Michael Berk, MD, PhD

Serendipity has played a significant role in many scientific advancements in mental health throughout history, like the discovery of lithium as a treatment for bipolar disorder. Now more than ever, we are in desperate need of similarly impactful discoveries in mental health. Adopting a serendipity mindset—the ability to use uncertainty as a pathway to a more successful and purposeful life—to reverse engineer the systems needed for more breakthroughs, and to span and fuse disciplines, might be the way to achieve this.

The Leading Cause of Ill-Health and Disability

The world is in the throes of a global mental health crisis with severe physical, social, and economic ramifications. According to a recent World Health Organization (WHO) 

, around 450 million individuals currently suffer from mental health conditions, marking mental health disorders among the leading causes of ill-health and disability worldwide.

 Mental disorders account for 5 out of the top 10 causes of global disability. Although treatments are available, 

 of individuals with a known mental health disorder will never seek help from a health professional.

 Surveys in India and China, which represent a third of the global population, have suggested this number is even higher, with more than 80% of people with any mental health or substance use disorder not seeking treatment. In part, this is due to the pervasive stigma of mental illness that permeates societies and healthcare systems, resulting in systemic underinvestment in mental health.

When individuals do seek help, they may not be able to receive the care they need. According to a recent report from a team of 28 global experts assembled by Lancet, the world’s failure to respond to the mental health crisis has resulted in a “

monumental loss of human capabilities and avoidable suffering.

 The commission estimates more than 13 million lives could be saved every year if mental illness was treated properly—or at all. Alongside the profound costs of human lives and avoidable suffering, there are colossal financial ramifications. Indeed, epidemiological modelling suggests the rising cost of mental illness will hit $16 trillion USD by 2030.

 COVID-19 has amplified many of these issues, triggering social and physical distancing, economic hardship, and challenges in accessing care. 

The 21st century will be largely defined by our collective response to the global mental health crisis—and beacons of hope are beginning to emerge. Stigma is reducing, awareness is increasing, allowing people to slowly overcome back the barriers to seeking care. Meanwhile, venture capital funding for mental health start-ups has been growing rapidly and accelerated even more during COVID. 

 showed 146 deals ranked in nearly $1.6 billion in venture capital investments as of December 10th, 2020.

 A decade ago, there were only 3 deals, worth $6.6 million, whereas last year the total was $893 million from 111 deals. However, these advances on their own will not be able to solve the above stated global challenges. A paradigm shift is needed to solve the unprecedented complexities and challenges associated with the current global mental health crisis. This shift will require the education of governments and healthcare systems of the world, empowerment of consumers to take charge of their own mental health, and the use of technology both for prevention and treatment of mental disorders.

Convergence Mental Health as a Mechanism for Serendipity

Mental health is a prototypical wicked problem in that it embodies large numbers of diverse factors from biology, sociology, genetics, and psychology to economics and beyond.

 can counteract those influences and ease the anxiety that comes with the inherent unpredictability of the world. This outlook centers on being the agent of one’s own good luck. An individual can shift from a passive victim of circumstance to an active creator of opportunities by embracing the uncertainty that happens each day.

 Training the serendipity muscle in turn trains one’s ability to solve problems by identifying positive outcomes from situations and making accidents more meaningful. 

Interdisciplinary collaboration is the driver of serendipity. Those who operate with a serendipity mindset are not luckier than others, but rather cultivate luck and solutions by consistently seeking out new experiences and reaching across multiple industries. Convergence science is “an approach to problem solving that cuts across disciplinary boundaries. It integrates knowledge, tools, and thought strategies from various fields for tackling challenges that exist at the interfaces of multiple fields.”

 It can be a mechanism for serendipity through integration of knowledge, tools, and thought-strategies from various fields for tackling challenges that exist at the interface of multiple disciplines.

In the context of mental health, convergence science involves the integration of scientists, clinicians, bioinformaticists, global health experts, social scientists, health economists, engineers, technology entrepreneurs, medical educators, caregivers, and patients—we call this Convergence Mental Health.

