Pharmacoligcal Treatments of impulse Control Disorders

Hertzman c15.tex V1 - 07/03/2009 11:07 A.M. 15 O FS Pharmacological Treatments of Impulse Control Disorders Helga Myrseth and Ståle Pallesen PR O University of Bergen, Department of Psychosocial Sciences, P.B. 7807, Bergen, Norway Abstract O R R EC TE D Impulse control disorders (ICDs) are commonly defined as the failure to resist an impulse, drive or temptation to perform harmful acts. In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) the following disorders are included in the section ‘Impulse control disorders not elsewhere classified’: intermittent explosive disorder, pyromania, kleptomania, trichotillomania and pathological gambling. Common to all these disorders are repeated failures to resist impulses to perform harmful acts. This chapter gives a brief outline of clinical characteristic and pharmacological treatments of each of these disorders. Pharmacological trials with selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, opioid antagonists, mood stabilizers and anti-epileptics have demonstrated potential effectiveness of pharmacological treatments for ICDs. However, several studies have limitations such as poor designs, relying on single cases, small sample sizes and lack of adequate control groups. More controlled studies in this area are needed to establish the effectiveness of pharmacological treatments for different impulse control disorders. U N C Key Words pharmacological treatment; impulse control disorders; intermittent explosive disorder; pyromania; kleptomania; trichotillomania; pathological gambling 15.1 Impulse control disorders In the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV), five separate disorders are outlined in the section ‘Impulse control disorders not Clinical Trials in Psychopharmacology, Second Edition  2010 John Wiley & Sons, Ltd Edited by Marc Hertzman and Lawrence Adler Page 289 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman 290 c15.tex V1 - 07/03/2009 11:07 A.M. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS TE D PR O O FS elsewhere classified’: intermittent explosive disorder (IED), pyromania, kleptomania, pathological gambling (PG) and trichotillomania (TTM). In ‘Impulse control disorders not otherwise specified’, skin picking, compulsive shopping and compulsive sexual behavior are included. The essential feature of ICDs is the failure to resist an impulse, drive or temptation to perform an act that is harmful to the person him/herself or to others. Common in ICDs is that the individual feels an increasing tension or arousal before engaging in the behavior, and experiences pleasure, gratification or relief when committing the act. After the act is carried out, there may or may not be regret, self-reproach or guilt [1]. Many of the underlying behaviors in ICDs, such as gambling, fire setting and shoplifting, are common in the general populations. However, only a small portion of the individuals performing these behaviors do it as a response to irresistible impulses or urges and can be classified as an ICD. In addition to the similarity of symptoms for these disorders, they also have similar ages at onset and courses [2]. However, the sex ratio seems to differ among the different disorders [1, 2]. With the exception of PG, all of these disorders are considered to be rare [2], and little research exists concerning epidemiology and treatment efficacy. Studies of phenomenology have shown that ICDs may be related to mood disorders, anxiety disorders and substance use disorders [2]. Although ICDs can often be significant disabling, these disorders often go undiagnosed and untreated [3]. EC Neurobiology of impulse control disorders R R Apart from the possible phenomenological relationship with other disorders, the nature of the core symptoms of ICDs allows us to make assumptions about the underlying neurobiology. Serotonin, which is a central neurotransmitter in behavior initiation/cessation, has been suggested to be involved in the failure to resist impulses which is the core criteria of ICDs as serotonergic dysfunction is often related to impulsivity [4]. Norepinephrine is involved in arousal and excitement, and might be central in the increasing arousal experienced before committing the impulsive behaviors [4]. Dopamine is a neurotransmitter central in the reward and reinforcement systems in the Ventral Tegmental Area and the Nucleus Accumbens, and it has been hypothesized that this reinforcement system is likely to be involved in the rewarding feeling of pleasure when committing the act [4]. In addition, opioids are usually involved in feelings of pleasure and urges, and it has also been suggested that this substance is involved in the rewarding, pleasurable experience when committing the act. Due the reinforcing properties, opioids have also been assumed to contribute to the urges experienced before committing the certain behavior. Since all the neurotransmitters and neurotransmitter systems mentioned here have been assumed to play a central role in ICDs, they have in clinical practice and in clinical studies been targets for pharmacological interventions of ICDs. Most studies of the neurobiology of ICDs have focused on the hypothalamicpituitary-adrenal axis, on serotonin, norepinephrine, glucose metabolism and on EEG data. The most consistent findings have suggested abnormalities, particularly in the serotonergic and, to a lesser extent, in the noradrenergic systems [2]. O C N U Page 290 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman c15.tex V1 - 07/03/2009 11:07 A.M. 291 15.2 PATHOLOGICAL GAMBLING PR O O FS Although Kim [5] suggests that symptoms of ICDs are generally refractory to psychotherapeutic or pharmacologic treatments, several pharmacological treatments have recently proven effective in the treatment of such disorders. Still, few controlled trials have been conducted and no empirically validated pharmacological treatments exist for these disorders. As little research investigating the efficacy of treatments for ICDs have been conducted, our understanding of efficacious and well-tolerated pharmacotherapies for ICDs lags behind those for other major neuropsychiatric disorders [3]. PG is the most common ICDs, and has received the most clinical and research attention. This chapter will give a brief outline of the clinical characteristics of these five disorders, and present empirical research on pharmacological treatments for each of these. 