Research reportCurcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study
Introduction
Disturbances in monoaminergic neurotransmission, particularly around serotonin availability, were originally posited as the primary cause of major depression (Cowen, 2008). However, studies now confirm that major depression is associated with a large array of biological disturbances. These include dysregulation in the hypothalamus-pituitary-adrenal (HPA) axis, activation of immune-inflammatory pathways, increased oxidative and nitrosative stress, neuroprogression, and mitochondrial dysfunction (Leonard and Maes, 2012, Maes et al., 2011). Consequently, this has sparked interest in compounds that target these pathways. Examples include anti-inflammatory treatments influencing immuno-inflammation such as cyclooxygensase-2 (COX-2) inhibitors, aspirin, minocycline and polyunsaturated fatty acids (Berk et al., 2013a, Fond et al., 2014, Muller, 2013) and antioxidant therapies to increase antioxidant defences and lower free radical damage such as n-acetyl cysteine, Ebselen, vitamin E and coenzyme-Q10 (Berk et al., 2013b, Scapagnini et al., 2012). Interestingly, despite pharmaceutical antidepressants originally being heralded as targeting monoaminergic actions, there is also evidence that they can modulate immuno-inflammation, reduce oxidative stress, enhance neurotrophic factors and influence HPA activity (Abdel-Wahab and Salama, 2011, Andrade and Rao, 2010, Hannestad et al., 2011, Kocki et al., 2012, Schule, 2007).
Curcumin is the most active compound of the Indian spice turmeric and comprises 2–8% of most turmeric preparations (Sharma et al., 2005). Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a low molecular weight polyphenol, first chemically characterised in 1910 by Milobedzka et al. (1910) and influences all of the aforementioned biological mechanisms (Aggarwal and Harikumar, 2009, Lopresti et al., 2012). More specifically, curcumin is a potent antioxidant that can lower markers of oxidative stress (Naik et al., 2011, Rai et al., 2010), modulate immuno-inflammation by acting as a COX-2 inhibitor (Lee et al., 2011, Plummer et al., 1999) and lower pro-inflammatory cytokines (Basnet and Skalko-Basnet, 2011, Belcaro et al., 2010), provide significant neuroprotection (Huang et al., 2011, Xu et al., 2007), modulate HPA activity (Huang et al., 2011, Li et al., 2009) and influence monoamine transmission through its effect on serotonergic and dopaminergic activity (Bhutani et al., 2009, Kulkarni et al., 2008, Xia et al., 2007). In animal studies, antidepressant effects of curcumin have been attributed to its serotonergic, dopaminergic, neuroprotective and HPA-modulating effects (Huang et al., 2011, Kulkarni et al., 2008, Xu et al., 2006). Two clinical trials have also now been completed investigating the antidepressant effects of curcumin in people with major depression. In the first study, curcumin as an add-on to antidepressant therapy did not enhance treatment outcome (Bergman et al., 2013), whereas in the second trial curcumin demonstrated similar antidepressant efficacy to fluoxetine (Sanmukhani et al., 2014). However, the latter study lacked a placebo-control and volunteers were not blinded.
The purpose of this study was to expand investigation into the antidepressant effects of curcumin supplementation in people with major depressive disorder. It was hypothesised that treatment with curcumin would lead to greater antidepressant benefits than a placebo, reflected by reductions in the administered depression and other mood-related self-report questionnaires. Curcumin was also hypothesised to have greater benefits for participants with atypical depression as it is associated with dysregulated immune-inflammatory pathways (Hickman et al., 2014, Lamers et al., 2013).
Section snippets
Study design
This study was an 8-week, randomised, double-blind, placebo-controlled clinical trial (Fig. 1). The trial protocol was approved by the Human Research Ethics Committee at Murdoch University, Western Australia. The trial was registered with the Australian New Zealand Clinical Trials Registry (no. 12612001260819) and participants were recruited between February and November 2013, across the Perth, Western Australia metropolitan area. Recruitment occurred through advertisements and promotions in
Baseline questionnaire and demographic information
Seventy-seven people were screened for participation in the study and 56 met inclusion/exclusion criteria and were enrolled to participate. Twenty-eight people were randomised into the placebo group and 28 into the treatment (curcumin) group. Fifty-two participants completed up to week 8. There were 4 drop-outs, one from the placebo group and three from the curcumin group, with no significant difference between the dropout rate in each group. Reasons for withdrawal included an unexpected visit
Discussion
The results of this study provide partial support for the antidepressant and anxiolytic effects of curcumin in people suffering from major depressive disorder. While curcumin and placebo were equally effective in reducing depressive and anxiety symptoms in the first four weeks of treatment, curcumin was significantly more effective than placebo in lowering self-reported depressive and anxiety symptoms from weeks 4 to 8. When examining the effects of curcumin in people with atypical depression,
Limitations and directions for future research
The relatively small samples size used in this study limits the reliability and statistical power associated with the findings. For evaluation of curcumin׳s antidepressant effects, data from approximately 50 participants was obtained. Sample sizes were even lower when evaluating the effects of curcumin on people with atypical depression. The results from this study therefore require replication with larger sample sizes.
