Curcumin and major depression: A randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change

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Abstract

A recent randomised, double-blind, placebo controlled study conducted by our research group, provided partial support for the efficacy of supplementation with a patented curcumin extract (500 mg, twice daily) for 8 weeks in reducing depressive symptoms in people with major depressive disorder. In the present paper, a secondary, exploratory analysis of salivary, urinary and blood biomarkers collected during this study was conducted to identify potential antidepressant mechanisms of action of curcumin. Pre and post-intervention samples were provided by 50 participants diagnosed with major depressive disorder, and the Inventory of Depressive Symptomatology self-rated version (IDS-SR30) was used as the primary depression outcome measure. Compared to placebo, 8 weeks of curcumin supplementation was associated with elevations in urinary thromboxane B2 (p<0.05), and substance P (p<0.001); while placebo supplementation was associated with reductions in aldosterone (p<0.05) and cortisol (p<0.05). Higher baseline plasma endothelin-1 (rs=−0.587; p<0.01) and leptin (rs=−0.470; p<0.05) in curcumin-treated individuals was associated with greater reductions in IDS-SR30 score after 8 weeks of treatment. Our findings demonstrate that curcumin supplementation influences several biomarkers that may be associated with its antidepressant mechanisms of action. Plasma concentrations of leptin and endothelin-1 seem to have particular relevance to treatment outcome. Further investigations using larger samples sizes are required to elucidate these findings, as the multiple statistical comparisons completed in this study increased the risk of type I errors.

Introduction

In medical and pharmaceutical practice biomarkers are regularly used to assist in the prediction, diagnosis and evaluation of treatments associated with disease (Biomarkers Definitions Working Group, 2001). However, in psychiatry, biomarkers are utilised primarily for research purposes and are seldom used in clinical practice. Greater understanding of biomarkers in psychiatry has the potential to enhance diagnostic accuracy, improve treatment-matching and evaluate treatment progress. Evaluation of biomarkers can also expand understanding into the mechanisms of change associated with specific treatments for depression (Lopresti et al., 2014b).

Several dysregulated biological pathways have been identified in major depressive disorder including disturbances in monoaminergic activity, immuno-inflammation, oxidative stress, hypothalamus-pituitary-adrenal (HPA) activity and neuroprogression (Leonard and Maes, 2012). Examination of biomarkers is particularly relevant as there are identified differences between depressed and healthy populations in markers of immuno-inflammation, such as C-reactive protein, interleukin-6 and tumour-necrosis factor-α (Howren et al., 2009); markers of oxidative stress such as malondialdehyde (MDA) (Galecki et al., 2009) and 8-Hydroxy-2-deoxyguanosine (8-OHdG) (Maes et al., 2009); and markers of HPA activity such as increased baseline or post-dexamethasone cortisol (Belvederi Murri et al., 2014).

Because of its effects on all of these pathways, interest in curcumin for the treatment of major depression has increased. In animal models of depression, curcumin has demonstrated antidepressant and anxiolytic effects (Lopresti et al., 2012). Three human-based trials on people with major depressive disorder have now been completed. In one study the addition of curcumin to antidepressant treatment provided no additional antidepressant benefit (Bergman et al., 2013), whereas in another study curcumin had similar antidepressant efficacy to fluoxetine (Sanmukhani et al., 2014). However, in this latter study there was no placebo-control or blinding of participants from treatment conditions. A recent randomised, double-blind, placebo controlled study conducted by our research team provided partial support for the efficacy of curcumin in reducing depressive symptoms in people with major depression, particularly in a subset of participants with atypical depression (Lopresti et al., 2014a). In the present paper, exploratory analysis of results from this study is provided with an emphasis on the effects of curcumin on blood, urinary and salivary biomarkers, and on the potential of biomarkers to predict treatment response. The primary goal of this exploratory-driven analysis was to identify potentially important biomarkers that will require validation in future, greater powered studies.

Section snippets

Study design

Details of this study have been previously published in Lopresti et al. (2014a). Briefly, this study was an 8-week, randomised, double-blind, placebo-controlled clinical trial (Figure 1). Investigators responsible for study administration, data collection, intervention allocation and data analysis were blinded to treatment conditions until the final collection of all participant data. The trial protocol was approved by the Human Research Ethics Committee at Murdoch University, Western Australia

Urinary biomarkers

A repeated measures MANOVA conducted on all urinary biomarkers revealed a significant group×time interaction (F8,41=2.62, p=0.021). Univariate tests exploring the effects of group by time on the different individual urinary biomarkers revealed significant group×time interactions for levels of Tbx-B2 (F1,48=4.63, p=0.036), SUB-P (F1,48=13.30, p=0.001), cortisol (F1,48=4.87, p=0.032) and aldosterone (F1,48=6.92, p=0.011). In the curcumin group, treatment was associated with significant increases

Curcumin and its effect on biomarkers

Eight-weeks of supplementation with either curcumin or placebo was associated with changes in several measured urinary biomarkers; namely urinary levels of Tbx-B2, SUB-P, cortisol and aldosterone. In curcumin-treated individuals Tbx-B2 and SUB-P increased over time whereas in placebo-treated individuals aldosterone declined. Urinary cortisol levels trended downward following placebo-treatment and trended upward following curcumin treatment, resulting in significant between group differences.

Limitations and directions for future research

The relatively small samples size and the large number of statistical analyses used in this study limits the reliability and statistical power associated with the findings. For evaluation of biomarker changes over time, 50 samples were collected and numbers were even lower when examining the antidepressant effects of curcumin on people with high ET-1. The likelihood of type 1 error is also increased due to multiple statistical testing. The results from this study therefore require replication

Conclusions

In this randomised, double-blind, placebo controlled study several important preliminary findings were identified:

  • 1.

    Eight-weeks of supplementation with either curcumin or placebo was associated with changes in several measured biomarkers; namely urinary levels of Tbx-B2, SUB-P, cortisol and aldosterone. In curcumin-treated individuals Tbx-B2 and SUB-P increased over time whereas in placebo-treated individual׳s aldosterone declined. Urinary cortisol levels trended downward following

Role of funding source

This study was supported in part by a Grant from Arjuna Natural Extracts Limited to Murdoch University. Arjuna Natural Extracts Limited had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Adrian Lopresti, Peter Drummond and Garth Maker designed the study and Adrian Lopresti wrote the protocol. Adrian Lopresti managed the literature searches and analyses. Adrian Lopresti, Peter Drummond and Michael Maes undertook the statistical analysis, and Adrian Lopresti wrote the first draft of the manuscript. All authors provided comment and assisted in the revision of following manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors report no biomedical financial interests or potential conflicts of interest.

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.

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