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Impulse Control Disorders: Clinical Characteristics and Pharmacological Management: Page 2 of 2

Impulse Control Disorders: Clinical Characteristics and Pharmacological Management: Page 2 of 2

Table 1
Table 2

In a double-blind, placebo-controlled study using sertraline, 60 individuals with PG were treated for 6 months (mean dosage, 95 mg/d).33 At the end of the study, there were 23 (74%) responders in the sertraline group and 21 (72%) in the placebo group; sertraline did not demonstrate superiority over placebo.

A double-blind, 16-week, crossover study of 15 patients with PG who received fluvoxamine demonstrated a statistically significant difference compared with placebo.34 Interpretation of the study is complicated, however, by a phase order treatment interaction (ie, the medication did not separate from placebo during the first phase but did in the second phase). A 6-month, double-blind, placebo-controlled trial of 32 gamblers who received fluvoxamine failed to show statistical significance compared with placebo; however, the results of this study were complicated by high rates of treatment discontinuation (only 3 subjects receiving medication completed the study)and a high placebo response rate (59%).35

An 8-week, double-blind, placebo-controlled study of paroxetine demonstrated possible efficacy in the treatment of PG.36 A larger multicenter double-blind, placebo-controlled trial, however, failed to reproduce the results.37 In this second study, a high placebo response rate was observed, with 48% of those assigned to placebo and 59% of those taking paroxetine considered responders.

An open-label, 12-week trial of escitalopram with an 8-week, double-blind discontinuation period for responders was recently undertaken in pathological gamblers with marked anxiety.38 Of the 13 patients treated with a mean dose of 25.4 mg of escitalopram daily, 62% were considered responders in terms of both PG and anxiety symptom reduction. Of the 6 patients who completed the study, the 4 who were responders were entered into an 8-week, double-blind discontinuation phase. For the 3 assigned to escitalopram, improvement continued for the next 8 weeks, whereas both gambling symptoms and anxiety returned within 4 weeks for the one patient assigned to placebo.

The findings from a 12-week, double-blind study of buproprion, the only non-SSRI antidepressant included in a double-blind study, showed that there was no statistical difference in rates of improvement between the 2 groups. In fact, 35.7% of bupropion and 47.1% of placebo recipients responded to treatment.39

Although the results have been mixed, the treatment data from these trials suggest that SSRIs may be beneficial for some persons with PG. There is also some indication that those with PG and anxiety may preferentially respond to these agents, but which variables predict response to serotonergic agents has not been fully examined. No positive, randomized, placebo-controlled study of an antidepressant in PG has been successfully reproduced, and there have been no comparison studies. Given the limitations of the existing literature, it is not yet possible to conclude which antidepressants should be recommended and which individuals with PG are more likely to respond to these agents.

Trichotillomania. Several controlled trials using antidepressants have been conducted in TTM. One study compared clomipramine and desipramine in a 10-week, double-blind, crossover (5 weeks for each agent) design (following 2 weeks of single-blind placebo lead-in).40 Of 13 participants, 12 had significant improvement with clomipramine, whereas only 1 patient preferentially responded to desipramine.

Fluoxetine has been studied in 4 randomized trials with conflicting results. Fluoxetine failed to separate from placebo in one 6-week, double-blind, crossover study.41 Another study compared fluoxetine with clomipramine in a double-blind, randomized, 20-week, crossover design (10 weeks on each agent) and found that both agents demonstrated a similar positive treatment effect.42 However, a third double-blind, placebo-controlled crossover study of 16 patients failed to show significant improvement with fluoxetine compared with placebo.43 Finally, a fourth study (12 weeks) that compared fluoxetine with behavioral therapy or a wait list found that although behavioral therapy demonstrated improvement in hair pulling compared with the wait list condition, fluoxetine did not.44

Clomipramine may benefit individuals with TTM, but there are conflicting data on the use of SSRIs. As in other ICDs, these results suggest that some patients with TTM may respond to these agents, but data on which individuals will respond to these agents has not been examined.

Pathological skin picking. Two double-blind studies of fluoxetine have been conducted for the treatment of PSP. In the first trial, 21 patients received 10 weeks of either placebo or active medication. The fluoxetine group improved significantly more than the placebo group at a mean dosage of 55 mg/d.45 The second study consisted of an open-label component for 6 weeks followed by a double-blind, 6-week discontinuation for responders. Eight subjects responded to open-label treatment; the 4 that were randomized to the fluoxetine group maintained their improvement, while the placebo group returned to their baseline symptom severity level.46

With 2 positive studies using fluoxetine in the treatment of PSP, there is some support for its use in this disorder. However, the studies consisted of small samples and were of short duration, therefore the data are limited. Given the mixed results seen for fluoxetine in the treatment of TTM, recommendations regarding the fluoxetine treatment of PSP await longer, larger studies.

