Combination of N-acetylcysteine and Risperidone Improves Irritability in Autistic Disorders More Than Placebo and Risperidone
In a 2013 study of 40 children and adolescents with autism spectrum disorders published by Ahmad Ghanizadeh and Ebrahim Moghimi-Sarani in the journal BMC Psychiatry, the combination of the over-the-counter nutritional supplement n-acetylcysteine (NAC) and the atypical antipsychotic risperidone alleviated irritability more than the combination of placebo and risperidone. Side effects were mild. The data extend 2012 observations by A.Y. Hardan et al. in which NAC improved irritability and stereotypy (repeated behavior) in autism more than placebo did.
The two studies taken together support the effectiveness of NAC prescribed either alone or in conjunction with an atypical antipsychotic for the treatment of autism.
New discoveries in neuroanatomy are helping clarify what addiction looks like in the brain. Peter Kalivas of the Medical University of South Carolina reported at the 2013 meeting of the Society of Biological Psychiatry that most drugs of abuse alter glutamate levels and the plasticity of synapses in the nucleus accumbens, the reward area of the brain. Glutamate is the main excitatory neurotransmitter in the brain, and compulsive habits may be associated with increased release of glutamate in this brain area.
During chronic cocaine administration, for example, the neurons in the nucleus accumbens lose their adaptive flexibility and their ability to respond to signals from the prefrontal cortex. Normally, low levels of stimulation would induce long-term depression (LTD) while high levels of stimulation would induce long-term potentiation (LTP). These are long-term changes in the strength of a synapse, which allow the brain to change with learning and memory. When long-term potentiation and long-term depression are no longer possible, memory and new learning in response to messages from the prefrontal cortex are diminished.
Given this absence of flexible responding, animals extinguished from cocaine self-administration (when a lever they had pressed to receive cocaine ceases to provide cocaine) are highly susceptible to cocaine reinstatement if a stressor is presented or if a signal appears that suggests the availability of cocaine. This cocaine reinstatement is associated with high levels of glutamate in the nucleus accumbens, so Kalivas reasoned accurately that lowering these levels would be associated with a lesser likelihood of cocaine reinstatement.
The drug N-acetylcysteine (NAC), which is available from health food stores, decreases the amount of glutamate in the nucleus accumbens by inducing a glutamate transporter in glial cells that helps clear excess synaptic glutamate. In Kalivas’ research, NAC prevented cocaine reinstatement, cocaine-induced anatomical changes in spine shape (bigger, stubby spines), and the loss of long-term potentiation and long-term depression in the nucleus accumbens.
The findings on NAC in animal studies led to a series of important small placebo-controlled clinical trials in people with a variety of addictions, and positive results have been found using NAC in people addicted to opiates, cocaine, alcohol, marijuana, and gambling. It also decreases hair-pulling in trichotillomania and reduces stereotypy and irritability in children with autism.
NAC also appears to be effective in the treatment of unipolar and bipolar depressed patients in placebo-controlled trials by Australian researcher Michael Berk. Thus, NAC could be useful for patients with affective disorders who are also having difficulties with comorbid substance use.
Some antibiotics (that are not commonly available) also induce the glutamate transporter and glial cells of the nucleus accumbens, offering a potential new approach to treating some addictions.
Michael E. Hoffer et al. reported in the journal PLosOne in 2013 that veterans with blast-induced mild traumatic brain injury had a better acute outcome when they were given the antioxidant N-acetylcysteine (NAC) within the first 24 hours after the trauma versus when they were given placebo during the same period. Forty-two percent of those receiving placebo had a good acute outcome, while 86% of those receiving N-acetylcysteine had a good acute outcome. Memory loss, sleep disturbance, dizziness, and headaches all improved more in the N-acetylcysteine group. NAC’s benefits diminished when it was given 3 or 7 days after the trauma.
Editor’s Note: These data add to the growing list of neuropsychiatric syndromes in which NAC has shown efficacy. These include schizophrenia, bipolar depression, unipolar depression, cocaine and heroin addiction, gambling addiction, trichotillomania (compulsive hair-pulling), obsessive-compulsive disorder (as an adjunctive treatment to SSRIs), and improvement in irritability and stereotypy (repetitive behaviors) in children with autism.
Given what appears so far to be a relatively benign side effects profile for NAC, and the potential for severe consequences from traumatic brain injury (TBI), a case for wider use of NAC (for example in emergency rooms) might be made.
The mechanisms of action of NAC in different syndromes remains to be clarified. Researcher Michael Berk used NAC in schizophrenia and bipolar disorder and more recently in unipolar depression because it has antioxidant properties. Peter Kalivas found that NAC can normalize glutamate in the reward area of the brain through actions on the cystine-glutamate exchanger, and it also increases clearance of glutamate by increasing the glutamate transporter in glial cells. NAC decreases the amount of cued glutamate release in a part of the brain called the nucleus accumbens, which may be helpful in recovery from pathological habits. NAC also has anti-inflammatory and perhaps neuroprotective effects, and it increases brain-derived neurotrophic factor (BDNF), which protects neurons and is important for long-term learning and memory. Which of these many actions is important in the treatment of PTSD is not yet known.