15.2 Pathological gambling O R R EC TE D Gambling can be defined as an activity that involves an attempt to win money by staking money on uncertain events [6]. For most people, gambling is a leisure activity without negative consequences. However, others develop excessive gambling behavior which has severe negative consequences for the gambler and his or her relationships with family members, friends or colleagues. According to DSM-IV-TR, the essential feature of PG is ‘persistent and recurrent maladaptive gambling behavior that disrupts personal, family or vocational pursuits’ which is not better accounted for by a manic episode [1]. The lifetime prevalence of PG is between 1 and 3% in the adult population of North America. The prevalence is even higher for adolescents [7–9]. The prevalence of gambling is assumed to be on the rise due to expanding gambling opportunities and the general social approval of the gambling industry [10, 11]. Consequently, the need for effective treatment seems to be self-evident. Most of the treatments of PG have been conducted within the behavioral, cognitive and cognitive-behavioral spectrum [12]. Recently, however, several studies have been conducted investigating different pharmacological approaches to the treatment of PG. N C Pharmacological treatments of pathological gambling U Page 291 Evidence suggests the involvement of both serotonergic, noradrenergic, dopaminergic and opioidergic systems in the etiology of PG [13], and pharmacological treatments targeting these neurotransmitter systems have shown promising results in the early stages of understanding and treating PG [14]. These systems are related to the mechanisms that underlie behavioral disinhibition (serotonergic system), reward mechanisms (dopaminergic and opioidergic system) and arousal (noradrenergic system) associated with impulse control and addictive disorders [15]. Although PG is classified as an impulse control disorder, it has also been described as an obsessive-compulsive spectrum disorder within the impulsive cluster [16]. Potenza et al. conducted a functional magnetic resonance imaging (fMRI) study of gambling urges in pathological gamblers [17] and found that PG has neural features more similar to other ICDs and distinct from those of obsessive-compulsive disorders. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman 292 c15.tex V1 - 07/03/2009 11:07 A.M. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS N C O R R EC TE D PR O O FS Hollander et al. [14] outline several psychopathological domains within PG which could conceivably be targeted for treatment: impulsive symptoms (arousal), compulsive symptoms (anxiety reduction) and addictive symptoms (symptoms of withdrawal). Pharmacological treatments of PG have usually involved the administration of either opioid antagonists, antidepressants or mood stabilizers [14]. Opioid antagonists block the effects of endogenous endorphins on central opiate receptors and inhibit dopamine release in the nucleus accumbens, involving reward, pleasure and urge mechanisms [14]. Several studies have also specifically indicated that pathological gamblers may be characterized by serotonergic dysfunction [18]. Most of the antidepressants drugs used in the treatment of PG are selective serotonin reuptake inhibitors (SSRIs) which appear to have anticompulsive and anti-impulsive effects [14]. Mood stabilizers have proven effective in treating mania, and recent studies have also demonstrated effectiveness in treating other impulsive disorders such as borderline personality disorder, disruptive behavior and TTM [14]. It has been suggested that impulse control disorders and bipolar spectrum disorders may be related, and the impulsivity in PG seems to resemble that of bipolar disorder. The co-morbidity between bipolar disorder and PG has been estimated to be as high as 30% [19]. Mood stabilizers are assumed to have anti-impulsive effects [20], and hence are assumed to potentially be effective in the treatment of PG. A recent meta-analysis of clinical trials using pharmacological interventions to treat PG identified 130 potential studies, but only 16 studies met the criteria for inclusion in the meta-analysis: (i) the target problem was PG, (ii) the treatment was pharmacological, (iii) the study was written in English and (iv) the study reported outcomes particularly pertaining to gambling [21]. A total of 597 subjects were included in the outcome analyses of these studies. Table 15.1 gives an overview of the included studies [19, 20, 22–35]. The analyses showed that at post-treatment the pharmacological interventions were more effective than no treatment/placebo, yielding an overall effect size (ES) of 0.78 (95% CI = 0.64, 0.92). A multiple regression analysis showed that the magnitude of ESs at post-treatment was lower in studies using a placebo-controlled condition compared to studies using pre-post design (without any control condition). No differences between the three main classes of pharmacological interventions (antidepressants, opiate antagonists and mood stabilizers) were detected. U Page 292 15.3 Trichotillomania TTM is defined as hair loss due to a patient’s irresistible urge to pull out his/her hair [1]. The sites of hair pulling may include any part of the body on which hair grows, but the most common sites are the scalp, eyebrows and eyelashes. Hair pulling usually occurs in states of relaxation and distraction (e.g. when reading a book), but may also occur under stressful circumstances. Usually increased tension is present immediately before hair pulling, and the act is followed by gratification, pleasure or a sense of relief. According to the DSM-IV, the disturbance must cause significant distress or impairment in either social, occupational or other important 