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Original Article |

N-Acetylcysteine, a Glutamate Modulator, in the Treatment of Trichotillomania:  A Double-blind, Placebo-Controlled Study FREE

Jon E. Grant, JD, MD, MPH; Brian L. Odlaug, BA; Suck Won Kim, MD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, University of Minnesota School of Medicine, Minneapolis.


Arch Gen Psychiatry. 2009;66(7):756-763. doi:10.1001/archgenpsychiatry.2009.60.
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Published online

Context  Trichotillomania is characterized by repetitive hair pulling that causes noticeable hair loss. Data on the pharmacologic treatment of trichotillomania are limited to conflicting studies of serotonergic medications. N-acetylcysteine, an amino acid, seems to restore the extracellular glutamate concentration in the nucleus accumbens and, therefore, offers promise in the reduction of compulsive behavior.

Objective  To determine the efficacy and tolerability of N-acetylcysteine in adults with trichotillomania.

Design  Twelve-week, double-blind, placebo-controlled trial.

Setting  Ambulatory care center.

Patients  Fifty individuals with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years).

Interventions  N-acetylcysteine (dosing range, 1200-2400 mg/d) or placebo was administered for 12 weeks.

Main Outcome Measures  Patients were assessed using the Massachusetts General Hospital Hair Pulling Scale, the Clinical Global Impression scale, the Psychiatric Institute Trichotillomania Scale, and measures of depression, anxiety, and psychosocial functioning. Outcomes were examined using analysis of variance modeling analyses and linear regression in an intention-to-treat population.

Results  Patients assigned to receive N-acetylcysteine had significantly greater reductions in hair-pulling symptoms as measured using the Massachusetts General Hospital Hair Pulling Scale (P < .001) and the Psychiatric Institute Trichotillomania Scale (P = .001). Fifty-six percent of patients “much or very much improved” with N-acetylcysteine use compared with 16% taking placebo (P = .003). Significant improvement was initially noted after 9 weeks of treatment.

Conclusions  This study, the first to our knowledge that examines the efficacy of a glutamatergic agent in the treatment of trichotillomania, found that N-acetylcysteine demonstrated statistically significant reductions in trichotillomania symptoms. No adverse events occurred in the N-acetylcysteine group, and N-acetylcysteine was well tolerated. Pharmacologic modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors.

Trial Registration  clinicaltrials.gov Identifier: NCT00354770.

Figures in this Article

Trichotillomania is a disabling, underrecognized condition in which individuals repeatedly pull out hair, which leads to noticeable hair loss. Trichotillomania is characterized by the following diagnostic criteria: the recurrent pulling out of one's hair, which results in noticeable hair loss; an increasing sense of tension immediately before pulling out the hair or when attempting to resist the behavior; and pleasure, gratification, or relief when pulling out hair.1 Psychosocial problems are common in individuals with trichotillomania and include significantly reduced quality of life, reduced work productivity, and impaired social functioning.2,3

Relatively little is known about the prevalence of trichotillomania in the general population. Clinically significant hair pulling that meets the diagnostic criteria for trichotillomania has been found in 0.6% to 3.9% of college students surveyed.4,5 Other studies examining the rates of trichotillomania in treatment samples have found lifetime rates of 4.4% in adult psychiatric inpatients (sample size = 204)6 and 4.6% in patients with obsessive-compulsive disorder (sample size = 153).7

Although trichotillomania has been described for almost 2 centuries,8 it remains a poorly understood disorder with limited data regarding pathogenesis and treatment.9 Currently, there is no Food and Drug Administration–approved treatment for trichotillomania, despite almost 2 decades of research. In fact, there have been only 6 small (sample sizes = 13-43) placebo-controlled trials of pharmacotherapy published for the treatment of trichotillomania.9 Four of these studies examined a selective serotonin reuptake inhibitor, and 2 investigated clomipramine hydrochloride. A recent meta-analysis10 demonstrated that although clomipramine has moderate efficacy compared with placebo (effect size, −0.68; 95% confidence interval, −1.28 to −0.07), there is no evidence to suggest any benefit for selective serotonin reuptake inhibitors (SSRIs) (effect size, −0.02; 95% confidence interval, −0.32 to 0.35). Even in the case of clomipramine, however, there is little evidence that initial benefits are maintained.11 Given the lack of clearly effective pharmacologic treatments for trichotillomania, additional treatment options are needed.

Glutamatergic dysfunction has been implicated in the pathogenesis of obsessive-compulsive disorder,12,13 a disorder with phenomenologic and possible neurobiological links to trichotillomania.1417 Clinical studies1820 support the possible efficacy of glutamatergic modulators, such as N-acetylcysteine, in the treatment of repetitive or compulsive disorders. N-acetylcysteine is a hepatoprotective antioxidant that is converted to cystine, a substrate for the glutamate-cystine antiporter. This antiporter allows for the uptake of cystine, which causes the reverse transport of glutamate into the extracellular space, which stimulates inhibitory metabotropic glutamate receptors and, thereby, reduces synaptic release of glutamate.13,18,2124 The restoration of the extracellular glutamate concentration in the nucleus accumbens seems to block reinstitution of compulsive behaviors.21,25 Pharmacotherapies that target the prefrontal glutamatergic drive to the nucleus accumbens,25 such as N-acetylcysteine, may, therefore, correct the underlying pathophysiologic abnormalities and symptoms of trichotillomania. Based on these data, we conducted a placebo-controlled, double-blind study to examine the tolerability and efficacy of N-acetylcysteine in the treatment of trichotillomania. We hypothesized that the use of N-acetylcysteine would reduce compulsive hair-pulling behavior in individuals with trichotillomania.

PATIENTS

Men and women aged 18 to 65 years with a primary DSM-IV26 diagnosis of trichotillomania were recruited via newspaper advertisements and referrals for medication treatment. All the patients met the DSM-IV criteria for current trichotillomania using the physician-administered Trichotillomania Diagnostic Interview.27 Because 17% of individuals with trichotillomania do not meet the DSM-IV criteria of either tension before or relief or gratification after pulling hair,28 this criterion was not required for study inclusion (46 patients, however, met the full DSM-IV criteria for trichotillomania). The participation of women required a negative β–human chorionic gonadotropin pregnancy test result and the stable use of a medically accepted form of contraception.