 Synergy between government, academia, and industry is also vital. Convergence science is the Ariadne thread necessary to navigate the intricate labyrinth of global mental health problems, bringing about urgently needed progress in science and society. Examples of Convergence Mental Health-associated advances are outlined in the 

Table. Convergence Mental Health-Associated Advances

Innovations at all different levels are urgently needed. Solutions will need sociologists, psychologists, philosophers, ethicists, scientists, media practitioners, crisis management experts, policy makers, senior civil servants, and more. 

 provides direction for these shifts in how teams work. As COVID-19 has demonstrated, distance does not stop the wheel of innovation, and in fact can propel it by lowering the perceived barriers to novel ways of working and collaborating. As we embark on building the new normal, Convergence Mental Health will play a key role in this rapidly unfolding change.

 provides a historic opportunity to lead to a new era of innovation and progress, leading to improved outcomes for all people and preparing psychiatry to meet the unprecedented mental health challenges of the 21st century. By adopting a serendipity mindset, we can learn to harness uncertainty to create unique solutions across industries.

is an associate with the PRODEO Institute and Thiel Fellow at Stanford University.

is Director of Innovation at a major mental health association and expert in residence at Georgetown University, and the author of

 is a masters candidate in Global Affairs from New York University. 

is Senior Advisor to the OECD Secretary General and Head of the New Approaches to Economic Challenges Unit at the OECD.

is a professor of psychiatry at University of California in Los Angeles (UCLA).

professor of psychiatry at the Institute for Mental and Physical Health and Clinical Translation (IMPACT) at Deakin University.

cofounder of the PRODEO Institute, adjunct associate professor with IMPACT at Deakin University, and co-lead of the OECD Neuroscience-inspired Policy Initiative.

The World Health Report 2001: Mental health: new understanding, new hope

2. Bosely S. World in mental health crisis of ‘monumental suffering’, say experts

https://www.theguardian.com/society/2018/oct/09/world-mental-health-crisis-monumental-suffering-say-experts

3. Patel V, Saxena S, Lund C, et al. The Lancet Commission on global mental health and sustainable development.

4. Lee JL. Mental health tech startups fetch record investments with COVID-19. 

https://www.reuters.com/article/health-coronavirus-mental-health/mental-health-tech-startups-fetch-record-investments-with-covid-19-idUKKBN28P1SA

Convergence: Facilitating Transdisciplinary Integration of Life Sciences, Physical Sciences, Engineering, and Beyond

7. Eyre HA, Berk M, Lavretsky H, Reynolds C. 

8. Eyre HA, Lavretsky H, Forbes M, et al. Convergence science arrives: how does it relate to psychiatry? 

10. Richardson S, Sinha A, Vahia I, et al. Brain health living labs. 

Why mental health matters to global health.

12. Shah RN, Berry OO. The rise of venture capital investing in mental health. 

13. Chang DD, Storch EA, Black L, et al. Promoting tech transfer between space and global mental health. 

14. Ternes K, Iyengar V, Lavretsky H, et al. Brain health INnovation Diplomacy: a model binding diverse disciplines to manage the promise and perils of technological innovation. 

15. Smith E, Ali D, Wilkerson B, et al. A Brain Capital Grand Strategy: toward economic reimagination. Mol Psychiatry. 2021;26(1):3-22.

16. New Approaches to Economic Challenges, PRODEO Institute. Neuroscience-inspired Policy Initiative. Organisation for Economic Co-operation and Development. Accessed March 23, 2021. 

Articles

This mindset might be the key to mental health breakthroughs. 

Feeling Lucky? Convergence Mental Health as a Mechanism for Serendipitous Innovation

Decades of research have investigated inflammation and mental illness, suggesting that there is a robust and complex link. However, the link lacks diagnostic specificity and varies considerably among individuals, and with each stage of illness. Chronic, low-grade 

appears to precede the initial illness episode, at least in some individuals.

 Drugs that modulate the immune system may also affect an individual’s mood and have possible psychiatric adverse effects (AEs). Perhaps the best example is that interferon-α treatment of hepatitis C precipitates depressive episodes.

 is associated with reduction in inflammatory markers.

Statins are best known as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statin treatment results in lower low-density lipoprotein cholesterol levels and in benefits to cardiovascular health. Statins also have anti-inflammatory mechanisms of action, including T-cell downregulation, suppression of cytokines, production of chemokines and C-reactive protein, and downregulation of transcription factors.3 In a post hoc, pooled analysis (N = 969) of data collected at baseline and at a 1-year follow-up from a study of patients with acute coronary syndrome, statin treatment was shown to reduce levels of interleukin (IL)-6 and IL-18. Raised levels of these cytokines appeared to predict depression after acute coronary syndrome.