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 C N U Table 15.1 Studies examining the effectiveness of pharmacological treatments for pathological gambling [21]. O Design Black [22] Bupropion vs. Open-label placebo 400 Blanco et al. [23] Dannon et al. [24] Fluvoxamine Double-blind vs. placebo Topiramate vs. Single-blind fluvoxamine 200 Dannon et al. [25] Bupropion vs. Single-blind naltrexone 424 and 116, 12 respectively R 8 Mean age Attritionb Proportion Formal Treatment (%) males diagnosis response (%) 44.6 0.0 40.0 Yes 24 32 42.1 59.4 65.6 Yes 200 and 200, 12 respectively 20 34.9 35.5 100.0 Yes 30.6 100.0 Yes 70% partial/ complete remission 73% complete remission Topiramate and fluvoxamine: 75% complete remission 25% partial remission Bupropion: 25 D TE EC 10 29.1 16 71 45.4 44.7 60.5 Yes 11:07 A.M. 293 FS (continued overleaf) V1 - 07/03/2009 20–60 c15.tex Double-blind 75% complete remission 25% partial remission Naltrexone: 23% partial remission 59% partial/ complete remission Hertzman Paroxetine vs placebo O O PR Grant et al. [26] 15.3 TRICHOTILLOMANIA Trial R Mean dose at endpoint (mg/d) Duration (wk) Na Study Page 293 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 25.4 11 46.0 64.7 56.5 Yes 59% partial/ complete remission 13 55.8 30.8 53.8 Yesc 38.9 23.1 100.0 Yes 27.5 58.6 Yesd 17.6 41.2 Yes 19.6 33.3 Yes 62% partial/ complete remission 70% partial/ complete remission 83% partial/ complete remission Most patients improved 75% partial/ complete remission 48% complete remission 13% partial remission 195 8+8 15 (crossover) Hollander et al. [29] 1150 10 29 44.5 Kim and Grant [30] Kim et al. [31] LithiumDouble-blind carbonate vs. placebo Naltrexone vs. Open-label pre-treatment Naltrexone vs. Double-blind placebo 157 6 17 44.6 187.5 11 45 48.6 Kim et al. [32] Paroxetine vs. placebo 51.7 8 45 49.3 Double-blind 8.9 33.3 Yes 11:07 A.M. FS O Fluvoxamine vs. Double-blind placebo O Hollander et al. [19] V1 - 07/03/2009 146 c15.tex Treatment Hertzman Attritionb Proportion Formal PR Mean TE Na CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS 25, 50 and 16 100, respectively EC Nalmefene (25, Double-blind 50 and 100 mg) vs. placebo Grant and Escitalopram vs. Open-label Potenza [28] pre-treatment R Grant et al. [27] Mean dose at Duration D Design R Trial O Study (continued) 294 C N U Table 15.1 Page 294 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 C N U Nefazodone vs. pre-treatment Open-label Pallanti et al. [20] Lithium carbonate Single blind and Valproate vs. pre-treatment 345.8 8 12 48.5 14.3 71.4 Yes 1200 and 1500, 14 respectively 42 31.6 26.2 76.% Yes 95.0 24 Zimmerman et al. [35] Citalopram vs. pre-treatment Open-label 34.7 12 number for which the data analyses are based. 44.1 90.0 Yes 40.0 60.0 Yes fulfilled the criteria for at least one anxiety disorder. addition to the DSM-criteria for pathological gambling the patients also fulfilled the criteria for a bipolar spectrum disorder. 11:07 A.M. 295 FS O V1 - 07/03/2009 d In 15 38.3e O b Discontinued medication or withdrew from the study after randomization. c In addition to the DSM-criteria for pathological gambling the patients also 38.9 c15.tex a The 60 61% partial/ complete remission Valproate: 68% partial/ complete remission 74% partial/ complete remission 33% complete remission 54% partial remission Hertzman Double-blind PR Sertraline vs. placebo D Sáiz-Ruiz et al. [34] 25% complete remission 50% partial remission Lithium carbonate: 15.3 TRICHOTILLOMANIA TE EC R R O Pallanti et al. [33] Page 295 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman 296 c15.tex V1 - 07/03/2009 11:07 A.M. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS areas of functioning [36]. Although TTM has been sparsely studied and may be under-diagnosed, the lifetime prevalence of TTM is estimated to be 0.6–3.6% [37]. Pharmacological treatments of trichotillomania R R EC TE D PR O O FS The most common treatments for TTM are habit-reversal therapy (HRT), pharmacotherapy with fluoxetine or sertraline (SSRI) and pharmacotherapy with clomipramine (tricyclic antidepressant). A recent systematic review [38] compared the efficacy of behavioral treatment (HRT) and pharmacotherapy with either SSRI or clomipramine. Seven studies [39–45] met the criteria for inclusion in the study: (i) randomized clinical trial with control group or comparison group with active treatment, (ii) blinded assessment of the clinical outcomes, (iii) primary diagnosis of TTM and (iv) comparison of HRT, SSRI and clomipramine to each other or to a control condition. A total of 157 patients were included in the overall analysis in the systematic review (see Table 15.2). Six different outcomes were examined: (i) SSRI vs. control condition, (ii) clomipramine vs. control condition, (iii) HRT vs. control condition, (iv) HRT vs. SSRI, (v) HRT vs. clomipramine and (vi) clomipramine vs. SSRI. A total of 72 completers from four different studies investigating the effect of SSRI vs. a control condition contributed to the first outcome. None of the four studies reported significant differences between SSRI and control conditions, and in the overall meta-analysis no significant differences between SSRI and the control conditions were found either (z = 0.09, p = –0.93). The overall estimated ES was 0.02 (95% CI = –0.32, 0.35). Two studies investigated the effects of clomipramine. They comprised 24 completers, demonstrating a significant treatment effect favoring clomipramine when compared to control conditions (ES = –0.68, 95% CI = –1.28, –0.07). HRT was compared to control conditions in three trials, involving a total of 59 completers contributing to the analysis. The overall meta-analysis demonstrated beneficial effects of HRT compared to the control conditions (ES = –1.14, 95% CI = –1.89, –0.38) [38]. Two of these studies demonstrated a significant effect of HRT compared to the wait-list/placebo control condition [41, 44]. Only one study, Minnen et al. [45] compared HRT (n = 14) with SSRI (n = 11). There was no statistical significant difference between these two. However, there was a tendency toward a better effect of HRT compared