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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    • "Moreover, early objections to its "construct validity" (Swerdlow and Sutherland, 2005, 2006) – namely, that its neuropotentiated "hyperactive" circuits did not concord with then-claimed "hypoactive" circuits in TS; and that it was an "artificial" construct without etiological relevance – have subsequently diminished with the awareness that, first, premonitory urges and tics in TS show hypoactivity only within executive-control circuits, but primary hyperactivity within the same somatosensory, insular and efferent motor output circuits hyperactivated in the mice (Campbell et al., 1999a; Bohlhalter et al., 2006; Wang et al., 2011; Church and Schlaggar, 2014); and, second, that such transgenic brain circuittesting approaches, including later optogenetic techniques (Ahmari et al., 2013; Ahmari and Dougherty, 2015), impart knowledge about the circuitry and therapy of TS-and OC-like behaviors irrespective of etiology. Awareness of glutamate's role in eliciting tics and compulsions in D1CT-7 mice (Sah and Sallee, 2002; Burke and Lombroso, 2004; Joel, 2006; Ting and Feng, 2008; Wang et al., 2009; Pittenger et al., 2011; Wu et al., 2012; Ahmari and Dougherty, 2015) has helped inspire clinical studies of this neurotransmitter's role in TS and OCD (Chakrabarty et al., 2005; Singer et al., 2010); successful trials of antiglutamatergics for OCD and TTM (Lafleur et al., 2006; Grant et al., 2007, 2009); and trials of a D1 antagonist for TS (Gilbert et al., 2014) and OC-spectrum gambling disorder (Grant et al., 2014). "
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    ABSTRACT: The brain circuits underlying tics in Tourette's syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice's tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we've examined whether these mice's tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons' glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.
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    • "N-acetyl cysteine, an amino acid that restores extracellular glutamate concentration in the nucleus accumbens has demonstrated efficacy in reducing the reward-seeking behaviour in individuals with a range of substance addictions, including nicotine dependence and marijuana addiction (Asevedo et al., 2014). Nacetyl cysteine has also demonstrated promise in the treatment of behavioural addictions such as gambling disorder and trichotillomania (Grant et al., 2007aGrant et al., , 2009bOdlaug and Grant, 2007). Another pharmacological agent with glutamatergic effects is memantine, a medication that has also demonstrated early promise in treating substance use disorders and behavioural addictions. "
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    ABSTRACT: The term 'addiction' was traditionally used in relation to centrally active substances, such as cocaine, alcohol, or nicotine. Addiction is not a unitary construct but rather incorporates a number of features, such as repetitive engagement in behaviours that are rewarding (at least initially), loss of control (spiralling engagement over time), persistence despite untoward functional consequences, and physical dependence (evidenced by withdrawal symptoms when intake of the substance diminishes). It has been suggested that certain psychiatric disorders characterized by maladaptive, repetitive behaviours share parallels with substance addiction and therefore represent 'behavioural addictions'. This perspective has influenced the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which now has a category 'Substance Related and Addictive Disorders', including gambling disorder. Could other disorders characterised by repetitive behaviours, besides gambling disorder, also be considered 'addictions'? Potential examples include kleptomania, compulsive sexual behaviour, 'Internet addiction', trichotillomania (hair pulling disorder), and skin-picking disorder. This paper seeks to define what is meant by 'behavioural addiction', and critically considers the evidence for and against this conceptualisation in respect of the above conditions, from perspectives of aetiology, phenomenology, co-morbidity, neurobiology, and treatment. Research in this area has important implications for future diagnostic classification systems, neurobiological models, and novel treatment directions.
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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.
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