N-acetylcysteine (NAC) is a drug available over-the-counter in health food stores that is effective in a variety of disorders, including trichotillomania (compulsive hair-pulling) in adults. Researcher Michael Block of Yale University reports that, in contrast to NAC’s robust effects in adults, the drug was not effective in children with trichotillomania aged 8 to 17. However, behavior therapy has been reported to be effective in both adults and children.
Editor’s Note: Why a drug that is so effective for trichotillomania in adults does not work well or at all in children is not clear. It is even more perplexing given that NAC has shown robust effects on some other childhood disorders, such as irritability and stereotypy in children with autism. However, if this discrepancy and other differences in pharmacological response across demographics are replicated, the reasons for differential response should be investigated.
As many researchers have emphasized, kids are not just shorter adults, but might have entirely different brains that are in a different stage of development. Extrapolating the therapeutic effects that occur in adults to children may not always be a valid strategy.
The antioxidant N-acetylcysteine (NAC), which can be found in health food stores, seems to be effective for irritability and repetitive behaviors in children with autism. In a small controlled study that was published by Hardan et al. in the journal Biological Psychiatry in 2012, 33 mostly male children with autism (aged 3-12 years) received either placebo or NAC at doses of 900mg daily for 4 weeks, followed by 900mg twice daily for 4 weeks, then 900mg three times a day for 4 weeks. Beginning in week 4, the children receiving NAC showed significantly improved irritability scores, and a trend for improvement in repetitive behaviors.
Social responsiveness did not improve significantly, but the children receiving NAC did show some improvement in some areas of social behavior, such as social cognition and autism mannerisms.
There were few side effects associated with NAC. The most significant were gastrointestinal side effects, but these were mild, especially when compared with the side effects associated with FDA-approved treatments for autism, such as the atypical antipsychotics risperidone and aripiprazole.
The authors of the study plan to expand their research in a study of more than 100 children with autism.
Editor’s Note: It should we previously summarized this study in the BNN based on research presented by Fung et al. at a meeting of the American Academy of Child and Adolescent Psychiatry two years ago. The study has now been published.
N-acetylcysteine (NAC) is a drug available over-the-counter in health food stores that seems to be effective for a variety of disorders, including depression and many different habits and addictions. Preventing relapse of cocaine abuse is one of its uses. Researcher Kathryn Reissner at the Medical University of South Carolina found that NAC increases the expression of a glial glutamate transporter (GLT-1) that helps clear excessive glutamate in the nucleus accumbens, and that this mechanism is critical to preventing the reinstatement of cocaine self-administration in rodents.
As we have previously described in the BNN, NAC also decreases cued release of glutamate in the nucleus accumbens by potentiating the cystine-glutamate exchanger. This initially increases extrasynaptic glutamate, but subsequently downregulates glutamate release in the nucleus accumbens through actions at an inhibitory presynaptic metabotropic glutamate receptor.
However, the new data indicate that this action at the cystine-glutamate exchanger is not required for NAC’s effects on cocaine reinstatement, but the induction of GLT-1 is. Furthermore, another compound, propentofylline, which increases glutamate GLT-1, is also effective in suppressing cocaine reinstatement. Cocaine decreases a marker of glial activity, glial fibrillary acidic protein (GFAP), in the nucleus accumbens, suggesting that deficient glial functioning and uptake of glutamate could be another target of therapeutics in cocaine addiction.
Editor’s Note: There are also glial deficits in depressed patients, so it is conceivable that NAC’s effect on GLT-1 glutamate clearance is also involved in the antidepressant effects of NAC.
Glutamate is the major excitatory neurotransmitter in the brain, while GABA is the main inhibitory neurotransmitter. Too much or too little of one or the other can lead to an imbalance in neuronal communication. In a 2012 study by Schmaal et al. published in the journal Neuropsychopharmacology, cocaine-dependent patients were found to have high levels of glutamate in the dorsal anterior cingulate cortex. A single administration of N-acetylcysteine (NAC) at a dose of 2400mg lowered these levels.
Healthy (non-addicted) participants who received the same administration of NAC did not show the same drop in glutamate levels.
The study also observed levels of impulsivity in the patients. Higher baseline levels of glutamate were associated with greater impulsivity, and both higher baseline level of glutamate and greater impulsivity were predictive of a larger drop in glutamate levels following NAC administration.
The researchers suggest that these findings may eventually be used in the treatment of cocaine-addicted people, since abnormal glutamate levels are related to risk of relapse. In drug-dependent rodents, NAC was found to normalize hyper-responsive glutamate release in the nucleus accumbens (the brain’s reward center) and prevent cocaine-reinstatement or relapse.
Editor’s Note: When these data from the lab of Peter Kalivas at the Medical University of South Carolina were initially collected, it was thought that NAC’s effect on a cystine-glutamate exchanger in the nucleus accumbens explained its treatment success, but new data suggest that NAC may actually facilitate glutamate clearance by increasing the number of glutamate transporters in glial cells.
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.