to SSRI (ES = –0.73, 95% CI = –1.60, 0.14). One study [41] comparing the effects of HRT (n = 5) and clomipramine (n = 6) found a significant difference in favor of HRT (ES = –1.74, 95% CI = –3.23, –0.25). No blinded studies directly comparing the effects of clomipramine with SSRI were included in the meta-analytic review [38]. The results from the systematic review showed that HRT was the most effective treatment for TTM when practiced in this particular setting (by experienced clinicians in academic research settings). HRT demonstrated the largest ESs of these interventions. Compared to the most prevalent pharmacological treatments for TTM, clomipramine and SSRI, HRT demonstrated superiority. Clomipramine also demonstrated efficacy for TTM when compared to placebo or active control condition, while SSRI did not prove effective when compared to control conditions. This O C N U Page 296 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 C N U O Table 15.2 Studies examining the effectiveness of pharmacological treatments for trichotillomania. Trial Design Dose per day at endpoint Swedo et al. [43] Clomipramine vs. placebo Crossover trial, Mean 180.8 mg 10 double-blind Max 250 mg Duration (wk) 0 100.0 16 31.6 23.8 93.8 23% complete remission 69% partial remission No response 16 39.0 23.8 87.5 No response 16 33.4 30.4 81.3 HRT: 80% complete remission 20% partial remission Clomipramine: 67% partial remission 95.0 HRT: 40 31.3 7.0 c15.tex 31.6 Hertzman 13 15.3 TRICHOTILLOMANIA 12 Proportion Treatment females response (%) V1 - 07/03/2009 64% remission Fluoxetine: No response 11:07 A.M. 297 FS O O HRT vs. waitlist Randomized, Mean 60 mg controlHRT parallel group Max 60 mg vs. fluoxetine trial, blinded assessment of outcome Attrition (%) PR Van Minnen et al. [45] Mean age D Christenson Fluoxetine vs. Crossover trial, Mean 77.5 mg 18 et al. [39] placebo double-blind Max 80 mg Fluoxetine vs. Crossover trial, Mean 78.8 mg 12 Strichenwein placebo double-blind Max 80 mg and Thornby [40] Ninan et al. Clomipramine Randomized, Mean 116.7 mg 9 [41] vs. palcebo parallel group Max 250 mg HRT vs. trial, blinded waitlist assessment of control HRT outcome vs. clomipramine Na TE EC R R Study Page 297 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 298 C N U Attrition Proportion Treatment Randomized, Max 200 mg parallel group, Double-blind 22 24 28.7 16.2 95.8 Single modality: 15.4% remission Dual modality: 54.5% remission Randomized parallel group trial, blinded assessment of outcome 12 33.4 10.7 92.0 66% remission Woods et al. [44] HRT vs. waitlist control number on which the data analyses are based. 25 V1 - 07/03/2009 11:07 A.M. FS O O a The – PR Sertraline vs. HRT Sertraline and HRT D Dougherty et al. [42] Dose per day c15.tex Mean Design Hertzman Na Trial TE Duration Study CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS (continued) EC R R O Table 15.2 Page 298 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman c15.tex V1 - 07/03/2009 11:07 A.M. 299 15.4 KLEPTOMANIA PR O O FS finding is not in line with earlier reviews where SSRIs are recommended as the preferred pharmacological treatment for TTM [46]. However, methodological limitations of the trials included in this systematic review may have influenced these conclusions [38]. Firstly, no single clinical rating scale was used consistently in the included studies to assess severity and improvement of TTM symptoms, and it is possible that the different rating scales used may have different sensitivity to detect changes in TTM severity. Secondly, most of the studies did not report the number of subjects with co-morbid Obsessive Compulsive Disorder (OCD), which quite frequently co-occur with TTM. Subjects with co-morbid OCD would probably respond to SSRI and clomipramine since these are both first-line treatment for OCD. Thirdly, all of the parallel-group trials included trial completers only in the analyses, which may have affected the results. Future studies should investigate whether HRT can demonstrate efficacy against more rigorous control conditions accounting for the non-specific effects of therapy, and determine if HRT is effective in treating TTM beyond the few sites where it is currently practiced [38]. D 15.4 Kleptomania O R R EC TE Kleptomania is characterized by recurrent failure to resist impulses to steal items even though the items are not needed for personal use or for their monetary value [1]. Increased sense of tension is usually experienced before the theft, and pleasure, gratification or relief when committing the theft. Many report guilt, remorse and depression afterwards. The stolen objects are often affordable and of little value to the individual and are often given away, discarded or secretly returned afterwards [1]. The disorder is disabling and often goes undiagnosed in clinical practice [47]. So far, no prevalence studies in general populations have been conducted. Hence the prevalence in these populations is unknown [48]. However, several studies of clinical samples suggest that the disorder is not uncommon. A recent study of psychiatric inpatients (n = 204) with multiple disorders found prevalence rates of 7.8 and 9.3% for current and lifetime diagnosis of kleptomania, respectively [49]. The fact that the current and lifetime prevalence rates are almost identical suggests that the condition is chronic if not treated [47]. One study of 107 patients diagnosed with depression found a prevalence rate of kleptomania of 3.7% [50] and, in a study of patients with substance abuse (n = 79), a prevalence of 3.8% was found [51]. Two studies of patients diagnosed with PG found that 2.1 and 5%, respectively, also met the criteria for kleptomania [52, 53]. The condition appears, however, to occur in less than 5% of shoplifters. Evidence suggests that approximately two-thirds of the individuals with kleptomania in clinical samples are female [1]. The onset of kleptomania usually occurs during adolescence, although early childhood onset and late adulthood onset have been reported [1]. Kleptomania was originally classified within the OCDs spectrum. However, recent evidence – such as clinical characteristics, familial transmission and treatment response – suggests that it has important similarities with addictive disorders and mood disorders. Kleptomania has also been shown to frequently co-occur with substance abuse [47]. C N U Page 299 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman 300 c15.tex V1 - 07/03/2009 11:07 A.M. