Overview

An initial search returned 47 papers, of which 11 met inclusion criteria (Fig. 2). Thirty-two papers were excluded on the basis of being either review articles (n=16), treatment protocols for OCD or OCRD (n=5), preclinical studies (n=4) or neurobiological investigations (n=7). Of the remaining 15, four clinical trials were excluded, as they did not investigate NAC for OCD, OCRD or similar conditions. This left four randomized, double blind, placebo controlled trials, one open label pilot study and six case reports. The mean trial length or length of supplementation with NAC was 13 weeks (range, 8-28 weeks) with the mean number of participants being 19 (range, 1-44) with a mean age of 30 years (range, 5-68 years). The mean of the peak NAC dose used in the studies was 1,587 mg/day (range, 800-3,000 mg/day). Sample sizes varied greatly due to the inclusion of case reports. Co-morbidities and additional treatments utilised by the participants were unspecified in some of the studies. No unpublished literature was available for inclusion.

N-Acetyl Cysteine for Obsessive Compulsive Disorder

Case reports One of the first published findings of NAC in the treatment of OCD was a case study reported by Lafleur and colleagues,67) published in 2006. A 58 year old, peri-menopausal woman was supplemented with NAC which was titrated from 600 mg to 3,000 mg daily over six weeks, and continued at the latter dose for the remaining six weeks. A dramatic drop in symptom severity was detected in the first week as determined by the Yale Brown Obsessive Compulsive Scale (Y-BOCS), with baseline 32 reduced to 24. However, this may be attributable to psychological factors associated with clinician interaction rather than pharmacological effects of NAC. A steady decrease continued from week two to week five, and despite fluctuations in symptom severity observed between weeks five and 10, there was an overall trend of improvement over the 12 weeks (Y-BOCS score of nine at endpoint). Of note, the patient’s Hamilton Rating Scale for Depression (HAM-D) score also decreased significantly over the 12 weeks, from a baseline score of 14 to an endpoint score of five. After her discharge from the hospital at the end of the 12 weeks, NAC therapy (3,000 mg/day) was maintained and a 2-month follow up demonstrated continued improvements in OCD symptoms. However, it is unclear from this case report whether symptomatic improvement at follow up was assessed based on a Y-BOCS score or self/clinician-reporting. Although the significant improvement in this patient’s OCD suggests a promising application for the use of NAC in others, great caution needs to be exercised in interpreting case reports. In contrast, a more recent series of six retrospective case reports concluded little efficacy of NAC for OCD.71) All six patients were considered to have severe OCD (Y-BOCS score of 29.3±4.3) and were treatment-resistant (i.e., unresponsive to at least two first line pharmacotherapies). The NAC dose was titrated to 3,000 mg/day, however titration lengths for each patient were not controlled, therefore the length of time each patient received the 3,000 mg/day dose of NAC was unidentified. However, five out of six patients reported to be on 3,000 mg/day for four weeks. NAC was used adjunctively in this series and all patients were receiving pharmacotherapies (as outlined in Table 1) at doses which had been stable for a minimum of eight weeks prior to supplementation with NAC. The only patient who demonstrated a modest response to NAC in this series began with ‘moderate’ OCD severity (Y-BOCS of 26 baseline, 17 at endpoint) and MDD was the only identified comorbidity, as compared to other patients who experienced multiple co-morbidities. This response is comparable to previous studies involving cohorts of OCD patients with similar symptom severities to this patient67,68) and suggests that individuals with more severe and chronic OCD may be treatment-resistant to NAC at the 3,000 mg/day dose for this length of time. Interestingly, the two patients who were non-responsive to glutamatergic medications (topiramate and lamotrigine) did not show an improvement on NAC, but instead demonstrated a worsening in their symptom severity according to their Y-BOCS score. This highlights the increasingly accepted concept of the heterogeneous nature of OCD neurobiology and suggests that NAC may ineffective against glutamate-independent presentations of OCD. The NAC dosage and treatment regimen associated with this case report is questionable. Patients were relied upon for the purchase and consumption of the correct dose of NAC. No method was employed by researchers to monitor adherence to the correct treatment regimen. For example, remaining pills were not counted and the quality of the NAC was not assessed. Thus, the low response rate reported could be attributable to poor patient compliance, or use of potentially substandard quality NAC products. For these reasons, and the small sample size of the paper, the use of NAC cannot be discredited in a larger cohort until further clinical trials are conducted.