The exclusion criteria included (1) unstable medical illness or clinically significant abnormalities on laboratory tests or physical examination at the screening visit; (2) a history of seizures; (3) myocardial infarction within 6 months; (4) current pregnancy or lactation or inadequate contraception in women of childbearing potential; (5) any reported thoughts of suicide; (6) a lifetime history of bipolar disorder type I or II, dementia, or schizophrenia or any other psychotic disorder according to DSM-IV criteria; (7) current (past 3 months) DSM-IV–designated substance abuse or dependence; (8) previous treatment with N-acetylcysteine; and (9) a diagnosis of asthma (owing to the potential of N-acetylcysteine to worsen asthma).

Patients who were currently taking psychotropic medications were allowed into the study as long as the dose of medication had been stable for 3 months before study inclusion and there were no plans to modify the dose during the study. Similarly, patients who were attending individual or group psychotherapy were allowed to participate if attendance had been ongoing weekly for at least 6 months before study entry. Patients who had changed doses of medication or started therapy, based on self-report, were discontinued from the study (changes in treatment were assessed at each study visit, and no one was withdrawn for this reason).

Of 77 individuals screened for the study, 50 with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years) were randomized to receive N-acetylcysteine or placebo. Twenty-seven individuals did not meet the inclusion and exclusion criteria: 13 reported a current substance use disorder, 6 reported symptoms consistent with a lifetime bipolar disorder, 5 had severe asthma, and 3 felt unable to comply with the study schedule.

The 50 randomized patients as a whole reported a mean (SD) age at trichotillomania onset of 12.1 (5.0) years (range, 3-27 years). Patients spent a mean (SD) of 64.9 (59.1) minutes each day pulling hair. Although many patients had multiple triggers, the most common triggers of actual pulling were the feel of the hair (eg, coarse, kinky, or out-of-place hairs) (60%; n = 30), stress (34%; n = 17), and the sight of a hair (22%; n = 11). Most patients (n = 37; 74%) pulled from multiple sites: 33 (66%) pulled from their heads, 30 (60%) from their eyebrows, 25 (50%) from their eyelashes, and 7 (14%) from their pubic area. Twelve patients (24%) pulled without complete conscious awareness. Ten patients (20%) reported ingesting at least part of the hair (ie, root or shaft) after pulling. Seven patients (14%) reported pulling the hair of someone else in addition to their own. Of the 50 patients, 31 (62%) had never sought outpatient mental health treatment for hair pulling.

Although individuals with current bipolar, psychotic, and substance use disorders were excluded, 30 enrolled patients (60%) reported at least 1 clinically important current comorbid disorder: 14 (28%) reported symptoms consistent with major depressive disorder, 14 (28%) had an anxiety disorder (eg, generalized anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, or anxiety disorder not otherwise specified), 18 (36%) had another impulse control disorder (most commonly pathologic skin picking and compulsive nail biting), and 1 (2%) had an eating disorder (ie, bulimia nervosa). Rates of comorbid disorders did not differ between treatment groups, and no particular comorbid disorder was associated with treatment response.

Of the 50 patients, 4 (8%) had ongoing psychotherapy and 28 (56%) were taking a psychotropic medication. Of the 4 patients undergoing psychotherapy, all had been with the same therapist for at least 1 year, and no one was receiving cognitive behavior therapy (when efficacy analyses were performed without these 4 patients, the results were the same). Of the 28 patients taking medication, all had been taking stable doses for at least 6 months: 18 were taking a selective serotonin reuptake inhibitor, 8 were taking a serotonin-norepinephrine reuptake inhibitor, and 2 were taking a stimulant. Rates of psychotropic medication use did not differ between the treatment groups (64% of the placebo group and 48% of the N-acetylcysteine group; χ21 = 1.299; P = .25), and no particular medication was associated with treatment response.

The institutional review board of the University of Minnesota approved the study and the informed consent. One of 2 investigators (J.E.G. or S.W.K.) discussed potential risks of the study, as well as alternative treatments, with the patients. After having received a complete description of the study, patients provided written informed consent. This study was performed in accordance with the Declaration of Helsinki. Data were collected between September 1, 2006, and August 1, 2008.

STUDY DESIGN

After screening, eligible patients were assigned to 12 weeks of double-blind N-acetylcysteine or placebo therapy. The investigational pharmacy of the University of Minnesota randomized all the patients (in block sizes of 8 using computer-generated randomization with no clinical information) to either N-acetylcysteine or placebo in a 1:1 manner. All eligible study participants were first given N-acetylcysteine, 1200 mg/d, or matching placebo for 6 weeks. At week 6, the dose was increased to 2400 mg/d (or the same number of matching placebo pills) for the remaining 6 weeks of the study. Dose range selection was based on safety and efficacy data from studies using N-acetylcysteine in human immunodeficiency virus, cocaine dependence, and other impulse control disorders, such as pathologic gambling.2931 At week 6, the dose was increased unless clinical improvement (ie, cessation of all hair pulling for the entire 3-week period as assessed by the investigator) was attained at a lower dose. Twenty-two patients (88%) in the placebo group received the dose increase, whereas 18 (72%) assigned to N-acetylcysteine received a dose increase (χ21 = 2.000; P = .16). Given the lack of difference between groups in terms of dose increase, change in dose would be unlikely to have affected the masking. Patients who were not compliant with their use of study medication (ie, who failed to take medication for ≥3 consecutive days) were discontinued from the study. Patients were asked at each visit about the number of doses missed per week. Forty-four patients reported never missing a dose, and 6 reported missing at most 1 or 2 doses each month.

SCREENING ASSESSMENTS

Patients were evaluated at study entry using the Trichotillomania Diagnostic Interview, a reliable and valid diagnostic instrument that uses the DSM-IV criteria for trichotillomania.27 Demographics and clinical features of trichotillomania were assessed by the use of a semistructured interview. The ethnicity of patients in the study was defined by self-report and was included to learn more about this variable in trichotillomania. Psychiatric comorbidity was assessed using the Structured Clinical Interview for DSM-IV.32 Medical history, physical examination, and routine laboratory testing were performed. Patients reported the severity of trichotillomania symptoms using the self-rated Massachusetts General Hospital Hair Pulling Scale (MGH-HPS).33 Investigators assessed trichotillomania symptoms by the use of the physician-administered Psychiatric Institute Trichotillomania Scale (PITS).34 Anxiety symptom severity was rated using the Hamilton Anxiety Rating Scale (HAM-A).35 Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAM-D).36 Psychosocial functioning was evaluated using the self-report version of the Sheehan Disability Scale (SDS),37 and quality of life was evaluated using the Quality of Life Inventory.38

EFFICACY ASSESSMENTS

Patients were seen every 3 weeks for 12 weeks. Whichever investigator (J.E.G. or S.W.K.) did not see a particular patient at baseline conducted the progress evaluations for that patient. The primary outcome measure was the MGH-HPS.33 The MGH-HPS is a 7-item self-report scale that rates urges to pull hair, actual amount of pulling, perceived control over the behavior, and distress associated with hair pulling in the past 7 days on a severity scale from 0 to 4 for each item (total scores range from 0 to 28, with higher scores reflecting greater illness severity). The MGH-HPS has demonstrated excellent test-retest reliability, convergent and divergent validity, and sensitivity to change.39 Analysis of the MGH-HPS has demonstrated 2 separate factors, with acceptable reliability for both: “severity” and “resistance and control.”40 Separate treatment effects for these 2 factors were also analyzed.