In this study, a high proportion (approximately 70%) of participants
Conflict of interest
This study was supported in part by a grant from Arjuna Natural Extracts Limited to Murdoch University.
The authors report no biomedical financial interests or potential conflicts of interest.
Role of funding source
Financial assistance for this study was provided by Arjuna Natural Extracts Limited.
Acknowledgements
The authors acknowledge the gracious help of Arjuna Natural Extracts Limited for providing curcumin capsules and financial assistance to conduct the study. We also acknowledge infrastructure support provided by NCRIS BioPlatforms Australia.
References (56)
- et al.
Venlafaxine protects against stress-induced oxidative DNA damage in hippocampus during antidepressant testing in mice
Pharmacol. Biochem. Behav.
(2011) - et al.
Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases
Int. J. Biochem. Cell Biol.
(2009) - et al.
The promise of N-acetylcysteine in neuropsychiatry
Trends Pharmacol. Sci.
(2013) - et al.
Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes
Pharmacol. Biochem. Behav.
(2009) - et al.
IDS-C and IDS-sr: psychometric properties in depressed in-patients
J. Affect. Disord.
(1999) Serotonin and depression: pathophysiological mechanism or marketing myth?
Trends Pharmacol. Sci.
(2008)- et al.
Curcumin reverses corticosterone-induced depressive-like behavior and decrease in brain BDNF levels in rats
Neurosci. Lett.
(2011) - et al.
Antidepressant-like effects of curcumin in chronic mild stress of rats: involvement of its anti-inflammatory action
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2013) - et al.
Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression
Neurosci. Biobehav. Rev.
(2012) - et al.
Antidepressant-like effects of curcumin on serotonergic receptor-coupled AC-cAMP pathway in chronic unpredictable mild stress of rats
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2009)
The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression
Prog. Neuropsychopharmacol. Biol. Psychiatry
Protective effect of curcumin on experimentally induced inflammation, hepatotoxicity and cardiotoxicity in rats: evidence of its antioxidant property
Exp. Toxicol. Pathol.
Curcumin: the story so far
Eur. J. Cancer
The structure and dimensionality of the Inventory of Depressive Symptomatology Self Report (IDS-SR) in patients with depressive disorders and healthy controls
J. Affect. Disord.
Behavioral, neurochemical and neuroendocrine effects of the ethanolic extract from Curcuma longa L. in the mouse forced swimming test
J. Ethnopharmacol.
Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1 A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats
Brain Res.
Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB
Brain Res.
Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers
Br. J. Pharmacol.
Diagnostic and Statistical Manual of Mental Disorders
Bioavailability of curcumin: problems and promises
Mol. Pharm.
How antidepressant drugs act: a primer on neuroplasticity as the eventual mediator of antidepressant efficacy
Indian J. Psychiatry
Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment
Molecules
Efficacy and safety of Meriva(R), a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients
Altern. Med. Rev.
Curcumin as an add-on to antidepressive treatment: a randomized, double-blind, placebo-controlled, pilot clinical study
Clin. Neuropharmacol.
Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness
BMC Med.
Effectiveness and tolerance of anti-inflammatory drugs’ add-on therapy in major mental disorders: a systematic qualitative review
Acta Psychiatr. Scand.
Clinical patterns and treatment outcome in patients with melancholic, atypical and non-melancholic depressions
PLoS One
The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis
Neuropsychopharmacology
Cited by (144)
Targeting neuroinflammation by polyphenols: A promising therapeutic approach against inflammation-associated depression
2022, Biomedicine and PharmacotherapyEmulsion templated three-dimensional porous scaffolds for drug delivery
2022, Fiber and Textile Engineering in Drug Delivery SystemsShared metabolic and neuroimmune mechanisms underlying Type 2 Diabetes Mellitus and Major Depressive Disorder
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryReacting to prognostic covariate imbalance in randomised controlled trials
2021, Contemporary Clinical Trials