Many epidemiological studies have shown that 

 is associated with a lower risk for depression (

 A population cohort study (N = 4,607,990) using Swedish national registry data investigated the relationship between statin use and the development of depression. The use of any statin was associated with an 8% decrease in risk for depression (odds ratio [OR], 0.92) compared with individuals who did not use statins.

 Elsewhere, in a cohort of individuals 55 years and older (N = 2804), statin use was associated with decreased depression (OR, 0.71).

 However, no association between statin use and depression was determined in an analysis of data from 19,114 individuals, most of whom were 70 years and older, of whom 5987 used statins.

Evidence from clinical trials suggests that, adjuvant to treatment with antidepressants, some statins are associated with better treatment outcomes. A 

 showed that treatment with lovastatin, atorvastatin, and simvastatin, adjunctive to antidepressant treatment, was superior to treatment with a placebo adjunctive to antidepressant treatment for improving depression (indexed by the Hamilton Depression Rating Scale).

 More recently, the results of a trial of rosuvastatin for young individuals with depression indicated that rosuvastatin failed to beat the placebo on the primary outcome, but it was positive on a number of secondary outcome measures, leaving the benefit uncertain.

A trial comparing simvastatin (n = 33) with placebo (n = 33) in participants with schizophrenia treated with risperidone found significantly higher reduction in the first group in negative symptom scores (P = .003) and total score (P = .001). These results measured the time period from baseline to week 8, using the Positive and Negative Syndrome Scale (PANSS).

 Simvastatin did not significantly differ from placebo for treating schizophrenia in an underpowered study (N = 36).

Two meta-analyses of statin add-on therapy in the antipsychotic treatment of schizophrenia have been conducted. 

 identified 5 randomized controlled trials (N = 236) showing improvement of PANSS total score, but not of PANSS subscale scores.

 The meta-analysis included studies of atorvastatin, lovastatin, pravastatin, and simvastatin. Risperidone was used in 3 studies; antipsychotic use was varied or not reported for 2 studies. 

 identified 6 randomized controlled trials (N = 339) showing benefit for improvement of PANSS positive and negative subscales.

 The meta-analysis by Shen et al included all 5 trials from the Nomura et al meta-analysis plus an additional trial of simvastatin versus placebo.

 have been associated with an increased risk for cardiovascular disease (CVD), independent of psychotropic medication use. This comorbidity is bidirectional, since depression is a common outcome after myocardial infarction and is also associated with higher comorbidity and mortality.

 In this context, treatment with statins may have an important dual purpose, with benefits to both mental and cardiovascular health. Evidence from a nested case-control study has shown that exposure to statins and aspirin is associated with a reduced risk of de novo major depression.

Atorvastatin, lovastatin, and simvastatin are lipophilic, while pravastatin, rosuvastatin, pitavastatin, and fluvastatin are hydrophilic. The lipophilic statins readily cross the blood-brain barrier. Hydrophilic statins or their active metabolites may also be detected in the brain, although less readily. Laboratory studies have suggested that statins may be neuroprotective against a range of neurotoxic insults, but statins themselves may be neurotoxic at higher concentrations than those obtained at therapeutic doses.

The best evidence that statins reduce markers of inflammation is derived from the JUPITER study of rosuvastatin.

 It is unclear whether brain penetrance or reduction in peripheral markers of inflammation is the more important mechanism in terms of potential therapeutic efficacy.

There is a potential for drug-drug interactions between statins and psychotropic agents (

). Psychotropic agents with lower cytochrome P450 (CYP450)activity should be considered ahead of those with known strong CYP450 activity to reduce the risk of pharmacokinetic drug-drug interactions.

 Andrade suggests that risks of pharmacokinetic drug-drug interactions between selective serotonin reuptake inhibitors (SSRIs) and statins are negligible at standard therapeutic doses for escitalopram, citalopram, and paroxetine with rosuvastatin, pitavastatin, and pravastatin; there is possible but low risk of interactions for combinations of fluvoxamine with atorvastatin, simvastatin, or lovastatin.

 A study of blood specimens collected from elderly patients (N = 194) investigated the interactions between statins and antiepileptic drugs, including the mood stabilizers lamotrigine and carbamazepine. Carbamazepine, but not lamotrigine, significantly interfered with 

, with lipids reduced for patients taking either drug but significantly greater reduction in lipids for those taking 

 Risks of adverse events may be greater in elderly cohorts compared to nonelderly individuals.