Secondary measures used at each study visit included the following:

  • The PITS.34 This is a 6-item physician-administered scale that rates hair-pulling symptoms during the past week. The items assess number of hair-pulling sites, time spent pulling and thinking about pulling, resistance to hair-pulling urges, distress, and interference with daily activities. Items are rated from 0 to 7, with higher scores a reflection of greater severity and total scores ranging from 0 to 42. Although the psychometric properties of the PITS have not been well established,41,42 as 1 of the few physician-rated instruments for trichotillomania, it has shown strong correlation with the MGH-HPS (r = 0.63).39

  • The Clinical Global Impression (CGI) scale.44 This scale consists of a reliable and valid 7-item Likert scale used to assess the severity and improvement of clinical symptoms. The CGI severity scale was used at each visit and ranges from 1 (“not ill at all”) to 7 (“among the most extremely ill”). The CGI improvement scale was used at each follow-up visit and ranges from 1 (“very much improved”) to 7 (“very much worse”). The CGI scale was used to refer specifically to trichotillomania symptoms and not to the overall psychopathologic condition.

  • The SDS.37 This reliable, valid 3-item self-report scale assesses functioning in 3 areas of life: work, social or leisure activities, and home and family life. Scores on the SDS range from 0 to 30.

  • A secondary measure used only at baseline and the study end point was the Quality of Life Inventory.37 This inventory is a valid and reliable 16-item self-administered rating scale that assesses life domains such as health, work, recreation, friendships, love relationships, home, self-esteem, and standard of living.

  • The HAM-A and the HAM-D. The HAM-A35 is a reliable and valid physician-administered 14-item scale that provides a total measure of overall anxiety. The HAM-D36 is a valid and reliable 17-item physician-administered rating scale that assesses the severity of depressive symptoms.

SAFETY ASSESSMENTS

Safety assessments at each visit included evaluations of sitting blood pressure, heart rate, and weight. Adverse effects were documented and included time of onset and resolution, severity, action taken, and outcome. Common adverse effects of N-acetylcysteine therapy include headache, pruritus, flatulence, increased blood pressure, and fatigue. The investigator recorded the use of concomitant medications in terms of daily dosage, start and stop dates, and reason for use.

DATA ANALYSIS

Demographic and baseline visit characteristics of the N-acetylcysteine and placebo groups were compared using χ2 and t tests to determine whether group differences existed at randomization. Differences in response between the placebo and N-acetylcysteine groups were adjusted for baseline disparities by use of the baseline score as a covariate.

Primary and secondary measures were examined using analysis of variance modeling analyses (UNIANOVA, SPSS for Windows version 15.0; SPSS Inc, Chicago, Illinois). The baseline value of the measure being analyzed was used as a covariate. The difference in the overall level of posttreatment values, the main effect for treatment, was the test of primary interest. Analyses were performed on all available data by the use of an intention-to-treat population (last observation carried forward). All patients who returned for at least 1 postrandomization visit were included in the intention-to-treat population. Because 7 dependent variables were being examined, a Bonferroni correction was used; tests were 2-tailed, and α = .007 (0.05 / 7 = .007) was used to determine statistical significance.

A retrospective power analysis was performed using a bootstrap approach.43 A total of 10 000 repeated sampling iterations were performed, and significance at P = .007 was achieved in 99.9% of the 2-level active-placebo dichotomy using the primary outcome measure (the MGH-HPS). These results indicate that the significant findings reported are not likely to be based on chance.

Effect sizes were also calculated using the Cohen effect size index d. A d of 0.2 is considered a small effect size, 0.5 is medium, and 0.8 is large. Partial eta squared (η2), which is the proportion of the effect + error variance that is attributable to the effect, was calculated. Interpretation of η2 is that greater than 0.2 is a large effect size, greater than 0.1 is a medium effect size, and greater than 0.05 is a small effect size.

Clinically significant change was determined using the approach developed by Jacobson and Truax.45 The CGI severity scale was used to assess clinically significant change after treatment. For someone to have a clinically significant change, his or her final CGI severity score had to be less than the cutoff score, and his or her change from baseline had to be greater than the reliable change index.

PATIENT CHARACTERISTICS

Demographics and clinical characteristics of the patients at baseline are given in Table 1 and Table 2. There were no statistically significant imbalances regarding demographics or baseline trichotillomania symptoms between treatment groups. Baseline trichotillomania scores on both the MGH-HPS and the PITS were consistent with severity scores seen in other studies of trichotillomania.46 In addition, overall baseline psychosocial dysfunction, according to the SDS, was mild, and quality of life was assessed in the “low average” range, both of which are consistent with assessments made in other studies.3 Although some of the baseline scores on the MGH-HPS were in the low range at baseline, the low scorers did not experience a floor effect for symptom change during treatment. In the placebo group, only 2 patients had a minimum score on a single item, and at the end point neither of these patients had a minimum score on any item. In the N-acetylcysteine group, only 1 patient had a minimum item score, and at the end point, this patient also had a minimum score on each of 4 items.

Table Graphic Jump LocationTable 1. Baseline Comparison of Patients With Trichotillomania Assigned to Receive N-Acetylcysteine or Placebo
Table Graphic Jump LocationTable 2. Treatment Responses of Patients With Trichotillomania Assigned to Receive Placebo or N-Acetylcysteine (Intention-to-Treat)

Figure 1 shows the patient disposition throughout the study. Twenty-two of 25 patients (88%) assigned to receive N-acetylcysteine and 22 of 25 patients (88%) assigned to receive placebo completed the 12-week trial. There were no statistically significant pretreatment differences between completers and noncompleters on any measures. The rate of study completion did not differ between treatment groups. Of the 6 patients who did not complete the study, 1 withdrew for health concerns unrelated to the study and 5 withdrew because of an inability to comply with the study schedule. Reasons for study withdrawal did not significantly differ between groups.

