Accepted Manuscript Nutraceuticals for Major Depressive Disorder- More is Not Merrier: an 8-week double-blind, randomized, controlled trial Jerome Sarris PhDMHSc , Gerard J Byrne MBBSPhD , Con Stough PhD , Chad Bousman PhDMPH , David Mischoulon MDPhD , Jenifer Murphy BPsych (hons)PhD , Patricia MacDonald BPsych (Hons) , Laura Adams BPsychMCouns , Sonia Nazareth MPsych , Georgina Oliver MSc , Lachlan Cribb BSci (Hons) , Karen Savage BPsych (Hons) , Ranjit Menon MD , Suneel Chamoli MD , Michael Berk MDPhD , Chee Ng MBBSMD PII: S0165-0327(18)31411-3 DOI: https://doi.org/10.1016/j.jad.2018.11.092 Reference: JAD 10310 To appear in: Journal of Affective Disorders Received date: 29 June 2018 Revised date: 18 October 2018 Accepted date: 12 November 2018 Please cite this article as: Jerome Sarris PhDMHSc , Gerard J Byrne MBBSPhD , Con Stough PhD , Chad Bousman PhDMPH , David Mischoulon MDPhD , Jenifer Murphy BPsych (hons)PhD , Patricia MacDonald BPsych (Hons) , Laura Adams BPsychMCouns , Sonia Nazareth MPsych , Georgina Oliver MSc , Lachlan Cribb BSci (Hons) , Karen Savage BPsych (Hons) , Ranjit Menon MD , Suneel Chamoli MD , Michael Berk MDPhD , Chee Ng MBBSMD , Nutraceu- ticals for Major Depressive Disorder- More is Not Merrier: an 8-week double-blind, randomized, controlled trial, Journal of Affective Disorders (2018), doi: https://doi.org/10.1016/j.jad.2018.11.092 This is a PDF file of an unedited manuscript that has been accepted for publication. 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ACCEPTED MANUSCRIPT Highlights: A combination nutraceutical treatment did not outperform placebo in treating symptoms of depression, and was in fact less effective Genetic polymorphisms and BDNF levels were not related to treatment response A very high placebo response rate may have warranted a placebo run-in design Future research may focus on precision-based approaches tailoring treatment to deficiencies, neurochemical abnormalities, or pharmacogenetic differences ACCEPTED MANUSCRIPT 1 ACCEPTED MANUSCRIPT Nutraceuticals for Major Depressive Disorder- More is Not Merrier: an 8-week double-blind, randomized, controlled trial Jerome Sarris PhD, MHSc1,2, Gerard J Byrne MBBS PhD3, Con Stough PhD4, Chad Bousman PhD, MPH 5,6, David Mischoulon, MD, PhD7 Jenifer Murphy BPsych (hons), PhD2, Patricia MacDonald BPsych (Hons) 3, Laura Adams BPsych, MCouns, Sonia Nazareth MPsych 3, Georgina Oliver MSc2, Lachlan Cribb BSci (Hons)2, Karen Savage BPsych (Hons)2 Ranjit Menon MD6 Suneel Chamoli MD3, Michael Berk MD, PhD 6,8,9,10, Chee Ng, MBBS, MD6 1 NICM Health Research Institute, Western Sydney University 2 The University of Melbourne, Department of Psychiatry, The Melbourne Clinic, Professorial Unit 3 The University of Queensland, Department of Psychiatry 4 Swinburne University of Technology, Centre for Human Psychopharmacology 5 University of Calgary, Departments of Medical Genetics, Psychiatry, and Physiology & Pharmacology, Calgary, AB, Canada 6 The University of Melbourne, Department of Psychiatry, Parkville 7 Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School 8 Deakin University, IMPACT SRC, School of Medicine, Barwon Health, Geelong 9 Florey ACCEPTEDInstitute of Neuroscience and Mental Health, MANUSCRIPT The University of Melbourne, Parkville, 10 Orygen, The Centre of Excellence in Youth Mental Health, The University of Melbourne, Parkville Word Count: 4250 Figures and Tables: 6 2 ACCEPTED MANUSCRIPT Correspondence: Professor Jerome Sarris NICM Health Research Institute, Western Sydney University, Westmead, New South Wales [email protected] ACCEPTED MANUSCRIPT 3 ACCEPTED MANUSCRIPT ABSTRACT Background: One of the most pressing questions in “Nutritional Psychiatry” is whether using combinations of different nutraceuticals with putative antidepressant activity may provide an enhanced synergistic antidepressant effect. Methods: A phase II/III, Australian multi-site, 8-week, double-blind, RCT involving 158 outpatients with a DSM-5 diagnosis of MDD. The intervention consisted of a nutraceutical combination: S-adenosyl methionine; Folinic acid; Omega-3 fatty acids; 5-HTP, Zinc picolinate, and relevant co-factors versus placebo. The primary outcome was change in MADRS scores, and hypothesis-driven analyses of potential moderators of response involving key SNPs, and BDNF. Results: Placebo was superior to the nutraceutical combination in reducing MADRS score (differential reduction -1.75 points), however a mixed linear model revealed a non-significant Group X Time interaction (p = 0.33). Response rates were 40% for the active