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS Pharmacological treatments of kleptomania R R EC TE D PR O O FS The etiology of kleptomania is unclear, and little evidence concerning possible neurobiological correlates of the disorder exists [47]. It has been hypothesized that dysfunction in the serotonergic system in ventromedial prefrontal cortex contribute to poor decision-making characteristics of individuals with kleptomania [54]. Evidence also suggests a non-specific serotonergic dysfunction as lower levels of platelet 5-hydroxytryptamine (5-HT) transporters (evaluated by means of binding of 3H-paroxetine) have been found in kleptomaniacs (n = 20) as opposed to healthy controls [55]. There have also been reports of kleptomania occurring after damage to the orbitofrontal– subcortical circuits of the brain [56]. Neuroimaging techniques have shown significantly decreased white matter integrity in inferior frontal regions of kleptomaniacs compared to controls [57]. This supports the hypothesis that kleptomaniacs may not be able to control and resist impulses to steal [48]. Antidepressants, mainly SSRIs, have been considered the treatment of choice for kleptomania as for other ICDs [58]. However, evidence from case reports of responses to serotonergic medication in kleptomania have shown inconsistent results [47]. In one study using open-label escitalopram in the treatment of kleptomaniacs (n = 20), 79% reported improvement in stealing behavior. The responders were randomized to continue medication or receiving placebo. After the double-blind phase, 43% of those receiving medication and 50% in the placebo group no longer remained abstinent. There was no statistical difference in the treatment effect between the escitalopram and the placebo condition [59]. Still, it has been argued that there may exist patients suffering from a subtype of kleptomania sharing common features with OCD who may respond well to SSRIs [47]. Grant [47] suggests that kleptomaniac behaviors may be far more heterogeneous than initially thought, and that antidepressants or mood stabilizers may be beneficial for those kleptomania subjects with significant mood symptoms who may shoplift due to subsyndromal mania or depression. However, more well-controlled studies in this area are needed. According to Grant [47], emerging evidence suggests that SSRIs may lack effectiveness in treating kleptomania but that lithium, anti-epileptic and opioid antagonist seem to show promising results. No controlled studies of mood stabilizers or anti-epileptic medications in the treatment of kleptomania have been published, but case reports of lithium, valproate and topiramate have shown that these medications may be effective in the treatment of kleptomania [47]. A case series of three patients treated for kleptomania showed that treatment with topiramate was effective [58]. The biological mechanism of this effect is unknown, but is hypothesized to be related to the disinhibition of GABA input in the nucleus accumbens area, targeting the arachidonic acid cascade [58]. Studies with controlled designs are needed to confirm these preliminary findings. Lithium alone, or in combination with fluoxetine, has been associated with improvement in kleptomania in several reports [2, 58, 60]. However, some case studies of lithium as monotherapy or lithium augmentation have shown no effects in the treatment of kleptomania [47]. The efficacy of opioid antagonist in kleptomania has recently been examined because of the possible relationship and similarities to addictive disorders. The urge or craving state that people with kleptomania experience before engaging in the O C N U Page 300 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman c15.tex V1 - 07/03/2009 11:07 A.M. 301 15.5 PYROMANIA O O FS problematic behavior, and the hedonic experiences during the behavior, much resemble that of addictive behaviors. Opioid antagonists are assumed to work indirectly on dopamine reducing the subjective experience of reward and urges seen in kleptomania [61]. In one open-label study with naltrexone (n = 10) for 12 weeks (mean effective dose was 145 mg/day), 80% reported significant reduction in urges to steal and 20% reported complete remission of the symptoms [61]. A longitudinal study of naltrexone as monotreatment for kleptomania (n = 17) found that 76.5% had reduction in the urges to steal and 41.1% ceased to steal [62] at the most recent follow-up, where the mean duration of follow-up was 481.9 ± 280.9 days after baseline. Table 15.3 summarizes controlled studies of pharmacological treatments of kleptomania [59, 61, 62]. PR 15.5 Pyromania O R R EC TE D The essential feature of pyromania is repeated episodes of deliberate and purposeful fire setting, where the patient experiences tension or affective arousal before committing the act. There is also a fascination with, interest in, curiosity about or attraction to fire and its situational contexts. The patient usually experiences pleasure, gratification or release of tension when setting the fire and witnessing its effects and participating in its aftermath [1]. Research on pyromania has mainly focused on the criminal population. Although pyromania is considered to be a rare disorder [1], a recent study of psychiatric inpatients (n = 204) revealed that 3.4% met the DSM-IV criteria for current pyromania, whereas the lifetime prevalence was 5.9% [49]. Fire setting during adolescence does not necessarily reflect symptoms of pyromania, but may be a symptom of various psychiatric disorders [63]. A recent study of adolescent psychiatric inpatients (n = 102) found that, after excluding patients who set fire due to other disorders such as conduct disorder, bipolar disorder, psychotic disorders, substance use disorders and