Professor Michael Berk
Mental Health Research Institute, VIC
Mental Health Research 2009
Professor Michael Berk is currently appointed to the Chair of Psychiatry for Barwon Health and The Geelong Clinic at The University of Melbourne. He also is an Honorary Professorial Research fellow at the Mental Health Research Institute, and leads the first episode Bipolar program at Orygen Youth Health. He is Chairman of the International Society of Bipolar Disorders, and Vice Chairman of the Australasian Society of Bipolar Disorders, and is a committee member of both the Collegium Internationale Neuro Psychopharmacologicum (CINP) and World Federation of Societies of Biological Psychiatry.
Professor Berk has published over 200 papers on a range of topics with his research interests focusing on mood and psychotic disorders, particularly bipolar disorder and depression. He has published 15 self-initiated randomised controlled trials, predominantly in bipolar disorder. These include:
► the first two published randomised trials of the atypical antipsychotics and lamotrigine in bipolar disorder, both of which are now established treatments
► the largest trials of verapamil in mania and norethisterone in depression and
► three Random Controlled Trials of antidepressants in schizophrenia
Professor Berk is regularly invited as a guest speaker at international meetings. He is the recipient of a number of current grants, including:
► a NHMRC CCRE grant
► 3 NHMRC project grants
► a beyondblue grant
► a 2009 Australian Rotary Health Mental Illness Research Grant
He received two Stanley Medical Research Institute awards and he is the principal investigator on a number of current trials. These include two randomised placebo controlled trials of N-acetyl cysteine in both depression and Bipolar Disorders. They follow up two positive trials of NAC in schizophrenia and bipolar disorder that have broken new ground in establishing both an entirely novel treatment and implicating a novel mechanism of disease.
Professor Berk was the founding editor of The Journal of Depression and Anxiety, has served as guest editor, and is on the editorial board of four other journals as well as being a reviewer of 26 other journals.
SUMMARY OF PROJECT:
Antioxidants In Unipolar Depression: A Double Blind Randomised Placebo Controlled Trial of N-Acetyl Cysteine
Hypothesis: Adjunctive N-acetylcysteine (NAC) will lead to superior outcomes in the treatment of Major Depressive Episodes (MDE) compared with treatment-as-usual.
Background: Unipolar depression is a Major Depressive Disorder (MDD) characterized by depressed mood, lack of interest in activities, changes in weight and sleep, fatigue, feelings of worthlessness and guilt, difficulty concentrating and thoughts of death and suicide. If a person experiences most of these symptoms for longer than a two-week period they may be diagnosed with MDD.
Unipolar depression is a common condition. Despite the availability of various classes of antidepressants it is has poor remission rates. Its frequency and limited response to treatment contribute to its considerable illness burden and socio-economic costs.
There is a persuasive collection of studies that support the critical role of oxidative stress in the pathophysiology of MDD, thus introducing a promising new framework for therapeutic intervention. A number of studies have confirmed altered levels of antioxidants and antioxidative enzymes in patients with MDE. These patients also had increased oxidative products, particularly lipid peroxidation – where free radicals rob electrons from the lipids in cell membranes resulting in cell damage.
The scale of these changes correlated positively with the severity of patients’ depressive illness symptoms. These markers returned to normal with symptom reduction. Antidepressants are known to reduce oxidative stress. It has been proposed that oxidative stress mediates, through oxidative neuronal damage, the progressive brain structural changes in depression. Targeting oxidative stress in treatment may therefore be of value in both symptomatic improvement and neuroprotection.
NAC delivers l-cysteine in a bioavailable form, which enhances the production of glutathione (GSH), as the supply of l-cysteine is a rate-limiting step in GSH synthesis. Of all endogenous antioxidants, GSH has the broadest antioxidant action and is the most favourable therapeutic mediator in oxidation biology. NAC replenishes brain GSH and has neuroprotective effects in animal models.
Professor Berk’s research group has completed two placebo-controlled trials of NAC as adjunctive treatment in schizophrenia and bipolar disorder.
Research Plan: This study is a 12-week, double-blind, randomised, placebo-controlled trial of adjunctive NAC in the treatment of MDD. Sites include Geelong, Bendigo and Sydney, with a target sample size of 120. Patients included into the trial must fulfil the DSM-IV-TR diagnostic criteria for Major Depressive Disorder, Single Episode or Recurrent, as well as scoring 18 or over on the MADRS. Change in symptomatic measures of depression and anxiety, global illness status, quality of life, functioning, substance use and tolerability will be assessed.
Outcomes and significance: Existing antidepressants act primarily on monoamine neurotransmitters and have limited efficacy. There is now convincing evidence to support an intrinsic role of oxidative stress in the pathophysiology of MDD, and the available clinical trial data indicate the potential efficacy of NAC in treating depressive symptoms.
Our completed clinical trials of NAC in schizophrenia and bipolar disorder have provided infrastructure, experience and collaborations, which create a secure basis for the efficient conduct of this trial. This trial can confirm the therapeutic value of NAC in MDD, which may lead to the introduction of a safe and well-tolerated treatment option, and direct clinical benefits in symptomatic treatment.
NAC is a safe, tolerable and affordable option, with the added appeal of being a nutraceutical agent. Pursuing this new treatment founded on oxidative stress pathophysiology holds promise in the development of pharmacotherapeutics to address the current inadequacies in MDD treatment and illness burden.