N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action

Olivia Dean; Frank Giorlando; Michael Berk

doi:10.1503/jpn.100057

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Fig. 1
Mechanisms of action of N-acetylcysteine (NAC). Top to bottom: increased activity of cystine–glutamate antiporter results in increased activation of metabotropic glutamate receptors on inhibitory neurons and facilitates vesicular dopamine release; NAC is associated with reduced levels of inflammatory cytokines and acts as a substrate for glutathione synthesis. These actions are believed to converge upon mechanisms promoting cell survival and growth factor synthesis, leading to increased neurite sprouting. BDNF = brain-derived neurotrophic factor; IL = interleukin; NADP = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of NADP; TNF = tumour necrosis factor.

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Table 1

Summary of clinical findings of N-acetylcysteine (NAC) treatment in psychiatric illness

Study	Disorder	No. study participants	Total daily dose, mg	Study design	Outcome measures	Findings
Gray et al.31	Marijuana addiction	24	2400	4-wk open-label trial	Marijuana Craving Questionnaire	Improvement in 3 of the 4 domains of the scale
Knackstedt et al.32	Reduction in nicotine use	29	2400	4-wk double-blind placebo-controlled trial	Questionnaire for Smoking Urges- Brief, Minnesota Nicotine Withdrawal Scale	Trend for improvement after covarying for alcohol use but overall a negative trial
Van Schooten et al.33	Chemo-prevention trial in healthy smokers (unable to quit)	41	1200	6-mo double-blind placebo-controlled trial	Cotinine (plasma and BAL fluid), urine mutagenicity, 4-ABP-Hb adducts, lipophilic-DNA adducts (PBL and BAL cells), 8-OH-dG adducts (BAL cells), PAH-DNA adducts (MFC and BMC), micronuclei (MFC and SPC), TEAC (plasma and BAL fluid)	Decreases in lipophilic DNA adducts, 8-OH-dG levels and number of micronuclei
LaRowe et al.34	Cocaine addiction	13	2400	Crossover design, treatment for 2 d in each arm (NAC and placebo)	CSSA, self-reported cocaine use, reported cravings, routine blood tests	Significant decrease in craving, withdrawal and self-reported use in NAC but not placebo group (no between- group differences)
LaRowe et al.35	Cocaine addiction	15	2400	Crossover design, treatment for 2 d in each arm (NAC and placebo)	Cue-reactivity (general and motivational measures)	Decreased desire and interest in cocaine and reduced time spent looking at cocaine-related slides
Mardikian et al.36	Cocaine addiction	23	1200, 2400 and 3600	4-wk, open-label trial	Days and amount of money spent on cocaine, CSSA and urine drug screen	Nonsignificant trends in reductions of amount spent and number of days of use on cocaine and improvements based on CSSA
Grant et al.37	Pathological gambling	29 O/L 16 random	1800^†	8-wk O/L study followed by a 6-wk double-blind, placebo- controlled trial (in responders only)	Y-BOCS adapted for Pathological Gambling (PGYBOCS), G-SAS, CGI Improvement and Severity scales, Sheehan Disability Scale, HAM-D, HAM-A, Quality of Life Inventory	Decreased PG-YBOCS scores during O/L phase. Sixteen of original 27 were classified as responders, 13 of whom continued to double-blind phase. There was an increased number of continued response in the NAC group and trends toward significance in the PG-YBOCS and G-SAS scales.
Lafleur et al.38	OCD	1	3000^†	13 wk	Y-BOCS and HAM-D	Improvements between baseline and end point on Y-BOCS and HAM-D
Odlaug et al.39	TTM	2	1800	10 and 13 wk	Self-reported behaviour	Complete abstinence from hair pulling
Grant et al.40	TTM	50	1200–2400	12-wk double-blind, placebo-controlled trial	MGH-HPS, CGI, PITS, Sheehan Disability Scale, Quality of Life Scale, HAM-A and HAM-D	Significant improvements in MGH-HPS, PITS, CGI severity scale scores in the NAC group compared with placebo
Odlaug et al.39	Nail biting	1^*	1800^†	13 wk	Self-reported behaviour	Complete abstinence from nail biting after 9 weeks of treatment. A 2-week hiatus caused reinstatement of symptoms, but subsequent NAC treatment again ameliorated this.
Berk et al.41	Nail biting	3	2000	6 mo	Self-reported behaviour	Complete abstinence of symptoms that continued after 1-month washout period
Odlaug et al.39	Skin picking	1	1800^†	13 wk	Self-reported behaviour	Decreased urge and act of skin picking
Berk et al.42	Schizophrenia	140	2000	6-mo double-blind placebo-controlled trial	PANSS, CGI, GAF, SOFAS, BAS, Simpson–Angus Scale and the Abnormal Involuntary Movements Scale	Improvements seen in negative symptoms based on PANSS; improvements also seen on CGI and BAS. Improvements were lost at the 1-month follow-up visit.
Lavoie et al.12	Schizophrenia	11	2000	8-wk double-blind crossover design	Mismatched negativity and plasma glutathione concentration	Significant improvements in mismatch negativity in NAC group. Plasma glutathione levels were increased following NAC treatment.
Bulut et al.43	Schizophrenia	1	600	30 d	PANSS, CGI and Calgary depression scale	Reduction in PANSS and CGI scores
Berk et al.44	Bipolar disorder	76	2000	6-mo double-blind placebo-controlled trial	MADRS, Bipolar Depression Rating Scale, Young Mania Rating Scale, CGI-bipolar version, GAF, SOFAS, SLICE/LIFE, LIFE-RIFT, and the Quality of Life Enjoyment and Satisfaction Questionnaire	Positive results showed improvements on most rating scales (including primary outcome measure MADRS) in NAC group compared with placebo group

BAL = bronchoalveolar lavage; BAS = Barnes Akathisia Scale; BMC = buccal mucosa cell; CGI = Clinical Global Impression; CSSA = Cocaine Selective Severity Assessment; GAF = Global Assessment of Functioning; G-SAS = Gambling Symptom Assessment Scale; HAM-A = Hamilton Rating Scale for Anxiety; HAM-D = Hamilton Rating Scale for Depression; LIFE-RIFT = Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool; MADRS = Montgomery–Åsberg Depression Rating Scale; MFC = mouth floor cell; MGH-HPS = Massachusetts General Hospital Hair Pulling Scale; OCD = obsessive–compulsive disorder; O/L = open label; PAH = polycyclic aromatic hydrocarbon; PANSS = Positive and Negative Symptoms Scale; PBL = peripheral blood lymphocyte; PITS = Psychiatric Institute Trichotillomania Scale; random. = randomized; SLICE/LIFE = Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation; SOFAS = Social and Occupational Functioning Scale; SPC = soft palate cell; TEAC = trolox equivalent antioxidant capacity; TTM = trichotillomania; Y-BOCS = Yale–Brown Obsessive Compulsive Scale.
↵* This participant also had TTM.
↵† Titrated dose.