developmental disorders, seven patients met the criteria for current pyromania [64]. Pharmacological treatments of pyromania To our knowledge, only one relatively large study of pharmacological treatment of pyromania has yet been published. The study recruited 14 adults and 7 adolescents with lifetime DSM-IV pyromania from inpatient and outpatient studies of impulse control disorders. Of the 21 subjects, 14 had previously received treatment for psychiatric disorders, and only two had received treatment specific for pyromania. All 14 had received psychotropic medication, but only two had received medication specifically prescribed for pyromania symptoms. Partial or complete remission of pyromania urges and behavior were reported in 6 of the 14 cases (see Table 15.4). The medications used included topiramate, escitalopram, sertraline, fluoxetine and lithium. In three of the cases, pyromania symptoms recurred when the medication was discontinued. In the cases not responding to psychopharmacology, different medication had been tried: fluoxetine, valproic acid, lithium, sertraline, olanzapine, escitalopram, C N U Page 301 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 302 C N U Mean dose at endpoint (mg/d) Duration Na Mean age Attrition (%) Proportion Treatment response women (%) Abiujaiude et al. [59] Escitalopram vs. placebo Open label 20 4–7 wk 11 46.0 15.4 81.8 Grant and Kim [61] Naltrexone Open label 148 12 wk 37.0 33.3 70.0 Grant [62] Naltrexone Retrospective longitudinal study 135.3 3 yr D 17 PR 39.6 0 70.6 V1 - 07/03/2009 11:07 A.M. FS O O number of subjects included in the analyses TE a The 10 79% improved 43% partial remission 57% complete remission 20% partial remission 70% complete remission 36% partial remission 41% complete remission c15.tex Design Hertzman Trial EC Study R Studies examining the effectiveness of pharmacological treatments for kleptomania. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS R O Table 15.3 Page 302 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 EC R R O C N U Table 15.4 Pharmacological treatments of pyromania: an overview [63]. Pharmacologic treatment for pyromania (N = 14) Fluoxetine N=2 Lithium n=2 No response 2 partial/ complete remission 1 no response 1 partial/ complete remission 1 no response 1 partial/ complete remission 1 no response 1 partial/ complete remission 1 no response Olanzapine n=1 No response Valproic acid n=1 Clonazepam n=1 Topiratmate n=1 No response No response Partial/ complete remission Hertzman Sertraline n=2 11:07 A.M. 303 FS O V1 - 07/03/2009 O c15.tex PR Escitalopram n=3 D Citalopram n=1 Anti-epileptic 15.5 PYROMANIA Mood stabilizer Antipsychotic TE SSRI Page 303 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman 304 c15.tex V1 - 07/03/2009 11:07 A.M. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS FS citalopram and clonazepam [63]. Treatment with escitalopram, sertraline, fluoxetine and lithium has demonstrated inconsistent results and, beyond the above-mentioned study, the rest of the pharmacological treatment literature on pyromania comprises single case studies. More research in this area is therefore needed in order to draw conclusions about the effectiveness of pharmacological treatment for pyromania. 15.6 Intermittent explosive disorder TE D PR O O IED is characterized by repeated episodes of serious assaultive acts or destruction of property that are out of proportion to any provocation or precipitating psychosocial stressor, and are not due to the direct physiological effects of a substance or better accounted for by another mental disorder [1]. Thus, IED must be distinguished from episodes of aggressive behavior that are due to antisocial personality disorder, borderline personality disorder, psychotic disorder, manic episode, conduct disorder or attention-deficit/hyperactivity disorder. IED usually starts during adolescence [65], and is more prevalent among males [1]. A recent prevalence study showed that the lifetime and last year prevalence rates of IED in the United States were 7.3 and 3.9% respectively [65]. High levels of co-morbidity with mood, anxiety and substance use disorders are reported [65, 66]. Pharmacological treatments of intermittent explosive disorder N C O R R EC Results from an epidemiologic study in the US showed that the majority (60.3%) of those diagnosed with lifetime IED had received treatment for emotional problems, but only 28.8% had received treatment specifically for IED [65]. It has been hypothesized that dysregulation of the serotonergic system and mild brain injuries may be central in the etiology of IED. The medications offered in treatment of patients with IED are mainly SSRIs, mood stabilizers and beta-blockers. However, the efficacy of these medications has mainly been determined through case reports, and controlled trials are needed to confirm the utility of these medications [66]. To the best of our knowledge, no randomized controlled trial of pharmacotherapy for IED has been conducted. U Page 304 15.7 Conclusions Common features of impulse control disorders include urges, pleasure-seeking and inability to resist impulses. Several studies have demonstrated dysfunctions in neurotransmitter systems involved in these mechanisms, which may be targeted through pharmacological treatment. Pharmacological trials of different ICDs have shown promising results and demonstrated potential effectiveness of pharmacological treatments for these disorders. Still, several studies have limitations such as poor designs, relying on single cases, small sample sizes and lack of adequate control groups. More controlled studies in this area are needed to establish the effectiveness of pharmacological treatments for different impulse control disorders. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman c15.tex V1 - 07/03/2009 11:07 A.M. 305 REFERENCES References O R R EC TE D PR O O FS 1. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, text revision, 4th edn, American Psychiatric Association, Washington, DC. 2. McElroy, S.L., Hudson, J.I., Pope, H.G. Jr et al. (1992) The DSM-II-R impulse control disorders not elsewhere classified: clinical characteristics and relationship to other psychiatric disorders. The American Journal of Psychiatry, 149 (3), 318–327. 