Place holder to copy figure label and caption
Figure 1.

Patient flow diagram for N-acetylcysteine vs placebo in the treatment of trichotillomania.

Graphic Jump Location
EFFICACY RESULTS

Significantly better results on the primary efficacy variable, the MGH-HPS total score, were observed for patients assigned to receive N-acetylcysteine by the study end point (F1,47 = 32.152; P < .001) (Table 2). A significant treatment effect was first detected after 9 weeks of active medication use (P = .002) (Figure 2). In terms of the 2 factors of the MGH-HPS, those assigned to the N-acetylcysteine group demonstrated significant improvement on the severity subscale (F1,47 = 18.245) and on the resistance and control subscale (F1,47 = 37.067; P < .001 for both) (Table 2). The PITS scores were consistent with the MGH-HPS total scores, and the difference between groups on the PITS was significant at the study end point (F1,47 = 12.03; P = .001) (Table 2).

Place holder to copy figure label and caption
Figure 2.

Massachusetts General Hospital Hair Pulling Scale (MGH-HPS) total scores adjusted for a baseline score of 17.18.

Graphic Jump Location

The CGI improvement scale score also demonstrated significant improvement by the study end point. Of patients assigned to the N-acetylcysteine group, 56% were “much” or “very much” improved by the study end point compared with 16% of those taking placebo (χ21 = 8.681; P = .003) (Figure 3). Of patients assigned to receive N-acetylcysteine, 44% (n = 11) had a 50% or greater reduction on the MGH-HPS compared with 0% in the placebo group (χ21 = 14.103; P < .001). Of those who were “much” or very much” improved at the end point according to CGI scale score, a significantly larger percentage reported a 50% reduction in the MGH-HPS score compared with those who were not responders according to CGI scale scores (χ21 = 12.850; P < .001).

Place holder to copy figure label and caption
Figure 3.

Percentage of patients with trichotillomania with a score of 1 or 2 on the Clinical Global Impression (CGI) improvement scale.

Graphic Jump Location

Patients assigned to receive N-acetylcysteine, however, did not demonstrate greater response with respect to psychosocial functioning. Although functioning and quality of life improved to a greater numerical extent for those assigned to the N-acetylcysteine group, neither the SDS total score (F1,47 = 2.683; P = .11) nor the Quality of Life Inventory score (F1,47 = 1.337; P = .25) demonstrated a significant difference between the 2 groups (Table 2).

Clinically significant change was calculated for the CGI severity scale. Patients with a CGI severity scale posttreatment score lower than 3 and a change from baseline of at least 2 points achieved a clinically significant change. Clinically significant change was seen in 11 (44%) patients assigned to the N-acetylcysteine group and in 1 (4%) of those assigned to the placebo group (Pearson χ21 = 10.965; P = .001).

Analyses performed on the subset of 44 patients who completed the study demonstrated significant reductions on all measures consistent with the intention-to-treat analyses.

Analysis of baseline variables demonstrated no significant moderators of treatment effect. Preexisting medication status, age, sex, age at trichotillomania onset, education, psychiatric comorbidity, previous treatment history, baseline trichotillomania severity, and psychosocial functioning measures were not statistically significantly correlated with treatment response. In addition, there were no differences in treatment response between patients who met the full DSM-IV diagnostic criteria for trichotillomania compared with those who did not.

SAFETY AND TOLERABILITY

There were no reported adverse experiences in patients who received N-acetylcysteine (Table 3). The few adverse experiences were of mild intensity and were reported only by those taking placebo. There were no statistically significant differences in the incidence of adverse events between groups. Mean HAM-D and HAM-A scores remained low throughout the study in both treatment groups (Table 2). No patient reported any subtle physiologic or mood changes that would have allowed him or her to suspect the condition to which they were assigned.

Table Graphic Jump LocationTable 3. Patients With Trichotillomania Reporting Any Adverse Drug Experiences

This randomized, double-blind, clinical trial indicates that N-acetylcysteine is safe and more effective than placebo for the treatment of trichotillomania. N-acetylcysteine was effective for trichotillomania on the primary and secondary outcome measures as assessed by physician and patient ratings, with medium to large effect sizes. The beneficial effects of N-acetylcysteine use were seen within 9 weeks of treatment initiation, and this result is consistent with those of previous studies that have found N-acetylcysteine therapy to be effective within days (3 days for the reduction of cocaine urges)47 to a few weeks (8 weeks for gambling behavior).29N-acetylcysteine is an amino acid, is available in health-food stores, is cheaper than most insurance copayments, and seems to be well tolerated. N-acetylcysteine could be an effective treatment option for people with trichotillomania.

Patients assigned to receive N-acetylcysteine experienced a mean reduction (improvement) of 40.9% on the primary outcome measure (ie, MGH-HPS), and a responder rate of 56% (ie, “much” or “very much” improved on the CGI by the study end point). Although a variety of outcome measures have been used in previous studies, when we compare the present results with those of previous studies we find that the percentage reduction in the MGH-HPS score in this study is higher than that seen with medications (8.4%),48 is similar to that reported for combined treatment (medications plus cognitive behavior therapy: 41.5%),46 and is within the range of improvement reported for cognitive behavior therapy alone (34.8%-66.4% reduction in the MGH-HPS score).49,50,57 These findings suggest that N-acetylcysteine compares favorably with existing treatment options available to physicians.

The efficacy of N-acetylcysteine in this study lends further support to the hypothesis that pharmacologic manipulation of the glutamate system (in the nucleus accumbens) may target core symptoms of compulsive behaviors. Pharmacotherapies that target the prefrontal glutamatergic drive to the nucleus accumbens,25 such as N-acetylcysteine, may, therefore, correct the underlying pathophysiologic abnormalities and symptoms of trichotillomania. In addition, N-acetylcysteine increases cysteine and glutathione levels in glial cells.51 Through its effects on glial functioning, N-acetylcysteine may be protective to glial cell functioning during hyperglutamatergic states and may enhance the glial uptake of glutamate by excitatory amino acid transporters.52 Because glial cells are primarily responsible for the clearance of glutamate from the synapse,53 this may be important for understanding the glutamate-modulating effects of N-acetylcysteine.