Antipsychotics may upregulate gene expression of lipid metabolism pathways, resulting in metabolic side effects, weight gain, and dyslipidemia. Individuals receiving antipsychotics may have reduced response to treatment with statins for dyslipidemia, with a common gene variant (SREBF1) for a transcription factor in the lipid metabolism pathway.

 Dyslipidemia in individuals treated with antipsychotics may benefit from personalised treatment plans, in which statins may have an important but variable role.

In the clinical setting, medication changes, dose adjustments, and polypharmacy are common in psychiatric practice and are associated with a greater risk of adverse effects. Adding a statin to an existing regimen entails an additional risk that needs to be considered when the statin is first introduced and whenever there are changes to comedications throughout the course of treatment. Case reports on statins and psychotropic comedications have identified rare adverse events of rash,25 QTc interval prolongation,

Preliminary evidence, mainly from small studies, suggests that adjuvant treatment with a statin may be beneficial for individuals taking psychotropic drugs for depression and schizophrenia. People with depression, bipolar disorder, and schizophrenia are substantially more vulnerable to metabolic syndrome and earlier age of mortality than the general population, predominantly from CVD. Such medical comorbidities warrant aggressive prophylactic therapy with available agents, including statins. Thus, there is sufficient evidence to suggest that combining statin therapy with antidepressant or antipsychotic therapy may be sensible for patients with comorbidities when both pharmacotherapies are indicated. However, adjuvant treatment with a statin purely as an augmentation strategy for psychopharmacotherapy is still experimental. Although there is a good theoretical basis and promising preliminary data, further research is required, especially larger, multisite, placebo-controlled randomized clinical trials.

 is a principal fellow in the Department of Psychiatry, University of Melbourne, a clinical associate professor at the Centre for Youth Mental Health, University of Melbourne, and a clinical associate professor in the School of Medicine, Deakin University, Melbourne, Australia. D

is a psychiatrist in the Hospital Clinic de Barcelona in Spain and a researcher at IMPACT, Univer-sity Hospital Geelong, Australia. 

is the Alfred Deakin Professor of Psychiatry and director of IMPACT, the Institute for Mental and Physical Health and Clinical Translation, Deakin University, Melbourne, Australia.

Inflammation and depression: a causal or coincidental link to the pathophysiology?

2. Qato DM, Ozenberger K, Olfson M. Prevalence of prescription medications with depression as a potential adverse effect among adults in the United States. 

3. Kim SW, Kang HJ, Jhon M, et al. Statins and inflammation: new therapeutic opportunities in psychiatry. 

4. Kim SW, Kang HJ, Bae KY, et al. Interactions between pro-inflammatory cytokines and statins on depression in patients with acute coronary syndrome. 

Prog Neuropsychopharmacol Biol Psychiatry. 

5. Köhler O, Benros ME, Nordentoft M, et al. 

Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials

6. Redlich C, Berk M, Williams LJ, . Statin use and risk of depression: a Swedish national cohort study. 

7. Feng L, Tan CH, Merchant RA, Ng TP. Association between depressive symptoms and use of HMG-CoA reductase inhibitors (statins), corticosteroids and histamine H(2) receptor antagonists in community-dwelling older persons: cross-sectional analysis of a population-based cohort. 

8. Agustini B, Mohebbi M, Woods RL, et al; ASPREE Investigator Group. Association between statin use and depressive symptoms in a large community-dwelling older population living in Australia and the USA: a cross-sectional study. 

9. Salagre E, Fernandes BS, Dodd S, Brownstein DJ, Berk M. 

Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials

10. Quinn AL, Dean OM, Davey CG, et al. Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin. 

11. Tajik-Esmaeeli S, Moazen-Zadeh E, Abbasi N, et al. Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial. 

12. Chaudhry IB, Husain N, Drake R, et al. Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: pilot study.

13. Nomura I, Kishi T, Ikuta T, Iwata N. 

Statin add-on therapy in the antipsychotic treatment of schizophrenia: a meta-analysis

Adjunctive therapy with statins in schizophrenia patients: a meta-analysis and implications

15. Van der Kooy K, van Hout H, Marwijk H, et al. Depression and the risk for cardiovascular diseases: systematic review and meta analysis. 

16. Batelaan NM, Seldenrijk A, Bot M, et al. Anxiety and new onset of cardiovascular disease: critical review and meta-analysis. 

17. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. 

