In 2008, Michael Berk and colleagues showed that N-acetylcysteine (NAC) is effective as an adjunctive treatment for bipolar depression. At the 2012 meeting of the International Congress of Neuropsychopharmacology, Berk reported that NAC (1000 mg twice a day) was also effective in unipolar depression, significantly beating placebo in a randomized double-blind 12-week study.
Editor’s Note: NAC has a broad spectrum of clinical efficacy in bipolar and unipolar depression, negative symptoms of schizophrenia (such as apathy and withdrawal), irritability in autism, trichotillomania (compulsive hair-pulling), gambling addiction, obsessive-compulsive disorder, and many substance-abuse disorders, such as cocaine, heroin, alcohol, and marijuana.
How can one substance do all this? NAC has antioxidant effects, it turns into glutathione (an antioxidant that is the body’s main defense against oxidative stress and free radicals), it has neuroprotective effects (causing neurite sprouting), and it re-regulates glutamate in the reward area of the brain, the nucleus accumbens. Berk believes it is NAC’s antioxidant properties that produce its positive effects in such a range of illnesses, while this editor (Robert M. Post) favors the glutamate mechanism (as discussed in BNN Volume 14, Issue 1 from 2010 and Volume 16, Issue 1 from 2012) as an explanation of NAC’s effects.
Whatever its mechanism turns out to be, NAC is worthy of consideration as an adjunctive treatment. It is readily available from health food stores without a prescription, relatively inexpensive (less than $20 for 100 pills), and relatively well-tolerated. Minor gastrointestinal upsets were the most common reported side effect in the Berk’s clinical trial. However, this editor has had one patient experience a worsening of psychosis.
Editor Robert M. Post’s Personal Opinion About NAC
With the usual caveat that all treatment strategies discussed in the BNN must be evaluated and administered by a physician, it may be useful to consider adding NAC to a treatment regimen for a patient struggling with recurrent unipolar or bipolar depression, and/or a comorbid substance use disorder. Using conventional treatments early in the course of these disorders for acute treatment and for long-term prevention would be the first approach. For less than satisfactory acute responses, conventional adjunctive treatments (as recommended in treatment guidelines elsewhere) might be considered along with NAC, which in some cases can have a delayed onset of action. (Three months may be required to see maximal effects in bipolar disorder.)
In a poster at the 9th International Conference on Bipolar Disorder (ICBD) held in Pittsburgh in 2011, Guy Goodwin and colleagues reported that relative to controls, blood from patients with bipolar disorder contained more total glutathione, a potent antioxidant, and a higher ratio of oxidized to reduced glutathione. Measurements of blood glutathione could eventually serve as a biomarker, suggesting when a diagnosis of bipolar disorder is likely.
Editor’s note: Glutathione is one of the major antioxidants in humans. Oxidized glutathione is a less active form, so the higher levels of oxidized glutathione compared to reduced glutathione in patients with bipolar disorder suggests they may have a relative deficiency of the active form. These data are consistent with reports that patients in manic and depressive phases of bipolar disorder have increased oxidative stress and free radicals that impair cellular functioning.
Together, these results highlight the potential utility of treatments that increase antioxidant activity. One option is N-acetylcysteine (NAC), which the body converts into glutathione. As previously noted in the BNN, Michael Berk reported in Biological Psychiatry in 2008 that NAC (1000 mg twice a day) appears to exert greater antidepressant effects over a period of 24 weeks than placebo when added into previously ineffective regimens in patients with bipolar disorder.
In another poster at the conference, Magalhaes and colleagues reported on NAC treatment for a subgroup of the bipolar patients in the study by Berk who were in a major depressive episode at the time of the study. They found that NAC had highly significant acute antidepressant effects of large magnitude in this subgroup of patients.
The glutathione data by Goodwin et al. provide a further rationale for consideration of the use of NAC in bipolar disorder, particularly in the acute and longer-term treatment of the depressive phases. As we reported in BNN Issue 1 from 2010, NAC also exerts positive effects in many illnesses that commonly occur comorbidly with bipolar disorder. These include cocaine and heroin addiction, gambling addiction, obsessive compulsive disorder (as an adjunct to selective serotonin reuptake inhibitors (SSRIs)), and trichotillomania (compulsive hair-pulling).