3. Grant, J.E. and Potenza, M.N. (2004) Impulse control disorders: clinical characteristics and pharmacological management. Annals of Clinical Psychiatry, 16, 27–34. 4. Potenza M. and Hollander E. (2002) Pathological gambling and impulse control disorders, in Neuropsychopharmacology The Fifth Generation of Progress (eds K.L. Davis D. Charney J.T. Coyle, and C. Nemeroff), Lippincott Williams & Wilkins, Philadelphia, pp. 1725–1742. 5. Kim, S.W. (1998) Opioid antagonists in the treatment of impulse-control disorders. The Journal of Clinical Psychiatry, 59 (4), 159–164. 6. Ladouceur, R., Sylvain, C., Boutin, C. et al. (2001) Cognitive treatment of pathological gambling. The Journal of Nervous and Mental Disease, 189, 774–780. 7. Cunningham-Williams, R., Cottler L.B., and Womack S.B. (2004) Epidemiology, in Pathological Gambling A Clinical Guide to Treatment (eds J.E. Grant and M.N. Potenza), American Psychiatric Publishing, Inc., Washington, DC, pp. 25–36. 8. Ladoceur, R. (1996) The prevalence of pathological gambling in Canada. Journal of Gambling Studies, 12, 129–142. 9. Shaffer, H.J., Hall, M.N., and Vander Bilt, J. (1999) Estimating the prevalence of disordered gambling behavior in the United States and Canada: a research synthesis. American Journal of Public Health, 89, 1369–1376. 10. Dowling, N., Smith, D., and Thomas, T. (2007) A comparison of individual and group cognitive-behavioural treatment for female pathological gambling. Behaviour Research and Therapy, 45, 2192–2202. 11. Ledgerwood, D.M. and Petry, N. (2005) Current trends and future directions in the study of psychosocial treatments for pathological gambling. Current Directions in Psychological Science, 14, 89–94. 12. Pallesen, S., Mitsem, M., Kvale, G. et al. (2005) Outcome of psychological treatments of pathological gambling: a review and meta-analysis. Addiction, 100, 1412–1422. 13. Shah K.R., Potenza M.N., and Eisen S.A. (2004) Biological basis for pathological gambling, in Pathological Gambling: A Clinical Guide to Treatment (eds J.E. Grant and M.N. Potenza), American Psychiatric Publishing, Inc., Washington, DC. 14. Hollander E., Kaplan A., and Pallanti S. (2004) Pharmacological treatments, in Pathological Gambling: A Clinical Guide to Treatment (eds J.E. Grant and M.N. Potenza), American Psychiatric Publishing, Washington, DC, pp. 189–205. 15. Petry, N.M. (2005) Pathological Gambling. Etiology, Comorbidity, and Treatment, American Psychological Association, Washington, DC. 16. Hollander, E. (1993) Obsessive-Compulsive-Related Disorders, American Psychiatric Press, Washington, DC. 17. Potenza, M.N., Steinberg, M.A., Skudlarski, P. et al. (2003) An fMRI study of gambling urges in pathological gamblers. Archives of General Psychiatry, 60, 828–836. 18. Blanco, C., Ibáñez, A., Sáiz-Ruiz, J. et al. (2000) Epidemiology, pathophysiology and treatment of pathological gambling. CNS Drugs, 13, 397–407. 19. Hollander, E., Buchalter, A.J., and DeCaria, C.M. (2000) Pathological gambling. Psychiatric Clinics of North America, 23, 629–642. C N U Page 305 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman 306 c15.tex V1 - 07/03/2009 11:07 A.M. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS R R EC TE D PR O O FS 20. Pallanti, S., Quercioli, L., Sood, E. et al. (2002) Lithium and Valproate treatment of pathological gambling: a randomized single-blind study. The Journal of Clinical Psychiatry, 63, 559–564. 21. Pallesen, S., Molde, H., Arnestad, H.M. et al. (2007) Outcome of pharmacological treatments of pathological gambling. Journal of Clinical Psychopharmacology, 27, 357–364. 22. Black, D.W. (2004) An open-label trial of Bupropion in the treatment of pathological gambling. Journal of Clinical Psychopharmacology, 24, 108–110. 23. Blanco, C., Petkova, E., Ibáñez, A. et al. (2002) A pilot placebo-controlled study of fluvoxamine for pathological gambling. Annals of Clinical Psychiatry, 14, 9–15. 24. Dannon, P.N., Lowengrub, K., Gonopolski, Y. et al. (2005) Topiramate versus fluvoxamine in the treatment of pathological gambling. Clinical Neuropharmacology, 28, 6–10. 25. Dannon, P.N., Lowengrub, K., Ernest, M. et al. (2005) Sustained-release Bupropion versus naltrexone in the treatment of pathological gambling: a preliminary blind-rater study. Journal of Clinical Psychopharmacology, 25, 593–596. 26. Grant, J.E., Kim, S.W., Potenza, M.N. et al. (2003) Paroxetine treatment of pathological gambling: a multi-center randomized controlled trial. International Clinical Psychopharmacology, 18 (4), 243–249. 27. Grant, J.E., Potenza, M.N., Hollander, E. et al. (2006) Multicenter investigation of the opioid antagonist nalmefene in the treatment of pathological gambling. The American Journal of Psychiatry, 163 (2), 303–312. 28. Grant, J.E. and Potenza, M.N. (2006) Escitalopram treatment of pathological gambling with co-occurring anxiety: an open-label pilot study with double-blind discontinuation. International Clinical Psychopharmacology, 21, 203–209. 29. Hollander, E., Pallanti, S., Allen, A. et al. (2005) Does sustained-release lithium reduce impulsive gambling and affective instability versus placebo in pathological gamblers with bipolar spectrum disorders? The American Journal of Psychiatry, 162, 137–145. 30. Kim, S.W. and Grant, J.E. (2001) An open naltrexone treatment study in pathological gambling disorder. International Clinical Psychopharmacology, 16, 285–289. 31. Kim, S.W., Grant, J.E., Adson, D.E. et al. (2001) Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling. Biological Psychiatry, 49, 914–921. 32. Kim, S.W., Grant, J.E., Adson, D.E. et al. (2002) A double.blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling. The Journal of Clinical Psychiatry, 63, 501–507. 33. Pallanti, S., Rossi, N.B., Sood, E. et al. (2002) Nefazodone treatment of pathological gambling: a prospective open-label controlled trial. The Journal of Clinical Psychiatry, 63, 1034–1039. 34. Sáiz-Ruiz, J., Blanco, C., Ibáñez, A. et al. (2005) Sertraline treatment of pathological gambling: a pilot study. The Journal of Clinical Psychiatry, 66, 28–33. 