18. Williams LJ, Pasco JA, Mohebbi M, et al. Statin and aspirin use and the risk of mood disorders among men. 

19. Wood WG, Eckert GP, Igbavboa U, Müller WE. Statins and neuroprotection: a prescription to move the field forward. 

20. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. 

21. Palleria C, Roberti R, Iannone LF, et al. 

Clinically relevant drug interactions between statins and antidepressants

22. Andrade C. Selective serotonin reuptake inhibitor drug interactions in patients receiving statins. 

23. Mintzer S, Trinka E, Kraemer G, et al. 

Impact of carbamazepine, lamotrigine, and levetiracetam on vascular risk markers and lipid-lowering agents in the elderly

24. Vassas TJ, Burghardt KJ, Ellingrod VL. Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychotics. 

25. Walder A, Baumann P. Mood stabilizer therapy and pravastatin: higher risk for adverse skin reactions? 

26. Furst BA, Champion KM, Pierre JM, et al. Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin. 

27. Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. 

Preliminary studies suggest that adjuvant treatment with a statin may be beneficial for patients who are also prescribed psychotropic drugs for depression and schizophrenia.

The Psychiatric Potential of Statins 

The goal of this activity is to provide an understanding of N-acetylcysteine, an agent with several mechanisms of action and efficacy in various conditions.

After engaging with the content of this CME activity, you should be better prepared to:

• Discuss how N-acetylcysteine can be effective for unrelated conditions by having several mechanisms of action.

• Understand that N-acetylcysteine may be useful in psychiatry and has been successfully trialed as an adjunctive therapy.

• Feel confident considering using N-acetylcysteine in patients who may benefit from this treatment.

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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is a Psychiatry Resident, Bipolar and Depressive Disorders Unit, Institute of Neuroscience, University of Barcelona, Spain.

is Clinical Associate Professor; Dr Dean is Associate Professor (Research)

is Alfred Deakin Postdoctoral Research Fellow; and 

is Alfred Deakin Professor, Faculty of Health, School of Medicine, Deakin University, Victoria, Australia.

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

-Acetylcysteine (NAC) is a synthetic derivate of the endogenous amino acid L-cysteine (

) and a precursor of glutathione. It is known for its role in modulating oxidative stress and several pathophysiological processes, such as apoptosis, inflammation, mitochondrial dysfunction, and neurotransmission. The clinical benefits of NAC have been widely studied.

NAC is available in oral, inhalation, and intravenous (IV) formulations. When it is orally administered, NAC reaches peak plasma concentrations between 30 minutes and 1 hour. After being absorbed in the small intestine, NAC undergoes first-pass hepatic metabolism to be finally hydrolyzed to cysteine and available to synthesize glutathione, especially in the liver. Its oral bioavailability is poor, and that is the reason why IV formulation is preferred in acute paracetamol (acetaminophen) overdose.

The first clinical use of NAC was in the 1960s for cystic fibrosis. In the 1970s, its efficacy for the treatment of paracetamol overdose was discovered. Since then, a great number of applications have been attributed to NAC mainly due to its implication in oxidative stress. Recent studies suggest potential implications of NAC in several psychiatric disorders.

Reactive oxygen species, such as superoxide radical, hydrogen peroxide, and the hydroxyl radical, are products from oxidative phosphorylation of the mitochondria, where water is produced from molecular oxygen and also from peroxisomes, which degrade fatty acids into hydrogen peroxide. These oxidant agents can produce oxidative stress, which occurs when oxidants exceed the antioxidant capacity.

Glutathione exerts a protective effect on cells as an antioxidant defense, since its free sulfhydryl group provides a source to reduce equivalents to scavenge harmful reactive oxygen species. The antioxidant activity of glutathione peroxidase, a defense mechanism against peroxides, is also allowed by the reducing equivalents that glutathione provides.

Regarding NAC, its free sulfhydryl group and its role as a glutathione precursor make it an antioxidant agent. The mechanisms of NAC on its most studied therapeutic effects are well known. Regarding mucolysis, NAC breaks the disulfide bonds of mucus glycoproteins, thereby reducing mucus viscosity. As an antidote to paracetamol poisoning, NAC restores the hepatic glutathione pool depleted in the drug detoxification process. Current evidence shows that NAC can potentially improve the course of many other illnesses related to oxidative stress.

Apart from its efficacy as a mucolytic agent for the treatment of respiratory diseases, NAC has been found to increase alveolar surfactant, to have antioxidant, antimicrobial, and anti-inflammatory properties.