At the 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) in October 2010, Lawrence Fung of Stanford University reported that N-acetylcysteine (NAC), a compound sold over-the-counter in health food stores, improved irritability and other symptoms of autism in children aged 8 to 17. In this double-blind, randomized study of NAC compared with placebo, the children who received NAC were treated with 900mg once a day for four weeks, then 900mg BID (twice a day) for four weeks, and finally 900mg TID (three times a day) for the last four weeks of this three-month study. These doses significantly improved irritability and stereotypy (repetitive behaviors) compared with placebo. Side effects were minimal.
Editor’s note: The potential for a safe compound such as N-acetylcysteine to show efficacy in autism is striking. Currently only risperidone and aripiprazole are FDA-approved for effectiveness treating irritability in autism. There has also been a positive study of valproate compared with placebo in autism, although it is not FDA-approved for this purpose.
Most double-blind, placebo controlled clinical trials of NAC have been in adults, so this is the first report that suggests NAC can safely be used in children.
NAC’s ability to improve irritability in autism raises the possibility that this drug may be useful in the treatment of irritability and repetitive behaviors in bipolar disorder, particularly since N-acetylcysteine has also been reported to improve mood, especially depression, in adults with bipolar disorder in the studies of Mike Berk and colleagues published in Biological Psychiatry in 2008.
This study adds to the evidence that suggests N-acetylcysteine may reset the brain’s habit system in the ventral striatum (also called the nucleus accumbens), which is involved in the assessment of the reward value of a variety of substances of abuse and behaviors (as described in BNN Volume 14, Issue 1 from 2010). NAC improves a number of habit-related syndromes including cocaine, heroin, and gambling addictions, trichotillomania (compulsive hair-pulling), and now the irritability and stereotypic behaviors of autism.
In light of NAC’s profile of efficacy and safety, systematic exploration of the drug in childhood-onset bipolar illness is indicated. We are aware of at least one group that is planning such a study.
At the 65th Annual Scientific Convention of the Society of Biological Psychiatry, researcher Christian Carmeli reported that N-acetylcysteine (NAC, 2 gm/day for six months) increased electroencephalogram (EEG) synchrony over the frontal cortical and left temporal regions in patients with schizophrenia. The EEG measures the frequency and amplitude of electrical activity on both sides of the brain.
Editor’s note: These data provide a neurophysiological mechanism that could explain the positive effects of NAC previously observed by researcher Mike Berk and associates in both schizophrenia and bipolar disorders and published in Biological Psychiatry in 2008. NAC is both a glutathione precursor providing antioxidant effects and a modulator of hyper-responsive glutamate reactivity in the n. accumbens or ventral striatum, the reward area of the brain. In placebo-controlled studies NAC appears effective in treating cocaine, heroin, and gambling addiction, as well as trichotillomania (compulsive hair-pulling). These effects are thought to be related to NAC’s dampening of glutamate responses in the n. accumbens, which, along with the dorsal striatum, appears to mediate habit memory. Read more
N-acetylcysteine (NAC), a readily available substance from health food stores, is able to reestablish glutamate homeostasis (regulation and balance) in the reward area of brain (the nucleus accumbens), reported Peter Kalivas of the University of South Carolina at the “Staging neuropsychiatric disorders: Implications for idiopathogenesis and treatment” meeting in Mojacar, Spain this past November. Kalivas reported that NAC appears to be effective across a spectrum of addictions, including cocaine, heroin, alcohol, cigarette smoking, and gambling.
Even more remarkably, NAC also appears to have positive effects in placebo-controlled studies in the treatment of patients with bipolar illness, report Mike Berk and colleagues, who are studying the same substance in Australia. Compared with placebo, patients taking adjunctive NAC showed improvement in all outcome measures, especially depression, after 3 and 6 months. In another article, also published in Biological Psychiatry in 2008, Berk’s research group demonstrated that NAC improved some negative symptoms of schizophrenia. NAC has also shown positive effects in trichotillomania and on nail-biting, suggesting that it has a variety of potential clinical uses in conditions associated with pathological compulsive behavioral patterns.