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Could a simple over-the-counter nutraceutical help in schizophrenia? Yes, it could. No, it doesn’t. Yes, it could. No, it doesn’t. What? Enter the world of wishing, disappointment, and evidence-based review in the hands of Dr. Chittaranjan Andrade, a reliable investigator.
Hi! Jim Phelps here for the Psychopharmacology Institute. As Dr. Andrade points out, many treatment strategies have been tried for patients with schizophrenia who don’t recover fully on their own or with routine treatment. These include a second antipsychotic, an antidepressant, a mood stabilizer, a cholinesterase inhibitor, an anti-inflammatory, and a glutamate modulator. The list is so long that, as Dr. Andrade says, “It appears that almost every class of agents in the pharmacopoeia has been trialled.”
Enter N-acetylcysteine (NAC), which modulates dopamine and glutamate, improves mitochondrial function, dampens inflammatory mechanisms, and exerts neuroprotective actions, all of which suggest potential benefits in schizophrenia. So, we need a randomized trial, or better yet, a meta-analysis of multiple trials. Here come both.
In this review, Dr. Andrade first examines a meta-analysis by Dr. Caitlin Yolland and colleagues. He dissects it with fine surgical technique, and the resulting conclusion is that although NAC is statistically superior to placebo, the margins are not likely to be clinically significant. But then comes a more recent, larger randomized trial, and here’s what it sounds like when Dr. Andrade approves of a study design: “Investigator initiated industry independent, moderately large, well conducted, well analyzed, a 52-week study of patients who had not improved on at least 3 classes of antipsychotic drugs leading to at least 6 months of treatment on clozapine.” In this group of patients, NAC was added and the patients were followed for an entire year. The results? NAC was not superior to placebo on any clinical or cognitive measure.
So, is there any psychiatric condition for which NAC has shown benefit in this kind of analysis? Dr. Andrade wrote a previous review of NAC for mood disorders, and he found a meta-analysis on bipolar depression with a net effect size of 0.45. Oh, that sounds good. Remember that based on the conventional interpretation of effect sizes, 0.2 is small, 0.5 is medium, and 1.0 is large. Indeed, 1 of those NAC trials had an effect size of 1.0, but Dr. Andrade points out that this was a per-protocol analysis rather than intent-to-treat analysis. In other words, the investigators assessed outcomes only for people who made it all the way through the official steps of this study—dropouts were not included, and this obviously presents the intervention in a more favorable light compared with looking at outcomes for everybody who was randomized. So, that study was a notable outlier in the meta-analysis, and when this and another outlier were removed, that net effect size of 0.45 in the bipolar depression studies decreased to 0.27, which in this new meta-analysis was not statistically significant.
So, why all of this interest in NAC? Well, it’s cheap and natural. That’s appealing. NAC is a precursor of the endogenous antioxidant glutathione, and that’s also appealing because oxidative stress, although not the principal cause of schizophrenia, might contribute to poor outcomes. So, it’s disappointing that augmentation with NAC appears to have had no impact in treatment-resistant schizophrenia. Animal studies and biochemical mechanisms suggest that NAC ought to help, so advocates like Bradlow, Berk, and colleagues in the references suggested recently that most studies have been underpowered and perhaps too brief. But Dr. Andrade’s reviews don’t support the use of NAC in schizophrenia or mood disorders, at least for now.
For more on this, the hopeful will want to read the review by Bradlow, Berk, and colleagues, whereas skeptics will find support for their views in Dr. Andrade’s review, which is linked here at the Psychopharmacology Institute.
Abstract
N-acetylcysteine (NAC) augmentation of antipsychotic medication is one of very many antipsychotic augmentation strategies that have been studied in schizophrenia. A recent systematic review and meta-analysis of 6 randomized controlled trials (RCTs) found that NAC (median dose, 2,000 mg/d) improved several clinical outcomes at different time points with medium to large effect sizes; however, many of the significant findings in this meta-analysis are suspect because they appeared to be influenced by 2 short-term (8-week) RCTs with outlying characteristics. Important findings not influenced by the 2 outlying RCTs were significant attenuation by NAC of negative symptom (3 RCTs) and total psychopathology (2 RCTs) ratings at ≥ 24 weeks and improvement in working memory but not processing speed (3 RCTs). Of these findings, reduction in psychopathology ratings, though statistically significant, appeared too small to be clinically meaningful. Finally, a newly published, moderately large RCT of NAC (2,000 mg/d) in schizophrenia patients refractory to clozapine found that 1 year of treatment with NAC did not outperform placebo for any clinical, cognitive, or quality of life outcome. The take-home message is that it is premature to recommend the use of NAC to treat schizophrenia for any target domain in routine clinical practice and that there does not appear to be a role for NAC for any indication in clozapine-refractory schizophrenia. However, it may be worth studying whether NAC, dosed at 2,000 mg/d or higher for 6 months or longer, improves functional outcomes in schizophrenia.
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Reference
Andrade, C. (2022). Antipsychotic augmentation with N-acetylcysteine for patients with schizophrenia. The Journal of Clinical Psychiatry, 83(5), 43016.
Related References
- Andrade, C. (2021). N-acetylcysteine augmentation for patients with major depressive disorder and bipolar depression. The Journal of Clinical Psychiatry, 82(1), 25943.
- Hu, C. C., & Xie, J. (2012). N-acetylcysteine add-on treatment for depressive symptoms in bipolar disorder: a comparative trial. Clinical Education of General Practice, 10, 515-517.
- Murray, A. J., Rogers, J. C., Katshu, M. Z. U. H., Liddle, P. F., & Upthegrove, R. (2021). Oxidative stress and the pathophysiology and symptom profile of schizophrenia spectrum disorders. Frontiers in Psychiatry, 1235.
- Bradlow, R. C., Berk, M., Kalivas, P. W., Back, S. E., & Kanaan, R. A. (2022). The potential of N-acetyl-L-cysteine (NAC) in the treatment of psychiatric disorders. CNS Drugs, 1-32.
