study.89,90 In a randomized, double-blind study of 69 patients, topiramate median dose, 100 mg/day reduced the number of mean binge and/or purge days by 45% compared to 11% seen in the placebo group.91 The mechanism of this effect has not been elucidated, but topiramate is an inhibitor of voltage-gated sodium and L-type calcium channels, an enhancer of γ-aminobutyric acid (GABA)A receptor-mediated chloride flux, and an inhibitor of glutamate-mediated excitation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors.92
Binge-eating disorder (BED) is characterized in the DSM-IV5 as recurrent episodes of binge eating in the absence of the inappropriate compensatory behaviors of bulimia nervosa. The prevalence of BED is estimated to be 1.5% to 2% in the general population, but approaches 45% in obese individuals.93 A recent study reported that mutation to the gene coding for the melanocortin 4 receptor is strongly associated with binge eating; all obese subjects with a mutation reported binge eating, compared to only 14% of obese subjects with the normal phenotype.94 In addition to its primary characteristics of bingeing and obesity, BED is strongly associated with mood symptoms, and those who are obese have more comorbid depression and personality disorders.95
Although CBT has been associated with reductions in binge eating, it typically has little effect on weight.93 Pharmacotherapeutic studies have centered on the use of SSRIs and D-fenfluramine. In a 6-week, double-blind study, Arnold and colleagues96 reported that fluoxetine reduced both binge frequency and body weight. In a similar study, D-fenfluramine reduced binge episodes with modest effect on weight loss.97 Other treatments associated with reductions in binge frequency and modest weight loss include fluvoxamine, sertraline, sibutramine, and venlafaxine.98-101
Naltrexone and topiramate have recently been studied for the treatment of BED. Although naltrexone reduced binge frequency in an 8-week, double-blind study, the effect was no different than that seen in the placebo group.102 In an open-label study of women with BED who were treated with topiramate 100–1,400 mg/day, 9 of 13 had at least a 50% decrease in binge-eating episodes.103 The mean body weight of all subjects decreased by an average of 12 kg during the 3–30 month study period.103 In a double-blind study, 61 obese patients were treated with topiramate 25–600 mg/day or placebo for 14 weeks. Those patients in the topiramate group experienced a greater reduction in binge frequency and BMI than placebo-treated patients.104 An open-label extension of this study demonstrated continued efficacy with significant reductions of binge frequency and weight over an additional 42 weeks.105
Kleptomania is defined by the DSM-IV5 as “the recurrent failure to resist impulses to steal items even though the items are not needed for personal use or for their monetary value.” The prevalence of kleptomania in the general population is estimated to be 0.6%, but this may be an underestimate because few people disclose their problem, even to their therapist, and most escape detection.106 Kleptomanic behavior is impulsive and repetitive. It is also associated with anxiety one fights to resist the impulse to steal and suffers guilt and shame over engaging in the act of stealing.107 Women are affected with kleptomania four times as often as men.106
Kleptomania shares comorbidity with mood and anxiety disorders, eating disorders, and substance-abuse disorders.108 It is through these comorbidities that patients with kleptomania are usually referred for treatment.109 The choices of therapy for the treatment of kleptomania have historically been antidepressants, AEDs, lithium, or valproate.110,111 The results of pharmacologic treatment are variable. For example, in a case series of 20 patients, only two cases of remission with fluoxetine were reported whereas seven others were unresponsive.112 The combination of SSRIs and mood stabilizers (lithium with fluoxetine,113 valproate with fluvoxamine114) has had some positive results. Topiramate was reported to reduce both the urge to steal and the pleasure derived from the act in a case series of three patients. The investigator hypothesized that the mechanism might be increased GABA input to the nucleus accumbens.107
Pathological gambling (PG) is characterized in the DSM-IV5 as an impulse-control disorder that is disabling and a public health issue because of its devastating effect on families. Its prevalence in the US has been estimated at between 1% and 3.4% of the adult population, with more men than women affected.115 Alcohol and substance abuse disorders are common in the PG populations, and have been reported in as many as 47% of inpatient pathological gamblers.116 PG is highly comorbid with mood disorders, substance-use disorders, attention-deficit/hyperactivity disorder, and other impulse-control disorders.111,117 Neurobiological studies have suggested the involvement of serotonin, norepinephrine, and dopamine neurotransmitter systems in the etiology of PG.118,119
Treatment of PG has traditionally centered on psychotherapy and self-help groups (eg, Gamblers Anonymous), but the evidence for success is not very convincing. However, the results of recent studies suggest the potential of pharmacotherapy to positively influence PG. Naltrexone has been reported to improve PG symptoms in open-label,120 double-blind, placebo-controlled,121 and retrospective chart review studies.122 The most common adverse effect of naltrexone in these reports was nausea. Naltrexone may, by blocking opioid receptors, blunt behavioral urges or decrease the biological reward associated with pathological gambling.123
At least four recent clinical studies suggest that SSRI therapy may be effective in the treatment of PG. For example, Zimmerman and colleagues124 reported that citalopram, in an open-label study of 15 adult PG subjects, significantly reduced all gambling measures, including number of days gambling, amount of money lost, and number of urges to gamble. The effect was independent of the antidepressant effects of citalopram. Others have reported similar benefits of SSRI treatment,125-127 although one study suggested a benefit only in men and younger patients.125 Nefazodone, a 5-HT2A receptor antagonist, may also be successful in treating PG.128
Lithium and valproate may also be effective in treating patients with PG. In one study, either drug was administered to nonbipolar PG subjects in a single-blind fashion.129 After 14 weeks, significant improvement was reported for both drugs on the Yale-Brown Obsessive Compulsive Scale modified for PG. Fourteen of 23 patients (61%) treated with lithium and 13 of the 19 patients (68%) taking valproate were much improved as assessed by the Clinical Global Impressions scale for Improvement.
Impaired impulse control is a common and prominent element of psychiatric disorders. Knowledge about the neuropathophysiology of impulse-control disorders is slowly emerging, but the complex interaction of the systems involved and the common presence of comorbidities has made the search for appropriate and specific pharmacotherapy difficult. Impulsivity seems to be closely connected to the serotonergic tone, with contributions of dopamine-, opioid-, and noradrenergic-responsive systems. As our ability to analyze the function of the brain improves, we will be able to add our already impressive armamentarium of psychotherapeutic and pharmacologic treatments. In the future, treatments for impulsivity will become more specific and effective, improving the lives of patients and their families. PP
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