Although N-acetylcysteine may be a promising treatment for trichotillomania, previous pharmacologic studies9 in trichotillomania have shown that particular treatments have not been effective for all individuals with trichotillomania. In the present study, 44% of patients treated with N-acetylcysteine did not respond. These results may reflect a failure to recognize the heterogeneity of individuals with trichotillomania and how that heterogeneity may necessitate individually tailored treatment approaches.15 Recent research54 has suggested that the obsessive-compulsive spectrum disorders may have various clusters that cohere based on clinical and possibly genetic grounds. Other trichotillomania research55 has suggested that automatic compared with focused pulling, and the degree of each type of pulling, may reflect meaningful differences in terms of clinical presentation, comorbid psychiatric disorders, neuropathophysiologic abnormalities, and treatment response. Although not examined in this study, differences in hair-pulling styles may also help identify subtypes of trichotillomania that respond differentially to N-acetylcysteine. Further research that examines various abnormalities of the impulsive-compulsive neurocircuitry may, therefore, result in the definition of a subtype of trichotillomania that is more likely to respond to glutamatergic agents, such as N-acetylcysteine, and a different trichotillomania subtype that may respond preferentially to serotonergic agents.15 Although these notions remain speculative and require additional research to examine their appropriateness, one future direction for the treatment of trichotillomania may be to better define subtypes of trichotillomania (using clinical symptoms, cognitive testing, neuroimaging, and pharmacogenetics) to guide pharmacologic treatment selection.

Although there were numerically greater improvements in the functional and quality-of-life measures in this study for N-acetylcysteine compared with placebo, we did not find statistically significant improvement for patients taking N-acetylcysteine. The only previous trichotillomania study46 that examined this question also found that neither cognitive behavior therapy nor medication use resulted in improved quality of life during an acute 12-week treatment trial. One possible explanation for the present findings might be the baseline scores. The patients in this study began with only mild functional impairment and a low-average quality of life. Given the limited range for improvement in these scales, it may not have been possible to see statistically significant improvement with the present sample size. Another explanation could be that the functional impairment and quality of life seen in patients with trichotillomania have more to do with the consequences of the pulling (eg, bald spots) than with the pulling itself. Because symptom improvement may occur many weeks before hair grows back, functional impairment and quality of life might be more relevant if measured after several months of symptom improvement. Finally, given that the Cohen d point estimate for the SDS was approaching a medium effect size, the nonsignificant findings for change in functional impairment might be due to low power for this measure (a bootstrap power analysis for the SDS resulted in an estimated power of 35.6% for P < .05).

This study represents, to our knowledge, the first trial of a glutamatergic agent in trichotillomania, but there exist several limitations. First, trichotillomania seems to be a chronic disease that may require long-term therapy. By design, this study did not assess treatment effects beyond the 12-week treatment period, and the longer-term effects of N-acetylcysteine therapy require further evaluation. It is possible that a longer course of therapy could result in continued and even greater reductions in trichotillomania symptoms. Second, this study did not include behavioral therapy. Cognitive behavior therapy has shown benefit for trichotillomania9,56,57 and should be considered in conjunction with pharmacotherapies. Finally, we have not yet examined the optimal N-acetylcysteine dose, and whether some patients would have responded to higher doses needs to be examined.

This investigation suggests that N-acetylcysteine may be effective in the acute treatment of trichotillomania. As effective treatments for hair pulling emerge, it becomes increasingly important that physicians and mental health care providers screen for trichotillomania to provide timely treatment.

Correspondence: Jon E. Grant, JD, MD, MPH, University of Minnesota School of Medicine, Department of Psychiatry, 2450 Riverside Ave, Minneapolis, MN 55454 (grant045@umn.edu).

Submitted for Publication: August 26, 2008; final revision received November 19, 2008; accepted November 25, 2008.

Financial Disclosure: Dr Grant has received research grants from the National Institute of Mental Health, Forest Pharmaceuticals, GlaxoSmithKline, and Somaxon Pharmaceuticals; has been a consultant to Pfizer Pharmaceuticals and Somaxon Pharmaceuticals; and has consulted for law offices as an expert regarding impulse control disorders.

