Bipolar disorders are relatively common psychiatric conditions with a lifetime prevalence of up to 4%. At least a quarter of sufferers will have a history of suicide attempts, with 10-20% of all patients ending their life by their own hand. Relapse, the recurring nature of the condition unless adequately treated, can gradually take its toll on the patient’s quality of life. The average patient experiences a major relapse every 17 to 30 months, with episodes frequently lasting between three and six months.

There are a variety of conventional mood stabiliser medications used in the treatment of bipolar, such as lithium and several antipsychotics and anticonvulsants. These drugs are an important component of treatment but may leave some patients with a shortfall in their recovery. The challenge for many clinicians is to ensure adequate long-term control of bipolar. Thus, new treatments are continually being sought from novel pathways with better efficacy profiles.

Over the years, the pathophysiology of bipolar disorder has continually been refined. The relationship between cell loss in specific regions of the brain and bipolar disorder is well documented. Recently however, the focus of research has been to further investigate how the oxidative pathways of ‘free radicals’ are linked to bipolar disorder and thus, the new types of treatment options available.

Free radicals are present in normal physiological processes and serve essential biological purposes in cellular signalling, immunological and inflammatory responses. Normally the free radicals are counterbalanced by a scavenging system. However, in disease the free radicals have the potential to cause cellular dysfunction and damage; this is known as oxidative stress.

There are two theories on how the body can undergo oxidative stress; the first being dysfunction of the mitochondria in the brain, and the second is dysfunction of the primary antioxidant ‘scavenger’ glutathione (GSH).

Mitochondria are structures inside cells which generate the body’s energy. The mitochondria can become damaged during oxidative stress and impairment of the mitochondria can lead to further oxidative stress and cell death. In turn, GSH is vulnerable to depletion during oxidative stress. These two processes can create a vicious cycle of damage and disrupt cellular homeostasis. Thus, interventions that restore GSH balance can intervene in this cycle of oxidative damage and prevent long-term illness.

GSH is not orally bioavailable. Synthetic versions of oral GSH and L-cysteine (precursor to GSH) have been ineffective due to poor blood-brain barrier transfer and/or first pass metabolism. However an agent that has been gaining increasing interest is N-acetylcysteine (NAC). NAC, also known just as acetylcysteine, is the N-acetyl derivative of the amino acid L-cysteine and is the precursor to the in vivo formation of glutathione. Oral administration of NAC allows good blood-brain barrier penetration and therefore increases in GSH levels. NAC can reverse mitochondrial toxicity; it has robust antioxidant effects and can enhance neurogenesis and reduce inflammation.

The discovery of NAC in the treatment of bipolar has been a case of an old medicine with a new indication. NAC has been used in the treatment of paracetamol poisoning for over 30 years. Newer indications include its use as a mucolytic, treatment of HIV, and in contrast-induced nephropathy. NAC can also be purchased from health food stores as an antioxidant supplement.

The results of some preliminary studies are positive in demonstrating the efficacy of NAC. In a recent 6-month double-blind, randomised, placebo-controlled study by Berk and colleagues, 2000mg daily of NAC or placebo was added to the existing treatment of 75 bipolar disorder sufferers.

Participant symptoms were measured using various rating tools such as the Montgomery-Asberg Depression Rating Scale (MADRS), the Bipolar Depression Rating Scale, the Quality of Life Enjoyment and Satisfaction Questionnaire, etcetera during the study, and also after completion of the study. Of significance was the difference in scores of the MADRS (a strong measure of depression) where the NAC group scored nine points better than placebo at endpoint, although similar at washout.

The recommended dose of NAC for bipolar is two x 500mg capsules, three times a day. Some side effects of NAC may include gastrointestinal upset (such as diarrhoea, constipation, nausea and heartburn). Rare side effects include aggravation of asthma, stomatitis, rhinorrhea, fever, and sedation.

Since its use in bipolar disorder, there has been growing interest in the use of NAC in other fields of psychiatry including addiction, obsessive-compulsive disorder, trichotillomania, grooming disorders, and schizophrenia. These initial results appear positive and require further research. NAC may also provide an opportunity for an alternative treatment option for these areas of psychiatry where current treatment options are limited or suboptimal.


  1. Angst J, Sallero R. Historical perspectives and natural history of bipolar disorder. Biol Psychiatry 2000; 48: 445–57.
  2. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder – a double blind randomised placebo-controlled trial. Biol Psychiatry 2008; 64(6): 468–75.
  3. Carlson PJ, Drevets WC, Manji HK, Singh JB, Zarate CA. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 2006; 3(1): 22–41.
  4. Dodd S, Dean O, Copolov DL, Malhi GS, Berk M. N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther 2008; 8(12): 1955–62.
  5. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem 2006; 97(6): 1634–58.
  6. Kessler RC, Berglund P, Demmler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593–602.
  7. Scalley RD, Donner CS. Acetaminophen poisoning: a case report of the use of acetylcysteine. Am J Hosp Pharm 1978; 35(8): 964–7.
  8. Schieke S M, Finkel T. Mitochondrial signalling, TOR, and life span. Biol Chem 2006; 387(10–11): 1357–61.
  9. Zarate CA, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006; 59(11): 1006–20.

Subscribe Knowledge Centre Updates

Enter your details to receive Knowledge Centre updates