Compulsive buying. Pharmacotherapy using antidepressants in treating CB has been examined in 3 double-blind, randomized, placebo-controlled trials, and 1 trial using an open-label design followed by a double-blind discontinuation. In one double-blind fluvoxamine study, 37 persons were treated for 13 weeks. Only 9 of 20 patients assigned to medication were responders (mean dosage, 215 mg/d), and this rate did not differ significantly from that in the placebo group (8 of 17 were responders).47 In the second study, Black and colleagues48 treated 23 patients for 9 weeks. With a mean dosage of 200 mg/d, no differences in response rates were observed between active drug and placebo. The third study involved a 7-week, open-label trial of citalopram with responders randomized to 9 weeks of double-blind medication or placebo.49 Individuals in the citalopram group demonstrated statistically significant decreases in the frequency of shopping and the intensity of thoughts and urges concerning shopping. Interestingly, a recent 7-week, open-label study followed by 9 weeks of randomization using escitalopram found that there were no statistical differences in relapse rates between those receiving the drug and those assigned to placebo.50

There is scant evidence concerning effective treatments for CB. As in TTM, trials of SSRIs have produced mixed results. The inconsistency of these results further suggests that there may be neurobiological heterogeneity within the disorders that has not yet been fully examined.

Compulsive sexual behavior. In the only double-blind study of CSB, 28 men were assigned to 12 weeks of either citalopram or placebo. The citalopram group (mean effective dosage, 43.4 mg/d)51 demonstrated significant reductions in sexual desire, frequency of masturbation, and use of pornography.

These results suggest that serotonergic agents may be beneficial in treating CSB. Given the mixed results of these agents in other ICDs, however, the question remains whether similar inconsistent results will emerge if further studies of these agents are performed.

Kleptomania. In an open-label study with a double-blind discontinuation phase, escitalopram was examined in 24 patients with kleptomania. There was no statistical difference in rates of relapse between those taking medication and those assigned a placebo.52 This study suggests that serotonergic agents do not appear beneficial for patients suffering from kleptomania.

Mood stabilizers

Comorbidity studies suggest that individuals with ICDs may experience elevated rates of co-occurring bipolar spectrum disorders (bipolar type I, bipolar type II, and bipolar NOS).8,53 Similarly, those with bipolar disorder may demonstrate impulsive behaviors that resemble the symptoms of ICDs. Mood stabilizers may be effective in controlling symptoms of certain ICDs. Double-blind studies of mood stabilizers in the treatment of ICDs, however, are limited.

Pathological gambling. In a double-blind, placebo-controlled study of 40 patients with PG and bipolar spectrum disorders, sustained-release lithium carbonate (mean lithium level, 0.87 mEq/L) was superior to placebo in reducing PG symptoms during 10 weeks of treatment.54 Lithium treatment resulted in statistically significant improvement in gambling thoughts and urges, but no differences were found in the amount of money lost, the number of gambling episodes per week, or the length of each gambling episode.

As one of the few studies to target a specific subtype of an ICD (ie, gamblers with bipolar disorders), this study suggests that pharmacological efficacy may depend on targeting specific ICD subtypes.

Intermittent explosive disorder. In a 12-week, randomized, double-blind study, 96 patients with cluster B personality disorders, 116 patients with IED, and 34 patients with posttraumatic stress disorder were randomized to receive divalproex sodium or placebo. Patients who met criteria for more than 1 of the 3 diagnostic categories were assigned to the diagnostic group most closely associated with their impulsive aggression. The study found that divalproex sodium had no significant influence on aggression in the participants with a primary diagnosis of IED.55

This was the only study of drug treatment for IED, and it failed to demonstrate benefit. IED is a disabling disorder with significant public health impact, and treatment studies for this disorder are needed.

Opioid antagonists

Alterations in dopaminergic pathways (Figure) have been proposed as underlying the reward seeking that triggers the release of dopamine and produces feelings of pleasure.56 Opioid antagonists are thought to decrease dopamine neurotransmission in the nucleus accumbens and linked motivational neurocircuitry, thus dampening ICD-related excitement and cravings.