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Odlaug  BLGrant  JE Prevalence of impulse control disorders in a college sample.  New Research Program and Abstracts, 161st Annual Meeting of the American Psychiatric Association May 3-8, 2008 Washington, DCAbstract NR2-069
Grant  JELevine  LKim  DPotenza  MN Impulse control disorders in adult psychiatric inpatients. Am J Psychiatry 2005;162 (11) 2184- 2188
PubMed Link to Article
Matsunaga  HKiriike  NMatsui  TOya  KOkino  KStein  DJ Impulsive disorders in Japanese adult patients with obsessive-compulsive disorder. Compr Psychiatry 2005;46 (1) 43- 49
PubMed Link to Article
Hallopeau  M Alopicie par grattage (trichomanie ou trichotillomanie). Ann Dermatol Venereol 1889;10440- 441
Chamberlain  SROdlaug  BLBoulougouris  VFineberg  NGrant  JE Trichotillomania: neurobiology and treatment. Neurosci Biobehav Rev 2009;33 (6) 831- 842
PubMed Link to Article
Bloch  MHLanderos-Weisenberger  ADombrowski  PKelmendi  BWegner  RNudel  JPittenger  CLeckman  JFCoric  V Systematic review: pharmacological and behavioral treatment for trichotillomania. Biol Psychiatry 2007;62 (8) 839- 846
PubMed Link to Article
Swedo  SELenane  MCLeonard  HL Long-term treatment of trichotillomania (hair pulling). N Engl J Med 1993;329 (2) 141- 142
PubMed Link to Article
Chakrabarty  KBhattacharyya  SChristopher  RKhanna  S Glutamatergic dysfunction in OCD. Neuropsychopharmacology 2005;30 (9) 1735- 1740
PubMed Link to Article
Lafleur  DLPittenger  CKelmendi  BGardner  TWasylink  SMalison  RTSanacora  GKrystal  JHCoric  V N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl) 2006;184 (2) 254- 256
PubMed Link to Article
Chamberlain  SRFineberg  NABlackwell  ADClark  LRobbins  TWSahakian  BJ A neuropsychological comparison of obsessive-compulsive disorder and trichotillomania. Neuropsychologia 2007;45 (4) 654- 662
PubMed Link to Article
Grant  JEPotenza  MN Compulsive aspects of impulse-control disorders. Psychiatr Clin North Am 2006;29 (2) 539- 551
PubMed Link to Article
Swedo  SELeonard  HL Trichotillomania: an obsessive compulsive spectrum disorder? Psychiatr Clin North Am 1992;15 (4) 777- 790
PubMed
Stein  DJSimeon  DCohen  LJHollander  E Trichotillomania and obsessive-compulsive disorder. J Clin Psychiatry 1995;56 ((suppl 4)) 28- 34; discussion, 35
PubMed
Coric  VTaskiran  SPittenger  CWasylink  SMathalon  DHValentine  GSaksa  JWu  Y-TGueorguieva  RSanacora  GMalison  RTKrystal  JH Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry 2005;58 (5) 424- 428
PubMed Link to Article
Odlaug  BLGrant  JE N-acetyl cysteine treatment of grooming disorders. J Clin Psychopharmacol 2007;27 (2) 227- 229
PubMed Link to Article
Coric  VKelmendi  BPittenger  CWasylink  SBloch  MHGreen  J Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with trichotillomania. J Clin Psychiatry 2007;68 (1) 170- 171
PubMed Link to Article
McFarland  KLapish  CCKalivas  PW Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 2003;23 (8) 3531- 3537
PubMed
Baker  DAMcFarland  KLake  RWShen  HToda  SKalivas  PW N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci 2003;1003349- 351
PubMed Link to Article
LaRowe  SDMardikian  PMalcolm  RMyrick  HKalivas  PMcFarland  KSaladin  MMcRae  ABrady  K Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 2006;15 (1) 105- 110
PubMed Link to Article
Kalivas  PWVolkow  NSeamans  J Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 2005;45 (5) 647- 650
PubMed Link to Article
Kalivas  PWVolkow  ND The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 2005;162 (8) 1403- 1413
PubMed Link to Article
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient Edition (SCID-I/NP).  New York Biometrics Research, New York State Psychiatric Institute2002;
Rothbaum  BONinan  PT The assessment of trichotillomania. Behav Res Ther 1994;32 (6) 651- 662
PubMed Link to Article
Christenson  GAMansueto  CS Trichotillomania: descriptive characteristics and phenomenology. Stein  DJChristianson  GAHollander  ETrichotillomania. Washington, DC American Psychiatric Press1999;1- 41
Grant  JEKim  SWOdlaug  BL N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry 2007;62 (6) 652- 657
PubMed Link to Article
Mardikian  PNLaRowe  SDHedden  SKalivas  PWMalcolm  RJ An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007;31 (2) 389- 394
PubMed Link to Article
Cavallini  LAlexandre  A Oral N-acetyl-cysteome increases the production of anti HIV chemokines in peripheral blood mononuclear cells. Life Sci 2000;67 (2) 147- 154
PubMed Link to Article
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV-Patient Edition (SCID-I/P, Version 2.0).  New York Biometrics Research Department, New York State Psychiatric Institute1995;
Keuthen  NJO'Sullivan  RLRicciardi  JNShera  DSavage  CRBorgmann  ASJenike  MABaer  L The Massachusetts General Hospital (MGH) Hair Pulling Scale, 1: development and factor analyses. Psychother Psychosom 1995;64 (3-4) 141- 145
PubMed Link to Article
Winchel  RMJones  JSMolcho  AParsons  BStanley  BStanley  M The Psychiatric Institute Trichotillomania Scale (PITS). Psychopharmacol Bull 1992;28 (4) 463- 476
PubMed
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Sheehan  DV The Anxiety Disease.  New York, NY Scribner1983;
Frisch  MBCornell  JVillaneuva  M Clinical validation of the Quality of Life Inventory: a measure of life satisfaction for use in treatment planning and outcome assessment. Psychol Assess 1993;4 (1) 92- 101
Link to Article
O'Sullivan  RLKeuthen  NJHayday  CFRicciardi  JNButtolph  MLJenike  MABaer  L The Massachusetts General Hospital (MGH) Hairpulling Scale, 2: reliability and validity. Psychother Psychosom 1995;64 (3-4) 146- 148
PubMed Link to Article
Keuthen  NJFlessner  CAWoods  DWFranklin  MEStein  DJCashin  SETrichotillomania Learning Center Scientific Advisory Board, Factor analysis of the Massachusetts General Hospital Hairpulling Scale. J Psychosom Res 2007;62 (6) 707- 709
PubMed Link to Article
Stanley  MACohen  LJ Trichotillomania and obsessive-compulsive disorder. Stein  DJChristianson  GAHollander  ETrichotillomania. Washington, DC American Psychiatric Press1999;225- 261
Diefenbach  GJTolin  DFHannan  SCrocetto  JWorhunsky  P Trichotillomania: impact on psychosocial functioning and quality of life. Behav Res Ther 2005;43 (7) 869- 884
PubMed Link to Article
Davison  ACHinkley  DV Bootstrap Methods and Their Application.  Cambridge, England Cambridge University Press1997;
Guy  W ECDEU Assessment Manual for Psychopharmacology.  Rockville, MD National Institute of Mental Health1976;Publication (ADM) 76-338
Jacobson  NSTruax  P Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol 1991;59 (1) 12- 19
PubMed Link to Article
Dougherty  DDLoh  RJenike  MAKeuthen  NJ Single modality versus dual modality treatment for trichotillomania: sertraline, behavioral therapy, or both? J Clin Psychiatry 2006;67 (7) 1086- 1092
PubMed Link to Article
LaRowe  SDMyrick  HHedden  SMardikian  PSaladin  MMcRae  ABrady  KKalivas  PWMalcolm  R Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 2007;164 (7) 1115- 1117
PubMed Link to Article
van Minnen  AHoogduin  KAKeijsers  GPHellenbrand  IHendriks  GJ Treatment of trichotillomania with behavioral therapy or fluoxetine: a randomized, waiting-list controlled study. Arch Gen Psychiatry 2003;60 (5) 517- 522
PubMed Link to Article
Woods  DWWetterneck  CTFlessner  CA A controlled evaluation of acceptance and commitment therapy plus habit reversal for trichotillomania. Behav Res Ther 2006;44 (5) 639- 656
PubMed Link to Article
Keijsers  GPvan Minnen  AHoogduin  CAKlaassen  BNHendriks  MJTanis-Jacobs  J Behavioural treatment of trichotillomania: two-year follow-up results. Behav Res Ther 2006;44 (3) 359- 370
PubMed Link to Article
Mayer  MNoble  M N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proc Natl Acad Sci U S A 1994;91 (16) 7496- 7500
PubMed Link to Article
Hart  AMTerenghi  GKellerth  JOWiberg  M Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of n-acetyl-cysteine after nerve injury. Neuroscience 2004;125 (1) 91- 101
PubMed Link to Article
Han  DSen  CKRoy  SKobayashi  MSTritschler  HJPacker  L Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants. Am J Physiol 1997;273 (5, pt 2) R1771- R1778
PubMed
Lochner  CHemmings  SMKinnear  CJNiehaus  DJNel  DGCorfield  VAMoolman-Smook  JCSeedat  SStein  OJ Cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder: clinical and genetic correlates. Compr Psychiatry 2005;46 (1) 14- 19
PubMed Link to Article
Flessner  CAConelea  CAWoods  DWFranklin  MEKeuthen  NJCashin  SE Styles of pulling in trichotillomania: exploring differences in symptom severity, phenomenology, and functional impact. Behav Res Ther 2008;46 (3) 345- 357
PubMed Link to Article
Flessner  CABusch  AMHeideman  PWWoods  DW Acceptance-enhanced behavior therapy (AEBT) for trichotillomania and chronic skin picking: exploring the effects of component sequencing. Behav Modif 2008;32 (5) 579- 594
PubMed Link to Article
Diefenbach  GJTolin  DFHannan  SMaltby  NCrocetto  J Group treatment for trichotillomania: behavior therapy versus supportive therapy. Behav Ther 2006;37 (4) 353- 363
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Patient flow diagram for N-acetylcysteine vs placebo in the treatment of trichotillomania.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Massachusetts General Hospital Hair Pulling Scale (MGH-HPS) total scores adjusted for a baseline score of 17.18.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Percentage of patients with trichotillomania with a score of 1 or 2 on the Clinical Global Impression (CGI) improvement scale.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Comparison of Patients With Trichotillomania Assigned to Receive N-Acetylcysteine or Placebo
Table Graphic Jump LocationTable 2. Treatment Responses of Patients With Trichotillomania Assigned to Receive Placebo or N-Acetylcysteine (Intention-to-Treat)
Table Graphic Jump LocationTable 3. Patients With Trichotillomania Reporting Any Adverse Drug Experiences