Clinical trials To our knowledge, there has been only one randomised clinical trial completed assessing the use of NAC in the treatment of OCD.68) This 12-week study was conducted in Iran where NAC was titrated from 600 mg/day and doubled weekly to reach a maximum dose of 2,400 mg/day (at week-3). This dose was maintained for the remaining nine weeks of the trial. Symptom severity was assessed by the Y-BOCS and Clinical Global Improvement (CGI) scales at four-week intervals. The mean age of study participants was 30.93 years (range, 23-44 years) and the cohort consisted predominantly of women (75%). The treatment group (n=20) demonstrated a significant effect over placebo (n=19) for ameliorating OCD symptoms according to the Y-BOCS. A gradual and continual decrease in symptom severity was evident from week-4, with the NAC showing significance over placebo from week-8 onwards. Although a promising result, there are various limitations associated with this study. Ten participants in the treatment group recorded a full clinical response, defined as a 35% or greater reduction in their Y-BOCS score compared to baseline. The remaining nine patients’ response rates were not specified, and can be assumed to be less than 35%. This further raises the possibility that NAC may be effective only in a subset of OCD patients. Co-morbidities were not noted by the researchers, and if recorded, may have identified whether NAC was more beneficial in patients with less complex presentations, as postulated by the van Ameringen et al.’ s case series.71) The severity of this particular group of OCD participants was moderate (mean Y-BOCS=27), representing a select population of OCD patients. Additionally, a longer clinical trial may have determined if NAC efficacy would have continued, as has been shown in clinical trials involving individuals with bipolar disorder (in the depressive phase) who experienced continual improvements in their depressive symptoms occurring over a 24 week period.61)

N-Acetyl Cysteine for Obsessive Compulsive Related Disorders

Case reports Several case reports exist for NAC in the treatment OCRD, including TTM, pathological nail biting and excoriation (Table 2). Promising results were obtained from case report of Rodrigues-Barata et al.72) involving two females (aged 23 years and 19 years) with chronic TTM, who were non-responsive to previous psychotherapy and SSRI medications. Both patients demonstrated complete regrowth of their hair within three months when supplemented with 1,200 mg/day of NAC. The authors noted that the positive results were maintained at a six-month follow up for the 23 year old, but did not specify if the NAC treatment was continued over this period. A follow up visit was not recorded for the 19 year old. Likewise, improvements were noted in another case report of a 40 year old female with TTM who was treatment-resistant to various medications and psychotherapy. Within three weeks of supplementation on NAC 1,200 mg twice daily she ceased hair pulling behaviour and noticed reductions in the urges to do so.73) Another patient, a 28 year old male with chronic TTM and nail biting demonstrated significant improvements on 1,800 mg/day NAC within two weeks. Of note, a return of symptoms was observed when the patient failed to comply with the dosing regime over a two week period. When taking the NAC consistently, he reported both the urge and thoughts to ‘indulge’ in these behaviours ameliorated, as well as the physical action of doing so.73) Excoriation symptom improvements have also been demonstrated in another case report, with picking urges decreasing by 50% within a week of NAC supplementation at 1,200 mg/day.73) Once the NAC dose was increased to 1,800 mg/day, complete abstinence was achieved within two days and was maintained at a four month follow up whilst continuing treatment at this dose. A more recent case report from Silva-Netto et al.74) further highlights NAC’s beneficial effects for excoriation. This report showed ‘major improvements’ in treatment resistant skin picking behaviours in three females who were supplemented with 1,200-1,800 mg daily of NAC. Of interest, one of the three women showed a relapse in picking behaviours when she discontinued the NAC and saw great improvements when it was reintroduced, demonstrating a direct correlation between NAC supplementation and symptom relief. Beneficial effects on nail biting were also detected in three patients participating in a clinical trial for bipolar disorder where NAC (1,000 mg twice daily) was used as an adjunctive strategy.75) A 46 year old female with bipolar disorder, episodes of psychosis and “life long” nail biting, reported a cessation of biting behaviour after two weeks of NAC supplementation. Cessation was maintained for the following seven months whilst remaining on the NAC as part of the study. A 44 year old female diagnosed with rapid cycling bipolar, also experienced “lifelong nail biting” behaviour. After four months, she noticed she was able to more consciously cease biting her nails after awareness that one nail had grown back strongly. The third in this case report series was a 46 year old male who had experienced manic and depressive episodes since 16 years of age, and obsessive thoughts concerning exercise and diet. The patient had a longstanding habit of biting his nails and chewing the surrounding skin on his fingers. By the end of the 28-week trial, he reported a reduction in his nail biting, but was unaware when he first noticed this since his participation. Of interest with this case series, two participants noted that cessation of their nail biting was autonomous, the other was able to consciously alter her behaviour after noticing an initial improvement. The participants were not taking NAC specifically to improve their nail biting behaviour, nor were they informed that NAC could do so by the researchers. This enhances the strength of the results from the case series and reduces the likelihood of a halo effect. As always, although case reports can demonstrate promising results, caution needs to be taken when applied to a larger population.