Pathological gambling. A study of 45 patients who completed a 12-week, double-blind trial of naltrexone (mean dosage, 188 mg/d) for PG showed significant improvement compared with placebo.57 Naltrexone was effective in reducing the frequency and intensity of gambling urges, as well as gambling behavior. A multicenter study further demonstrated the efficacy of another opioid antagonist, nalmefene, in the treatment of PG. In a sample of 207 subjects, nalmefene demonstrated statistically significant improvement in gambling symptoms compared with placebo in a 16-week, double-blind trial.58

These 2 large studies lend support to treating PG as an addiction and to using agents that have shown benefit in substance use disorders. Both studies also targeted gamblers with at least moderate urges to gamble (those with only minimal urges were not enrolled) and therefore support the notion of looking beyond the diagnosis and focusing on subtypes within the disorder.

Trichotillomania. A 6-week, placebo-controlled, randomized trial of the opioid antagonist, naltrexone, demonstrated significant improvement on 1 measure of TTM symptoms compared with placebo.42 Nearly half of those taking naltrexone (compared with none in the placebo group) reduced hair pulling by more than 50%.

As in PG, this study suggests that a subtype of ICD (for example, those with urges to engage in a behavior) may benefit from pharmacotherapy targeting those urges.

Glutamatergic agents

Dopaminergic systems, which influence rewarding and reinforcing behaviors, have been implicated in ICDs. Animal studies demonstrate that the key pathophysiology of addiction is mediated through glutamate and dopamine within the core of the nucleus accumbens. Repeated behaviors associated with reward produce persistent neuroplasticity in extracellular glutamate levels in the nucleus accumbens.59 The cysteine-glutamate antiporters are the source of extracellular glutamate, and they modulate the release of glutamate and dopamine.59 Recent research hypothesizes that agents that can improve glutamatergic tone within the nucleus accumbens may reduce reward-seeking behavior in persons with addictions.60

Pathological gambling. N-acetylcysteine (NAC), an amino acid and cysteine prodrug, appears to increase extracellular levels of glutamate and stimulate inhibitory metabotropic glutamate receptors thereby reducing synaptic release of glutamate. Restoring extracellular glutamate concentration in the nucleus accumbens appears to block reinstitution of compulsive behaviors and decrease cravings (Figure). Twenty seven patients with PG were treated in an 8-week, open-label trial of NAC. Responders to the open-label phase were randomized to 6 weeks of double-blind NAC or placebo. During the open-label phase, gambling symptoms were significantly reduced, with 59% of the study participants meeting responder criteria. Of those who entered the double-blind phase and were assigned to NAC, 83.3% met responder criteria at the end point, compared with only 28.6% of those assigned to placebo.61

This study focused on gamblers with at least moderate urges to gamble and used an agent that specifically targeted those urges. The study suggests that NAC may be beneficial in gamblers with urges to gamble. The study further supports the examination of glutamatergic agents in PG and other ICDs as well.

Summary

ICDs have received relatively little attention from clinicians and researchers. Despite a prevalence similar to or greater than that for schizophrenia and bipolar disorder, much less research has been undertaken. Nevertheless, the treatment data presented in this article represent significant advances from only several years ago.

With few published studies that even approximate large, well-powered controlled trials, it is not possible to make treatment recommendations with a substantial degree of confidence. No drugs are currently FDA-approved for the treatment of any of the formal ICDs. Specific drug therapies offer promise for the effective treatment of PG, although PG studies are substantially limited. Most published studies have employed relatively small sample sizes, are of limited duration, and involve potentially nonrepresentative clinical groups (eg, those without co-occurring psychiatric disorders). Heterogeneity of treatment samples may also complicate identification of effective treatments. At present, questions such as which medication to use and for whom, or the optimal duration of pharmacotherapy cannot be sufficiently addressed with the available data.

For other ICDs, there are less available data to generate empirically supported treatment recommendations. In conjunction with emerging epidemiological data supporting a relatively high prevalence of ICDs, the small amount of empirical data on effective treatments for ICDs highlights the clinical need for additional research. Definitive pharmacological treatment recommendations await completion of large-scale, controlled treatment studies for these disorders and comparative investigations of pharmacological agents. Advances in these areas hold the potential for significantly improving the lives of individuals with ICDs and those directly or indirectly affected by their conditions.

Pages

Disclosures

Dr Grant is associate professor in the department of psychiatry, Brian Odlaug is a research assistant, and Dr Kim is professor of psychiatry at the University of Minnesota, Twin Cities.

Dr Grant reports that he has received research support from Forest Pharmaceuticals, Somaxon Pharmaceuticals, and GlaxoSmithKline. Dr Kim and Mr Odlaug report no conflicts of interest concerning the subject matter of this article.

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