A Randomized Controlled Trial of N-Acetylcysteine in Clozapine-Resistant Schizophrenia

Getting the “NAC” of treating negative symptoms: Researchers performed a randomized controlled trial of N-acetylcysteine in clozapine-resistant schizophrenia.


“Mr Charles” is a 34-year-old Caucasian male with a 16-year history of schizophrenia. He has been on clozapine since age 21, at a current dose of 400 mg at bedtime. He previously took up to 500 mg clozapine, but the dose was reduced due to excessive sedation. He also currently takes risperidone 3 mg daily and lamotrigine 200 mg twice daily. He previously had significant persecutory delusions and associated auditory hallucinations, which largely resolved with clozapine. He also has chronic, enduring negative symptoms. Both Mr Charles and his parents report very few outside interests and no friends outside of family members. His affect is chronically restricted. He has stated that he has no motivation and has a diminished sense of purpose. He does not have any social drive. He currently attends adequately to activities of daily living (ADLs), but impaired hygiene was a problem in the past. He has not had any significant clinical improvement with trials of adjunctive lumateperone, topiramate, minocycline, doxycycline, celecoxib, or oxytocin. His parents inquire about a trial of adjunctive N-acetylcysteine. As his psychiatrist, how would you advise this patient and his family?

There are currently no approved pharmacologic agents for the treatment of negative symptoms of schizophrenia, which contribute to impaired functioning and quality of life.1 Clozapine is the gold-standard antipsychotic for treatment-resistant psychosis, but about 40% of patients are clozapine nonresponders.2 There is limited evidence for augmenting agents that improve residual negative symptoms in clozapine nonresponders.3,4

N-acetylcysteine (NAC) is a glutathione (GSH) precursor that modulates glutamate and dopamine and reduces oxidative stress and inflammation.5 There is evidence for decreased GSH levels in schizophrenia in CSF and MRI studies.6,7 One previous 24-week study of NAC in schizophrenia6 found a significant effect, particularly for negative symptoms. In that study, about half of participants treated with NAC were taking clozapine. There is also evidence from a meta-analysis for a large effect of NAC on negative symptoms in schizophrenia.8

The Current Study

Neill and colleagues performed a 52-week randomized, placebo-controlled trial of NAC in patients stabilized on clozapine but with residual symptoms in 4 Australian cities.9 Participants were allocated to 2 g/day NAC or placebo (2 capsules twice daily), and assessed at 0, 8, 24, and 52 weeks. Inclusion criteria were DSM-5 schizophrenia or schizoaffective disorder; age 18 to 65; on a stable dose of clozapine for at least 6 months with a blood level of > 350 µg/L; and residual symptoms (a score of > 4 on 2 or more PANSS negative scale items or PANSS total score ≥ 60).

Exclusion criteria were current treatment with NAC; allergy to NAC; currently taking nitroglycerin, aralen, or selenium; diabetes mellitus; history of autoimmune disorder, gastrointestinal ulcer, or kidney stones; and pregnancy or not using adequate contraception in females.

The primary outcome measure was change in the PANSS negative subscale. Secondary outcomes included PANSS positive and general symptoms, quality of life (Manchester short assessment), and mood (Calgary depression scale for schizophrenia and PANSS depression subscale). Cognition was assessed using the MATRICS consensus cognitive battery. Data were analyzed using mixed-model repeated-measures analysis, controlling for PANSS positive and depression subscale scores.

The authors randomized 85 participants (42 to NAC and 43 to placebo). There were no significant differences between the groups on baseline clinical and demographic variables. The mean subject age was 40, and 72% of subjects were male. The completion rate was 85% at 8 weeks, 71% at 24 weeks, and 48% at 52 weeks, and similar between groups. Clinic site was included as a covariate in the analyses, due to different attrition rates and number of prescribed medications between sites.

Although there was a significant time effect on improvement in negative symptoms, there was no significant group x time interaction (p=0.62). NAC did not significantly improve cognition (global or domain scores) or quality of life at any time point. There was some evidence for improvements in depression with NAC, although the association was no longer significant after removing patients with changes in clozapine dose. There was no significant increase in side effects over the trial with NAC.

Study Conclusions

The authors performed the first randomized controlled trial (RCT) of NAC for patients with clozapine-resistant schizophrenia. Although there was no difference in side effect burden, they did not find any efficacy of this adjunctive agent over 52 weeks. There was exploratory evidence for improvement in depression with NAC, although this finding warrants investigation in a group enriched for depressive symptoms. Study limitations included lower than expected recruitment and potential underdosing of NAC (a previous trial investigated 3.6 g/day).

The Bottom Line

This study did not support the efficacy of NAC for negative symptoms in clozapine-resistant patients with schizophrenia.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysisFocus (Am Psychiatr Publ). 2020;18(4):443-455.

2. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysisCan J Psychiatry. 2017;62(11):772-777.

3. Siskind DJ, Lee M, Ravindran A, et al. Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysisAust N Z J Psychiatry. 2018;52(8):751-767.

4. Wagner E, Kane JM, Correll CU, et al. Clozapine combination and augmentation strategies in patients with schizophrenia—recommendations from an international expert survey among the Treatment Response and Resistance in Psychosis (TRRIP) working groupSchizophr Bull. 2020;46(6):1459-1470.

5. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatryTrends Pharmacol Sci. 2013;34(3):167-177.

6. Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trialBiol Psychiatry. 2008;64(5):361-368.

7. Do KQ, Trabesinger AH, Kirsten-Krüger M, et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivoEur J Neurosci. 2000;12(10):3721-3728.

8. Yolland CO, Hanratty D, Neill E, et al. Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophreniaAust N Z J Psychiatry. 2020;54(5):453-466.

9. Neill E, Rossell SL, Yolland C, et al. N-Acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double-blind, randomized, placebo-controlled trial targeting negative symptoms [published online ahead of print, 2022 Jul 20]. Schizophr Bull. 2022;sbac065.