Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry 66: 756-763

Department of Psychiatry, University of Minnesota School of Medicine, Minneapolis, MN 55454, USA.
Archives of general psychiatry (Impact Factor: 14.48). 08/2009; 66(7):756-63. DOI: 10.1001/archgenpsychiatry.2009.60
Source: PubMed


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.
To determine the efficacy and tolerability of N-acetylcysteine in adults with trichotillomania.
Twelve-week, double-blind, placebo-controlled trial.
Ambulatory care center.
Fifty individuals with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years).
N-acetylcysteine (dosing range, 1200-2400 mg/d) or placebo was administered for 12 weeks.
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.
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.
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. Identifier: NCT00354770.

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Available from: Brian Odlaug, Mar 25, 2015
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    • "More recently, N-acetylcysteine (i.e., an over-the-counter amino acid supplement that acts as a glutamate modulator; NAC) has been evaluated in the treatment of individuals with TTM. While demonstrating efficacy in an RCT of adults with TTM (Grant et al., 2009), no significant benefit was found relative to placebo in a sample of youth with TTM (Bloch et al., 2013). Although offering promise for some individuals (Woods, 2013), the small number of RCTs limits inferences about NAC's efficacy for TTM. "
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    ABSTRACT: Few randomized controlled trials (RCTs) exist examining the efficacy of behavior therapy (BT) or serotonin reuptake inhibitors (SRIs) for the treatment of trichotillomania (TTM), with no examination of treatment moderators. The present meta-analysis synthesized the treatment effect sizes (ES) of BT and SRI relative to comparison conditions, and examined moderators of treatment. A comprehensive literature search identified 11 RCTs that met inclusion criteria. Clinical characteristics (e.g., age, comorbidity, therapeutic contact hours), outcome measures, treatment subtypes (e.g., SRI subtype, BT subtype), and ES data were extracted. The standardized mean difference of change in hair pulling severity was the outcome measure. A random effects meta-analysis found a large pooled ES for BT (ES= 1.41, p< 0.001). BT trials with greater therapeutic contact hours exhibited larger ES (p= 0.009). Additionally, BT trials that used mood enhanced therapeutic techniques exhibited greater ES relative to trials including only traditional BT components (p= 0.004). For SRI trials, a random effects meta-analysis identified a moderate pooled ES (ES= 0.41, p= 0.02). Although clomipramine exhibited larger ES relative to selective serotonin reuptake inhibitors, the difference was not statistically significant. Publication bias was not identified for either treatment. BT yields large treatment effects for TTM, with further examination needed to disentangle confounded treatment moderators. SRI trials exhibited a moderate pooled ES, with no treatment moderators identified. Sensitivity analyses highlighted the need for further RCTs of SRIs, especially among youth with TTM.
    Journal of Psychiatric Research 11/2014; 58. DOI:10.1016/j.jpsychires.2014.07.015 · 3.96 Impact Factor
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    • "In contrast to imipramine, NAC did not modify activity or temperature amplitudes. Beneficial effects of NAC have been reported in generalized anxiety disorder (Strawn & Saldañ a, 2012), obsessive compulsive disorder (Lafleur et al., 2006) and trichotillomania (Grant et al., 2009; Odlaug & Grant, 2007), conditions where anxiety is a major component or an aggravating confound. Both glutamate and rhythm changes have been shown to play roles in depression and anxiety, and the relevance of glutamate modulation by NAC FIGURE 3. Activity and temperature amplitude during 12:12 and 10:10 LD cycles. "
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    ABSTRACT: Circadian rhythm disturbances are among the risk factors for depression, but specific animal models are lacking. This study aimed to characterize the effects of acute rhythm disruption in mice and investigate the effects of imipramine and N-acetylcysteine (NAC) on rhythm disruption-induced changes. Mice were exposed to 12:12-hour followed by 10:10-hour light:dark cycles (LD); under the latter, mice were treated with saline, imipramine or NAC. Rhythms of rest/activity and temperature were assessed with actigraphs and iButtons, respectively. Hole-board and social preference tests were performed at the beginning of the experiment and again at the 8th 10:10 LD, when plasma corticosterone and IL-6 levels were also assessed. Actograms showed that the 10:10 LD schedule prevents the entrainment of temperature and activity rhythms for at least 13 cycles. Subsequent light regimen change activity and temperature amplitudes showed similar patterns of decline followed by recovery attempts. During the 10:10 LD schedule, activity and temperature amplitudes were significantly decreased (paired t test), an effect exacerbated by imipramine (ANOVA/SNK). The 10:10 LD schedule increased anxiety (paired t test), an effect prevented by NAC (30 mg/kg). This study identified mild but significant behavioral changes at specific time points after light regimen change. We suggest that if repeated overtime, these subtle changes may contribute to lasting behavioral disturbancess relevant to anxiety and mood disorders. Data suggest that imipramine may contribute to sustained rhythm disturbances, while NAC appears to prevent rhythm disruption-induced anxiety. Associations between sleep/circadian disturbances and the recurrence of depressive episodes underscore the relevance of potential drug-induced maintenance of disturbed rhythms.
    Chronobiology International 10/2014; 32(2):1-8. DOI:10.3109/07420528.2014.965315 · 3.34 Impact Factor
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    • "For example, craving to pull hair can escalate over time and this can be transiently relieved by undertaking the act; treatments of utility in substance dependence show promise for trichotillomania, e.g. opiate antagonists and glutamate modulators (Grant et al., 2009, 2014). Cognitive dyscontrol is suggested by neuropsychological assessments conducted in patients with trichotillomania. "
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    ABSTRACT: Trichotillomania is characterized by repetitive pulling out of one's own hair. Impaired response inhibition has been identified in patients with trichotillomania, along with gray matter density changes in distributed neural regions including frontal cortex. The objective of this study was to evaluate impaired response inhibition and abnormal cortical morphology as candidate endophenotypes for the disorder. Subjects with trichotillomania (N = 12), unaffected first-degree relatives of these patients (N = 10), and healthy controls (N = 14), completed the Stop Signal Task (SST), a measure of response inhibition, and structural magnetic resonance imaging scans. Group differences in SST performance and cortical thickness were explored using permutation testing. Groups differed significantly in response inhibition, with patients demonstrating impaired performance versus controls, and relatives occupying an intermediate position. Permutation cluster analysis revealed significant excesses of cortical thickness in patients and their relatives compared to controls, in right inferior/middle frontal gyri (Brodmann Area, BA 47 & 11), right lingual gyrus (BA 18), left superior temporal cortex (BA 21), and left precuneus (BA 7). No significant differences emerged between groups for striatum or cerebellar volumes. Impaired response inhibition and an excess of cortical thickness in neural regions germane to inhibitory control, and action monitoring, represent vulnerability markers for trichotillomania. Future work should explore genetic and environmental associations with these biological markers.
    Journal of Psychiatric Research 09/2014; 59. DOI:10.1016/j.jpsychires.2014.08.010 · 3.96 Impact Factor
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