35. Zimmerman, M., Breen, R.B., and Posternak, M.A. (2002) An open-label study of citalopram in the treatment of pathological gambling. The Journal of Clinical Psychiatry, 63, 45–48. 36. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn, American Psychiatric Association, Washington, DC. 37. Khouzam, H.R., Battista, M.A., and Byers, P.E. (2002) An overview of trichotillomania and its response to treatment with quetiapine. Psychiatry, 65 (3), 261–270. 38. Bloch, M.H., Landeros-Weisenberger, A., Dombrowski, P. et al. (2007) Systematic review: pharmacological and behavioral treatment for trichotillomania. Biological Psychiatry, 62, 839–846. O C N U Page 306 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman c15.tex V1 - 07/03/2009 11:07 A.M. 307 REFERENCES O R R EC TE D PR O O FS 39. Christenson, G.A., Mackenzie, T.B., Mitchell, J.E. et al. (1991) A placebo-controlled, double-blind crossover study of fluoxetine in trichotillomania. The American Journal of Psychiatry, 148, 1566–1571. 40. Streichenwein, S.M. and Thornby, J.I. (1995) A long-term, double-blind, placebo-controlled crossover trial of the efficacy of fluoxetine for trichotillomania. The American Journal of Psychiatry, 152, 1192–1196. 41. Ninan, P.T., Rotbaum, B.O., Marsteller, F.A. et al. (2000) A placebo-controlled trial of cognitive-behavioral therapy and clomipramine in trichotillomania. The Journal of Clinical Psychiatry, 61, 47–50. 42. Dougherty, D., Loh, R., Jenike, M.A. et al. (2006) Single modality versus dual modality treatment for trichotillomania: Sertraline, behavioral therapy, or both? The Journal of Clinical Psychiatry, 67, 1086–1092. 43. Swedo, S.E., Leonard, H.L., Rapoport, J.L. et al. (1989) A double-blind comparison of clomipramine and desipramine in the treatment of trichotillomania (hair pulling). The New England Journal of Medicine, 321, 497–501. 44. Woods, D.W., Wetterneck, C.T., and Flessner, C.A. (2006) A controlled evaluation of acceptance and commitment therapy plus habit reversal for trichotillomania. Behaviour Research and Therapy, 44, 639–656. 45. van Minnen, A., Hoogduin, K.A., Keijsers, G.P. et al. (2003) Treatment of trichotillomania with behavioral therapy or fluoxetine: a randomized, waiting-list controlled study. Archives of General Psychiatry, 60, 517–522. 46. Chamberlain, S.R., Menzies, L., Sahakain, B.J. et al. (2007) Lifting the veil on trichotillomania. The American Journal of Psychiatry, 164, 568–574. 47. Grant, J.E. (2006) Understanding and treating kleptomania: new models and new treatments. The Israel Journal of Psychiatry and Related Sciences, 43 (2), 81–87. 48. Grant, J.E. and Odlaug, B.L. (2008) Kleptomania: clinical characteristics and treatment. Revista Brasileira de Psiquiatria, 30 (Suppl 1), 11–15. 49. Grant, J.E., Levine, L., Kim, D. et al. (2005) Impulse control disorders in adult psychiatric inpatients. The American Journal of Psychiatry, 162 (11), 2184–21U6. 50. Lejoyeux, M., Arbaretaz, M., McLoughlin, M. et al. (2002) Study of impulse control disorders and depression. Journal of Nervous and Mental Diseases, 190, 310–314. 51. Lejoyeux, M., Feuche, N., Loi, S. et al. (1999) Study of impulse-control disorders among alcohol-dependent patients. The Journal of Clinical Psychiatry, 60, 302–305. 52. Grant, J.E. and Kim, S.W. (2003) Comorbidity of impulse control disorders in pathological gamblers. Acta Psychiatrica Scandinavica, 108, 207–213. 53. Specker, S.M., Carlson, G.A., Christenson, G.A., et al. (1995) Impulse control disorders and attention deficit disorder in pathological gamblers. Annals of Clinical Psychiatry, 7, 175–179. 54. Bechara, A., Tranel, D., and Damasio, H. (2000) Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. Brain, 123, 2189–2202. 55. Marazziti D., Presta S., Pfanner C. et al. (eds) (2000) Scientific Abstracts, The biological basis of kleptomania and compulsive buying. American College of Neuropsychopharmacology 39th Annual Meeting, December 10–14, San Juan, Puerto Rico. 56. Nyffeler, T. and Regard, M. (2001) Kleptomania in a patient with a right frontolimbic lesion. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 14 (1), 73–76. 57. Grant, J.E., Correia, S., and Brennan-Krohn, T. (2006) White matter integrity in kleptomania: a pilot study. Psychiatry Research, 147 (2–3), 233–237. 58. Dannon, P.N. (2003) Topiramate for the treatment of kleptomania: a case series and review of the literature. Clinical Neuropharmacology, 26 (1), 1–4. 59. Aboujaoude E., Koran L.M., and Gamel N. (eds) (2005) Escitalopram in the treatment of kleptomania. Scientific Abstract, 25th Meeting of the New Clinical Drug Evaluation Unit, June 6-9, Boca Raton. C N U Page 307 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Hertzman 308 c15.tex V1 - 07/03/2009 11:07 A.M. CH 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS N C O R R EC TE D PR O O FS 60. McElroy, S.L., Pope, H.Gj., Hudson, J.I. et al. (1991) Kleptomania: a report of 20 cases. The American Journal of Psychiatry, 148 (5), 652–657. 61. Grant, J.E. and Kim, S.W. (2002) An open-label study of naltrexone in the treatment of kleptomania. The Journal of Clinical Psychiatry, 63, 349–355. 62. Grant, J.E. (2005) Outcome study of kleptomania patients treated with naltrexone: a chart review. Clinical Neuropharmacology, 28 (1), 11–14. 63. Grant, J.E. and Kim, S.W. (2007) Clinical characteristics and psychiatric comorbidity of pyromania. The Journal of Clinical Psychiatry, 68, 1717–1722. 64. Grant, J.E., Wiliams, K.A., and Potenza, M.N. (2007) Impulse-control disorders in adolescent psychiatric inpatients: co-occurring disorders and sex differences. The Journal of Clinical Psychiatry, 68, 1584–1592. 65. Kessler, R.C., Coccaro, E.F., Fava, M. et al. (2006) The prevalence and correlates of DSM-IV intermittent explosive disorder in the National Comorbidity Survey replication. Archives of General Psychiatry, 63, 669–678. 66. Amara, G., Richa, S., and Baylé, F.J. (2007) Intermittent explosive disorder: current status. Encephale, 33, 339–345. U Page 308 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45