References

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision.  Washington, DC American Psychiatric Association2000;
Christenson  GAMackenzie  TBMitchell  JE Characteristics of 60 adult chronic hair pullers. Am J Psychiatry 1991;148 (3) 365- 370
PubMed
Woods  DWFlessner  CAFranklin  MEKeuthen  NJGoodwin  RDStein  DJWalther  MRTrichotillomania Learning Center Scientific Advisory Board, The Trichotillomania Impact Project (TIP): exploring phenomenology, functional impairment, and treatment utilization. J Clin Psychiatry 2006;67 (12) 1877- 1888
PubMed Link to Article
Christenson  GAPyle  RLMitchell  JE Estimated lifetime prevalence of trichotillomania in college students. J Clin Psychiatry 1991;52 (10) 415- 417
PubMed
Odlaug  BLGrant  JE Prevalence of impulse control disorders in a college sample.  New Research Program and Abstracts, 161st Annual Meeting of the American Psychiatric Association May 3-8, 2008 Washington, DCAbstract NR2-069
Grant  JELevine  LKim  DPotenza  MN Impulse control disorders in adult psychiatric inpatients. Am J Psychiatry 2005;162 (11) 2184- 2188
PubMed Link to Article
Matsunaga  HKiriike  NMatsui  TOya  KOkino  KStein  DJ Impulsive disorders in Japanese adult patients with obsessive-compulsive disorder. Compr Psychiatry 2005;46 (1) 43- 49
PubMed Link to Article
Hallopeau  M Alopicie par grattage (trichomanie ou trichotillomanie). Ann Dermatol Venereol 1889;10440- 441
Chamberlain  SROdlaug  BLBoulougouris  VFineberg  NGrant  JE Trichotillomania: neurobiology and treatment. Neurosci Biobehav Rev 2009;33 (6) 831- 842
PubMed Link to Article
Bloch  MHLanderos-Weisenberger  ADombrowski  PKelmendi  BWegner  RNudel  JPittenger  CLeckman  JFCoric  V Systematic review: pharmacological and behavioral treatment for trichotillomania. Biol Psychiatry 2007;62 (8) 839- 846
PubMed Link to Article
Swedo  SELenane  MCLeonard  HL Long-term treatment of trichotillomania (hair pulling). N Engl J Med 1993;329 (2) 141- 142
PubMed Link to Article
Chakrabarty  KBhattacharyya  SChristopher  RKhanna  S Glutamatergic dysfunction in OCD. Neuropsychopharmacology 2005;30 (9) 1735- 1740
PubMed Link to Article
Lafleur  DLPittenger  CKelmendi  BGardner  TWasylink  SMalison  RTSanacora  GKrystal  JHCoric  V N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl) 2006;184 (2) 254- 256
PubMed Link to Article
Chamberlain  SRFineberg  NABlackwell  ADClark  LRobbins  TWSahakian  BJ A neuropsychological comparison of obsessive-compulsive disorder and trichotillomania. Neuropsychologia 2007;45 (4) 654- 662
PubMed Link to Article
Grant  JEPotenza  MN Compulsive aspects of impulse-control disorders. Psychiatr Clin North Am 2006;29 (2) 539- 551
PubMed Link to Article
Swedo  SELeonard  HL Trichotillomania: an obsessive compulsive spectrum disorder? Psychiatr Clin North Am 1992;15 (4) 777- 790
PubMed
Stein  DJSimeon  DCohen  LJHollander  E Trichotillomania and obsessive-compulsive disorder. J Clin Psychiatry 1995;56 ((suppl 4)) 28- 34; discussion, 35
PubMed
Coric  VTaskiran  SPittenger  CWasylink  SMathalon  DHValentine  GSaksa  JWu  Y-TGueorguieva  RSanacora  GMalison  RTKrystal  JH Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry 2005;58 (5) 424- 428
PubMed Link to Article
Odlaug  BLGrant  JE N-acetyl cysteine treatment of grooming disorders. J Clin Psychopharmacol 2007;27 (2) 227- 229
PubMed Link to Article
Coric  VKelmendi  BPittenger  CWasylink  SBloch  MHGreen  J Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with trichotillomania. J Clin Psychiatry 2007;68 (1) 170- 171
PubMed Link to Article
McFarland  KLapish  CCKalivas  PW Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 2003;23 (8) 3531- 3537
PubMed
Baker  DAMcFarland  KLake  RWShen  HToda  SKalivas  PW N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci 2003;1003349- 351
PubMed Link to Article
LaRowe  SDMardikian  PMalcolm  RMyrick  HKalivas  PMcFarland  KSaladin  MMcRae  ABrady  K Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 2006;15 (1) 105- 110
PubMed Link to Article
Kalivas  PWVolkow  NSeamans  J Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 2005;45 (5) 647- 650
PubMed Link to Article
Kalivas  PWVolkow  ND The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 2005;162 (8) 1403- 1413
PubMed Link to Article
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient Edition (SCID-I/NP).  New York Biometrics Research, New York State Psychiatric Institute2002;
Rothbaum  BONinan  PT The assessment of trichotillomania. Behav Res Ther 1994;32 (6) 651- 662
PubMed Link to Article
Christenson  GAMansueto  CS Trichotillomania: descriptive characteristics and phenomenology. Stein  DJChristianson  GAHollander  ETrichotillomania. Washington, DC American Psychiatric Press1999;1- 41
Grant  JEKim  SWOdlaug  BL N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry 2007;62 (6) 652- 657
PubMed Link to Article
Mardikian  PNLaRowe  SDHedden  SKalivas  PWMalcolm  RJ An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007;31 (2) 389- 394
PubMed Link to Article