Clinical trials Promising results were obtained from Grant and colleagues’ pilot research,39) published in 2009 (Table 3). This randomized, double blind, placebo controlled trial demonstrated that 2,400 mg of NAC per day was superior to placebo for reducing TTM symptoms in 44 adults, displaying significance from week-9. Significant improvements across all TTM scales, including self-reported (Massachusetts General Hospital Hair Pulling Scale) and clinician-rated scales (Psychiatric Institute Trichotillomania Scales), were demonstrated in the NAC group. Of note, the treatment group recorded no adverse effects throughout the duration of the trial, highlighting that NAC has a good tolerability profile and appears safe as an adjunctive therapy. However, despite noticeable improvements reported by both patients and clinicians regarding TTM symptoms, Quality of Life Inventory, HAM-D and Hamilton Anxiety scales (HAM-A) did not record a significant improvement over placebo. In addition, the Sheehan Disability self reported scale, showed only a mild effect size (Cohen’s d=0.42). However, only low-mild functional impairment and mood was detected at baseline in both groups. For example, HAM-D mean scores were 3.68 in both, and HAM-A mean scores were 3.72 and 3.4 in the control and treatment groups respectively. Despite NAC demonstrating promising results over placebo for improving TTM in this study, it is important to note that 44% (n=11) of patients in the treatment group did not respond to NAC. This varied response rate may be due differences in disorder neurobiology or drug pharmacokinetics and/or pharmacodynamics between patients. As suggested by Grant et al.,39) future investigations involving NAC for TTM should explore the various subtypes of TTM (e.g., autonomous versus conscious hair pulling as well as the presentations of co-morbidities) to identify patient subgroups likely to be most responsive to NAC, enabling a ‘tailored’ treatment approach for each patient. More recently, NAC, titrated to a maximum dose of 2,400 mg over four weeks, failed to show significance over placebo in 35 pediatric TTM patients (aged 8-17 years).76) The authors noted that given that an improvement was seen in both groups, particularly in the first few weeks of treatment, the regular supportive assessments by the clinicians (every two weeks) and adjunctive psycho-education could have been responsible for strengthening the placebo effect. Differing pathophysiologies have also been suggested in pediatric TTM compared to adult TTM.77) The severity of the urge, the associated anxiety and frequency of these thoughts appears to increase in adults, and perhaps NAC is more specific for this population as shown by Grant et al.39) NAC has demonstrated significant improvements in relieving skin picking behaviours in an open label pilot study involving 35 children and adults (aged 5-39 years old) with Prader-Willi Syndrome (PWS).78) PWS is a neurodevelopmental disorder caused by chromosome abnormalities and presents with obsessive-compulsive behaviours.79) Although not considered an OCRD as per the DSM-5, skin picking is apparent in 80-95% of individuals with the syndrome80) and its similarities with OCD and OCRD warrants inclusion in this review. After 12 weeks of NAC supplementation, ranging from 450-1,200 mg, all participants showed a significant improvement in skin picking behaviours determined by lesion size, frequency and the presence of scarring versus open wounds. Seventy-one percent of participants had complete resolution of self-mutilating behaviours, the remaining 29% had lesions that were smaller in size and number and with signs of wound healing present, e.g., the presence of scabs and reduction in the number of open lesions. The NAC was tolerated extremely well amongst all participants and used adjunctively to various medications without negative interactions (Table 3). Only mild gastrointestinal upsets were reported, such as cramping, flatulence and diarrhea. These symptoms dissipated after the first few weeks of NAC supplementation. NAC (800 mg/day) has been studied versus a placebo comparator for treating nail biting in a double blind, randomized trial of 25 children and adolescents, aged 6-18 years old.81) The primary outcome was measured nail length and participants were seen before treatment, one month after baseline and two months thereafter. A statistically significant difference in nail length between the two groups occurred after the first month of treatment (p≤0.04). However, no between-group differences were seen after two months. While methodologically limited, the trial provides preliminary support of the efficacy of NAC in decreasing nail biting behaviour in children and adolescents.

Current NAC in OCD and OCRD Clinical Trials

Several clinical trials are currently underway investigating NAC for the treatment of OCD and OCRD (Table 4). Results from these studies may clarify the efficacy of NAC for these disorders. Studies are being conducted in several regions around the world, with trials in progress in Australia, the USA, the UK and Brazil. These, coupled with a previous clinical trial conducted in Iran,68) highlight the global interest in the potential use of NAC for OCD and OCRD. Longer treatment phases (16 weeks) are planned for the Sarris and Shavitt trials, which will be advantageous in identifying the therapeutic efficacy of NAC (as results may be found after 8-10 weeks of use), and determining if these effects are long lasting. In addition, current trials are better powered. The new trials will involve both pediatric and adult patient groups and may allow for determination of differences in NAC efficacy between patient subpopulations. Shavitt et al. will explore the symptom dimensions within their OCD participants (e.g., somatic obsessions and compulsions, aggressive obsessions and compulsions) using the Dimensional Yale-Brown Obsessive Compulsive Scale. This will potentially reveal if NAC is beneficial for particular presentations of OCD, as suggested from previous research where some patients appear treatment-resistant to NAC over others.71) The maximum dose of NAC used across these studies is 3,000 mg/day, which may consolidate previous research involving this dose, however, will not explore if a higher dose may be more effective in severe and chronic presentations of OCD or OCRD. The study of Sarris et al. attempts to recruit a wider patient demographic, which may incorporate a range of treatment histories, including treatment naïve patients. This may provide the first insight into NAC efficacy as a monotherapy. Unfortunately, one study (Pittenger et al.) has been terminated due to lack of participants and funding for the trial.