 This may explain why several clinical trials have assessed NAC for the treatment of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

In clinical practice, NAC is commonly used as an antidote to 

poisoning. Paracetamol is over 90% metabolized through phase II conjugation reactions, and a small part by cytochrome P450 2E1 to produce the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). After that, NAPQI is conjugated and detoxified with cellular glutathione, and a minimum quantity binds to proteins. When the amount of NAPQI is greater, protein adduct formation increases, including mitochondrial production, which promotes oxidative stress. Reactive species are responsible for acute liver injury induced by paracetamol overdose. Oxidative stress also activates a mitogen-activated protein (MAP) kinase pathway, which amplifies mitochondrial oxidative stress, leading to cell necrosis.

Considering that paracetamol hepatotoxicity is based on glutathione depletion, NAC can be considered a good 

for paracetamol overdose, which is the treatment of choice according to the established nomogram for paracetamol toxicity.

 It acts as a protector agent by scavenging NAPQI and by preventing protein adduct formation. Excess NAC not being used for glutathione synthesis is converted to Krebs cycle intermediates and supports mitochondria in order to produce higher ATP levels in hepatocytes and to avoid mitochondrial dysfunction, which is crucial in paracetamol-induced liver injury.

NAC has also been suggested to act as an antidote to other drugs, such as paraquat, mushroom toxins, essential oils, chloroform, carbon tetrachloride and heavy metals, but evidence is still limited.

The use of NAC has also been studied in cardiovascular diseases and in the prevention of contrast-induced nephropathy, but researches have yielded controverted results. NAC has shown favorable results in small clinical trials in ophthalmology. Regarding retinitis pigmentosa, cone photoreceptors death occurs due to the accumulation of oxygen in the retina as a product of rod cells death. Animal studies assessing NAC effects showed that it promoted cone cell function and survival in mice with retinitis pigmentosa.

Findings from animal models suggest that NAC has the potential for the treatment of chronic neuropathic pain.

 However, few human clinical trials have been conducted so far.

Other animal studies have also shown a beneficial action of NAC on cognition in cases of mitochondrial dysfunction, inherited metabolic disorders, heavy metal neurotoxicity, and Alzheimer disease, which is produced at least in part by increasing neuronal glutathione levels and by the maintenance of glutamate homeostasis.

The role of NAC in a great number of psychiatric disorders has been extensively studied.

 Many of these have a strong relationship with cognitive dysfunction, which is enhanced by oxidative stress. Some studies have shown that NAC significantly improves cognitive function in patients with neurological or psychiatric diseases, but the clinical relevance of the effects is still unclear. A great part of preclinical evidence has reported that NAC may be involved in glutamate homeostasis modulation.

Glutamate is the most abundant excitatory neurotransmitter in the CNS and participates in learning and memory processes. Its action enhances the influx of extracellular Ca2+, which is mediated by neuronal and glial membrane transporters in order to maintain the homeostasis of extracellular glutamate. NAC has demonstrated to activate presynaptic system Xc– (Sxc-) receptors, which mediate the exchange of extracellular cysteine and intracellular glutamate. When these presynaptic receptors are activated, glutamate release from excitatory nerve endings is inhibited. NAC also induces the expression of glutamate transporter-1 (GLT1) in astrocytes, which clears synaptic and extra-synaptic glutamate and enhances the maintenance of glutamate homeostasis.

Psychiatric and neurodegenerative disorders are known to be associated with excessive release of glutamate and impaired glutamate homeostasis. Current evidence suggests that NAC may be effective in treating various psychiatric conditions.

The hypothesized mechanism of action of NAC in substance use relies on the glutamate homeostasis hypothesis of addiction, where glutamate signaling in the nucleus accumbens has been disrupted. In drug-naive states, glutamate binds to postsynaptic receptors and glia clears excess of glutamate through the transporter GLT-1. The glia receptor Sxc- also enhances glutamate release by its exchange with cystine, thereby glutamate binds to presynaptic metabotropic receptors (mGluRs), which provides inhibitory feedback for further release (

Clinical data have supported the underlying hypothesis of imbalances in glutamate homeostasis in addictive brains by showing reductions in GLT-1 levels and of the catalytic union of Sxc-.