Cavallini  LAlexandre  A Oral N-acetyl-cysteome increases the production of anti HIV chemokines in peripheral blood mononuclear cells. Life Sci 2000;67 (2) 147- 154
PubMed Link to Article
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV-Patient Edition (SCID-I/P, Version 2.0).  New York Biometrics Research Department, New York State Psychiatric Institute1995;
Keuthen  NJO'Sullivan  RLRicciardi  JNShera  DSavage  CRBorgmann  ASJenike  MABaer  L The Massachusetts General Hospital (MGH) Hair Pulling Scale, 1: development and factor analyses. Psychother Psychosom 1995;64 (3-4) 141- 145
PubMed Link to Article
Winchel  RMJones  JSMolcho  AParsons  BStanley  BStanley  M The Psychiatric Institute Trichotillomania Scale (PITS). Psychopharmacol Bull 1992;28 (4) 463- 476
PubMed
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Sheehan  DV The Anxiety Disease.  New York, NY Scribner1983;
Frisch  MBCornell  JVillaneuva  M Clinical validation of the Quality of Life Inventory: a measure of life satisfaction for use in treatment planning and outcome assessment. Psychol Assess 1993;4 (1) 92- 101
Link to Article
O'Sullivan  RLKeuthen  NJHayday  CFRicciardi  JNButtolph  MLJenike  MABaer  L The Massachusetts General Hospital (MGH) Hairpulling Scale, 2: reliability and validity. Psychother Psychosom 1995;64 (3-4) 146- 148
PubMed Link to Article
Keuthen  NJFlessner  CAWoods  DWFranklin  MEStein  DJCashin  SETrichotillomania Learning Center Scientific Advisory Board, Factor analysis of the Massachusetts General Hospital Hairpulling Scale. J Psychosom Res 2007;62 (6) 707- 709
PubMed Link to Article
Stanley  MACohen  LJ Trichotillomania and obsessive-compulsive disorder. Stein  DJChristianson  GAHollander  ETrichotillomania. Washington, DC American Psychiatric Press1999;225- 261
Diefenbach  GJTolin  DFHannan  SCrocetto  JWorhunsky  P Trichotillomania: impact on psychosocial functioning and quality of life. Behav Res Ther 2005;43 (7) 869- 884
PubMed Link to Article
Davison  ACHinkley  DV Bootstrap Methods and Their Application.  Cambridge, England Cambridge University Press1997;
Guy  W ECDEU Assessment Manual for Psychopharmacology.  Rockville, MD National Institute of Mental Health1976;Publication (ADM) 76-338
Jacobson  NSTruax  P Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol 1991;59 (1) 12- 19
PubMed Link to Article
Dougherty  DDLoh  RJenike  MAKeuthen  NJ Single modality versus dual modality treatment for trichotillomania: sertraline, behavioral therapy, or both? J Clin Psychiatry 2006;67 (7) 1086- 1092
PubMed Link to Article
LaRowe  SDMyrick  HHedden  SMardikian  PSaladin  MMcRae  ABrady  KKalivas  PWMalcolm  R Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 2007;164 (7) 1115- 1117
PubMed Link to Article
van Minnen  AHoogduin  KAKeijsers  GPHellenbrand  IHendriks  GJ Treatment of trichotillomania with behavioral therapy or fluoxetine: a randomized, waiting-list controlled study. Arch Gen Psychiatry 2003;60 (5) 517- 522
PubMed Link to Article
Woods  DWWetterneck  CTFlessner  CA A controlled evaluation of acceptance and commitment therapy plus habit reversal for trichotillomania. Behav Res Ther 2006;44 (5) 639- 656
PubMed Link to Article
Keijsers  GPvan Minnen  AHoogduin  CAKlaassen  BNHendriks  MJTanis-Jacobs  J Behavioural treatment of trichotillomania: two-year follow-up results. Behav Res Ther 2006;44 (3) 359- 370
PubMed Link to Article
Mayer  MNoble  M N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proc Natl Acad Sci U S A 1994;91 (16) 7496- 7500
PubMed Link to Article
Hart  AMTerenghi  GKellerth  JOWiberg  M Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of n-acetyl-cysteine after nerve injury. Neuroscience 2004;125 (1) 91- 101
PubMed Link to Article
Han  DSen  CKRoy  SKobayashi  MSTritschler  HJPacker  L Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants. Am J Physiol 1997;273 (5, pt 2) R1771- R1778
PubMed
Lochner  CHemmings  SMKinnear  CJNiehaus  DJNel  DGCorfield  VAMoolman-Smook  JCSeedat  SStein  OJ Cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder: clinical and genetic correlates. Compr Psychiatry 2005;46 (1) 14- 19
PubMed Link to Article
Flessner  CAConelea  CAWoods  DWFranklin  MEKeuthen  NJCashin  SE Styles of pulling in trichotillomania: exploring differences in symptom severity, phenomenology, and functional impact. Behav Res Ther 2008;46 (3) 345- 357
PubMed Link to Article
Flessner  CABusch  AMHeideman  PWWoods  DW Acceptance-enhanced behavior therapy (AEBT) for trichotillomania and chronic skin picking: exploring the effects of component sequencing. Behav Modif 2008;32 (5) 579- 594
PubMed Link to Article
Diefenbach  GJTolin  DFHannan  SMaltby  NCrocetto  J Group treatment for trichotillomania: behavior therapy versus supportive therapy. Behav Ther 2006;37 (4) 353- 363
PubMed Link to Article

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Supplement may ease compulsive hair pulling. Harv Ment Health Lett 2009;26(4):7.
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Table 9.2-1 Refuted Evidence From Nonhuman Studiesa