intervention and 51% for the placebo; remission rates were 34% and 43% for active and placebo groups, respectively. No significant differences were found between groups on any other secondary depression, anxiety, psychosocial, or sleep outcome measures. Key SNPs and BDNF did not significantly moderate response. No significant differences occurred between groups for total adverse effects, aside from more nausea in the active group. Limitations: Very high placebo response rates suggest a placebo run-in design may have been valuable. Interpretation: The adoption of a nutraceutical „shotgun‟ approach to treating MDD was not supported, and appeared to be less effective than adding placebo to treatment as usual. Funding: NHMRC APP1048222 Trial Registration: ANZCTR 12613001300763 Key Words: Antidepressant, Nutraceutical, Nutrient, Depression, Clinical Trial, Pharmacogenomics RunningACCEPTED Header: Nutraceutical Combination Clinical MANUSCRIPT Trial in Major Depression 4 ACCEPTED MANUSCRIPT 1. Introduction Widespread use of nutraceuticals (standardised, pharmaceutical-grade nutrient-based supplements) for diverse medical issues is normative. Indeed the nutraceutical market is almost a quarter the size of the global pharmaceutical market, expected to continue to grow markedly in the next 5 years. Yet the efficacy of most supplements and nutraceuticals is not established. Against this background, people with Major Depressive Disorder (MDD), a prevalent and highly disabling mental illness, causing marked occupational and social impairment and reduced quality of life, are frequent users of such agents (Donohue and Pincus, 2007). This is understandable as current treatment outcomes are inadequate, with around two-thirds of those treated with first-line antidepressants not reaching remission (Rush, 2007). MDD is a chronic condition for many, often requiring multiple treatment attempts. One potential approach to improving non-response to antidepressants is the use of adjunctive nutraceuticals (J Sarris et al., 2015c, 2015a). The biopathophysiology of MDD involves a range of abnormalities such as monoaminergic system disturbance, neuro-endocrine changes, reduced brain-derived neurotropic factor (BDNF), and cytokine alterations (Antonijevic, 2006; Hindmarch, 2001; Plotsky et al., 1998; Raison et al., 2006; Ressler and Nemeroff, 2000). Several of these key neurobiological mechanisms may be modulated by nutraceuticals such as S-adenosyl methionine (SAMe), 5-hydroxytryptophan (5-HTP), eicosapentaenoic acid (EPA), zinc, and folic acid (either as folinic acid or methylfolate); with emerging evidence for the use of some of these nutraceuticals as adjunctive antidepressants (Sarris et al., 2016). While the conventional paradigm mandates the study of individual agents to avoid the confound of multiple interventions, this approach may not be beneficial in studying nutraceuticals. Nutrients commonly work in concert (Jacobs and Tapsell, 2007) and, as outlined above, a range of nutraceuticals modulate a range of key pathways involved with the pathogenesis of depression (see Figure 1). ACCEPTED ………………………. FigureMANUSCRIPT 1 About Here …………………… SAMe is an endogenous sulphur-containing compound that is a critical neurochemical component involved in the „one carbon‟ cycle responsible for the methylation of neurotransmitters that regulate 5 ACCEPTED MANUSCRIPT mood. SAMe may improve depressed mood via enhanced methylation of catecholamines and increased serotonin turnover, reuptake inhibition of norepinephrine, enhanced dopaminergic activity, decreased prolactin secretion, and increased phosphatidylcholine conversion (Bottiglieri and Hyland, 1994; Papakostas et al., 2003). Our previous 12-week 3-arm double-blind RCT (n=144) using SAMe monotherapy (1600mg/day) versus selective serotonin reuptake inhibitor (SSRI) escitalopram (20mg) and placebo in adults with MDD found a significant difference between SAMe from baseline to week 12 (p=0.039) versus placebo in a subset of the parent study sample (Sarris et al., 2014). At week 12 endpoint, the remission rates on the Hamilton Depression Rating Scale (HAM-D< 7) were 34% for SAMe, 23% for escitalopram and 6% for placebo, significantly in favour of SAMe (p=0.014). In addition, a 6-week double-blind RCT by colleagues Papakostas et al. (2010) involving 73 MDD patients non-responsive to SSRIs found response (HAM–D>50% reduction) and remission rates were significantly higher for patients treated with adjunctive SAMe (36.1% and 25.8% respectively) than adjunctive placebo (17.6% vs. 11.7% respectively). 5-HTP is an