 This leads to an increase of extrasynaptic glutamate and thus the activation of postsynaptic N-methyl-d-aspartate (NMDA) receptors, which increases the risk of relapse. Another consequence is the reduction of presynaptic inhibition through mGluR2/3 receptors. When NAC is converted to cysteine, it is exchanged into the glia for glutamate, which provides inhibitory feedback on presynaptic receptors, thereby limiting the release of glutamate. NAC has also been shown to increase the expression of GLT-1 and Sxc- transporters.

 Given that NAC has been shown to help to reach the glutamatergic homeostasis, most investigations of NAC in psychiatry focus on the treatment of addictions.

The therapeutic activity of NAC relies on several mechanisms of action, such as the reduction of oxidative stress, modulation of mitochondrial dysfunction, apoptosis, inflammatory processes, and modulation of glutamate homeostasis.

A few double-blind, placebo-controlled trials have reported a decrease in cocaine-related withdrawal symptoms, less craving and less cocaine use with NAC. An open-label trial of NAC among cocaine users showed a reduction in biochemically confirmed cocaine use.

 Moreover, NAC improved retention rates and, after a 4-week period, most subjects either discontinued the use of cocaine or significantly reduced the use of cocaine during treatment. On the other hand, a large randomized trial did not show a reduction in active cocaine use, although NAC seemed to increase the time to relapse and reduced craving.

 In an open-label, randomized, cross-over study, cocaine-dependent patients showed higher glutamate levels in the dorsal anterior cingulate cortex compared with healthy controls.

 In a recent randomized, placebo-controlled trial, a 25-day treatment with NAC was associated with less cocaine consumption, but did not show beneficial effects on cocaine craving.

A randomized clinical trial showed that NAC reduced cannabis use in adolescents, but this was not evidenced in adults.

 This improvement did not seem to be related with craving changes.

Regarding smoking cessation, an open label-study assessing the combination of NAC and varenicline showed a reduction of cigarettes consumption as well as a reduction in craving and smoking reward.

 A few clinical trials showed a significant reduction in cigarette consumption after 12 weeks as well as increased rates of abstinence and reduced craving with NAC.

 However, other studies did not show a significant decrease in tobacco use. In a double-blind, placebo-controlled, 4-day study of 23 young adults NAC produced no difference in nicotine craving but reduced withdrawal scores and measures of the rewarding properties of the first cigarette posttreatment.

A clinical trial showed contrary results regarding the reduction of metamphetamine craving with NAC.

 Another trial found benefits of NAC in gambling disorder.

A systematic review of 9 studies confirmed the potential of NAC for the treatment of addiction, especially to cocaine and cannabis.

showed that NAC is superior to placebo in reducing drug craving.

Despite controversy in current clinical evidence, most of the studies showed a potential therapeutic effect of NAC in addiction disorders.

Anxiety involves disruptions in the hypothalamic-pituitary-adrenal (HPA) axis signaling pathways and affects the stress response, which may be associated with oxidative stress. So far, only a case study using NAC in anxiety has been reported.

ADHD is a neurodevelopmental disorder where a disruption of brain dopamine, norepinephrine and glutamate systems, as well as oxidative stress and mitochondrial dysfunction may be involved. However, clinical trials assessing NAC treatment are still lacking.

Regarding the pathophysiology of autism spectrum disorders, evidence suggests mitochondrial dysfunction, oxidative stress and abnormalities in redox regulation, immune dysfunction and inflammation, environmental toxicants and disruption in other metabolic processes, including folate and cobalamin.

 Although some controlled trials failed to show improvements on clinical outcomes in autism, one of them showed improvement in oxidative stress, and others to have benefits in irritability, social abilities, and aggression.

 Larger clinical trials are needed to assess the response of core autism symptoms to NAC.

Bipolar disorder has been related to oxidative stress, mitochondrial dysfunction, and immune dysregulation. High-quality studies have demonstrated that NAC can improve depressive symptoms during maintenance phase treatment, the scores in MADRS and Bipolar Depression Rating Scale (BDRS), response rate, symptom remission, quality of life, and functioning.

 Time to a new mood episode has not shown significant differences with the use of NAC versus placebo.

Animal studies have shown reductions in hippocampal mGlu2 receptors in mice that were not resilient to stress and higher susceptibility to stress in mice lacking mGlu2 receptor.

A synthetic derivate of the endogenous amino acid L-cysteine and a precursor of glutathion, N-Acetylcysteine shows promise for treating a variety of psychiatric disorders.

Michael Berk, MD, PhD

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