Dear Editor,

N-acetylcysteine (NAC) is an acetylated derivative of cysteine, a sulfur-containing amino acid that has been long used as antidote for paracetamol overdose and commonly as a mucolytic.

NAC is a widespread, inexpensive nutraceutical sold over-the-counter and comes in different formulations. As complementary/alternative medicine (CAM) products are currently in vogue, NAC use in psychiatric practice is nowadays rife and trend of utilization is on the rise to address a multitude of indications with varying degrees of evidence-base. Efficacy, widespread availability, high tolerability, safety, and lack of abuse potential render NAC an appealing addition to the psychopharmacological armamentarium. Recently, heaps of data from neuroscience accrue speaking to the idea of a pluripotent molecule with an attractive composite mode of action that gained a foothold in psychopharmacotherapy.Reference Minarini, Ferrari and Galletti ^{1 ,} Reference Nocito Echevarria, Andrade Reis and Ruffo Capatti ²

Given the unmet clinical needs in schizophrenia pharmacotherapy particularly, exploring novel agents with qualitatively distinctive mechanisms of action is a pressing desideratum. Herein, we would try to shed some light on the promising therapeutic potential of NAC in schizophrenia spectrum disorders while examining the extant evidence.

NAC is a precursor to the antioxidant glutathione. It has been demonstrated to attenuate both glutamergic and dopaminergic dysregulation, modulate neurotropic and inflammatory pathways, ameliorate mitochondrial dysfunction, inhibit oxidative stress, and protect against apoptosis—all lie at the core of etiopathogenesis of schizophrenia.Reference Moodliar and Naguy ^{3 ,} Reference Dean, Giorlando and Berk ⁴ This portfolio might translate clinically into neuro-protective and pro-cognitive actions.Reference McCaddon and Hudson ⁵

NAC has an excellent safety profile; an oral dose as high as 10× 2800 mg was evaluated for safety in a clinical study with no major adverse effect reported. Mild gastrointestinal symptoms were the most common adverse effects reported in clinical trials.Reference BerK, Jeavons and Dean ⁶ One downside of NAC, although it does cross blood–brain barrier, might be the relative low bioavailability. One promising avenue of research may be to explore derivatives of NAC, such as N-acetylcysteine amide, which has been reported in preclinical studies to have higher permeability through cellular and mitochondrial membranes with increased central nervous system bioavailability compared to NAC.

A suggested dosing regimen (Naguy, Personal Communication): 600 mg bid × 7 days, then 1200 mg bid × 4 weeks, and then 3000 mg/d (divided as 1800 mg am and 1200 mg nocte with 10 hs apart).

We could locate three systematic reviews and meta-analyses in literature attesting to the efficacy of NAC in schizophrenia. Chen et alReference Chen, Chibnall and Nasrallah ⁷ included only two double-blind, placebo-controlled trials and found adjunctive NAC may be efficacious in reducing negative and general symptoms of schizophrenia. A meta-analysis by Zheng et alReference Zheng, Zhang and Cai ⁸ that included three randomized control trials with 307 participants (NAC: 153 and placebo: 154) showed that NAC significantly improved total symptom scores in schizophrenia. Yolland et alReference Yolland, Hanratty and Neil ⁹ conducted a systematic review yielding seven studies meeting study criteria (randomized, placebo-controlled trials assessing specific psychotic and cognitive symptoms in patients with schizophrenia or first-episode psychosis); all had low risk of bias. Among the 440 patients, mean duration of illness was 6.4 years; NAC (600–3600 mg/d) or placebo was added to stable antipsychotic regimens. No benefits for any symptoms were noted at ≤8 weeks. However, at ≥24 weeks and at the studies’ final timepoints, NAC was associated with large and significant beneficial effects on total and negative symptoms, but not on positive symptoms or general ones (a mix of positive, negative, cognitive, and mood symptoms). In the three studies measuring cognitive changes, NAC showed moderately positive effects on working memory (but not processing speed).

Apart from psychopathology, NAC was shown to have a moderate positive effect on akathisia in a randomized control trial after 24 weeks of treatment. If replicated these findings suggest that NAC may be effective as a neuroprotective strategy for akathisia and other extrapyramidal syndromes. Moreover, NAC supplementation has been shown to significantly decrease haloperidol-induced TD in rat models.Reference Salem, Nagpal and Pigott ¹⁰

Interestingly, NAC has been recently found to potentially prevent glucose metabolic disturbance by reshaping the structure of gut microbiota. This finding has been echoed in another study comparing NAC and metformin for metabolic and hormonal profiles in women with polycystic ovary syndrome, where NAC outperformed metformin with better tolerability. These might open new venues to tackle antipsychotic-related metabolic syndrome.Reference Zheng, Yuan and Zhang ¹¹

Recent preclinical study using a neurodevelopmental model of schizophrenia suggested that NAC may have promising effects in early stages of schizophrenia, at-risk mental state and prodroma phases preventing conversion to schizophrenia.Reference Miyake and Miyamoto ¹²

NAC adjuventia of 600 mg/d has also been reported to help in TR schizophrenia.Reference Bulut, Savas and Altindag ¹³

All-in-all, add-on NAC treatment in schizophrenia might span different symptom domains especially recalcitrant negative and cognitive domains, confer neuroprotection in early stages, halt progression of prodroma, mitigate antipsychotic neuro-metabolic derangements, and help with neuroleptic-resistant stages. It is an art rather than a science!Reference Koola ¹⁴