N-acetylcysteine appears to be promising in the treatment of several psychiatric disorders. Many of the psychiatric disorders discussed have shown only preliminary data regarding the efficacy of NAC in their treatment, and further research is required. However, NAC appears to be a promising therapeutic target and provides a window of treatment opportunity in a field where current treatments are limited or have remained suboptimal.
The apparent lack of specificity of NAC in initial studies is intriguing and suggests that it may be targeting pathways that are common across disorders; oxidative stress appears to be a fairly nonspecific finding in a range of psychopathologies, and dysregulation of glutamate, inflammatory pathways and DA are similarly widely reported. Given that the current diagnostic systems are phenomenologically based, and that in no other branch of medicine are phenomenology and pathophysiology linearly linked, this may reflect an intrinsic limitation of our classification system. This is high-lighted by the fact that there is extensive overlap of other treatments and biomarkers across disorders. As the body of evidence is currently provisional for many disorders, as the evidence base expands, it is possible that the efficacy will appear to be greater in some areas than others. Additionally, the precise dose of NAC remains to be definitively established. Dose-finding studies may reveal greater efficacy at higher doses or equal efficacy at lower doses. Whereas the tolerability profile of NAC appears benign, it needs to be stressed that there is no extensive evidence base with longer-term use. Some adverse events, such as pulmonary hypertension are reported in very high-dose animal studies, but have not been seen in human studies.79
Whereas NAC appears to be antiepileptic at low doses,80
seizures are reported with overdose.81
Vigilance is necessary.
Given that many of these disorders have many interacting potential pathophysiological pathways, further research is required to determine how NAC is exerting benefits. Bio-marker and neuroimaging platforms have the capacity to illuminate these issues. In disorders such as addiction, glutamate has been the primary candidate for the mechanism of action, whereas in schizophrenia and mood disorders, the GSH hypothesis has been the one postulated as explaining the mechanism of action of NAC. However, given the interaction between glutamate, the most abundant neurotransmitter, and other neurotransmitter pathways, including DA and serotonin, individuals with disorders such as depression and schizophrenia may benefit by indirect modulation of these pathways through changes in glutamatergic function. A common link in treatment efficacy may be oxidative stress, which has been shown to be altered in most of these disorders. However, in cocaine addiction, most of the research focusing on mechanisms of action has implicated the modulation of the cystine–glutamate antiporter by NAC as the most likely cause of benefit.26,82,83
Whereas there are similarities across these disorders with alterations to oxidative biology and neurotransmission, and changes in glutamate-dependent long-term potentiation and neuronal plasticity,84
perhaps the heterogeneity of the underlying pathologies, especially in brain regions implicated, may lead to the revelation of different actions of NAC depending on the disorder.
Similarly, the modulation of inflammatory pathways may also play a role in the benefits seen following NAC treatment. The role of inflammation in depression has received the greatest attention; however, inflammatory pathways are implicated in the etiology of other disorders, such as schizophrenia. As with the atypical antipsychotics, which have new data showing a diversity of mechanisms of action, including on inflammation,85
brain-derived neurotrophic factor86
and oxidative stress,87
efficacy may turn out to be a summative interaction of effects on various pathways.
Overall this unlikely therapeutic tool is implicating novel pathways as viable therapeutic targets. This opens the way for the development of other rational, hypothesis-based therapies. That NAC appears safe, tolerable and affordable and is readily available adds to its interest.