Adjunctive use of Nutraceuticals with Psychotropic Medications RANZCP, Vic Branch Conference Healesville; October, 2013 Dr Jerome Sarris Senior Research Fellow (NHMRC EC Fellow) The University of Melbourne Department of Psychiatry & Adjunct Research Fellow Centre for Human Psychopharmacology (SUT) jsarris@unimelb.edu.au
Introduction on the use of NUTRACEUTICALS in psychiatry Quality issues Clinical Considerations Use in Major Depressive Disorder Potential application for sexual dysfunction from SSRIs Use in Bipolar Disorder N-Acetyl Cysteine Nutrients which modify mitochondrial dysfunction N-Acetyl Cysteine in OCD and Trichotillamania
Always consider the quality of nutraceuticals Standardisation is important for herbal medicines Potential adjunctive benefit or for medication-intolerance A remarkable amount of studies have shown that combining nutraceuticals with standard psychotropic medication can increase efficacy Remember MOST patients are already taking nutraceuticals Consider potential interactions with medications e.g. St John s wort, Ginkgo/Vit E/Omega 3, Kava, Minerals Try to prescribe in the context of an integrative model Also consider diet quality and other lifestyle factors
S-Adenosyl Methionine (SAMe) SAMe serves as a necessary methyl donor of methyl groups involved with the metabolism and synthesis of neurotransmitters Folate deficiency is implicated in causing increased homocysteine levels, linked to poor response to antidepressants (Williams et al. 2005) Metabolism of homocysteine to SAMe or back to methionine requires folate, B6 & B12 SAMe and folate are involved with the methylation pathways in the one-carbon cycle, responsible for the metabolism and synthesis or various monoamines SAMe Dose (800mg-1600mg/day)
S-Adenosyl Methionine/ Folate Cycle (Mischoulon & Fava cited in Papakostas 2009)
A 6-week RCT using adjunctive oral SAMe (target dose: 800 mg twice daily: n=73) in MDD patients unresponsive to stable SSRIs
Folate deficiency has been reported in approximately one third of people suffering from depressive disorders Several studies testing folic acid adjunctively with antidepressants All of these studies yielded positive results in regard to enhancing either antidepressant response rates or increasing response onset Current concerns over high synthetic folic acid supplementation with increased rates of certain types of cancer 5-methlytetrahydrofolate or folinic acid considered to be good forms Dosage: 400mcg 5-MTHF, or 800mcg folic acid
Omega-3 fatty acids Thymoleptic effect: Reuptake inhibition of serotonin & dopamine Modulation of secondary messengers Enhanced cell membrane fluidity Anti-inflammatory effects Mood stabilisation: Modulation of cell-signalling pathways via effects such as T 2 reduction (increasing cell membrane fluidity) Select cytokine modulation and arachidonic acid inhibition, and phosphoinositide (PI)-protein kinase C antagonism (Sarris, Mischoulon, Schweitzer 2011)
(Martins 2009)
Studies using augmentation of omega-3 in BD have been conducted: evidence indicates a positive effect Often not significant. Due to small sample sizes? Meta-analytic pooling of the studies may be beneficial PubMed, CINAHL, Web of Science and Cochrane Library databases were searched during mid 2010: RCTs four weeks or longer Omega-3 in combination with pharmacotherapies or treatment as usual to treat BD depression and mania
Clinical Recommendations Take Home Messages Food Sources EPA is more effective than DHA May have an especially beneficial role in comorbidcardiovascular conditions, if diet is deficient, or in inflammatory-based depression BMJ
Essential monoamine precursor required for the synthesis of serotonin Studied extensively as an antidepressant Eight controlled adjuvancy studies using L-tryptophan with antidepressants provide encouraging evidence Tryptophan augmentation was found to be effective in increasing the antidepressant response with phenezine sulphate, clomipramine, tranylcypromine, and fluoxetine Best form 5-HTP (direct precursor for serotonin) Dose: 100mg of 5-HTP bid
Zinc is one of the most prevalent trace elements in the amygdala, hippocampus, and neocortex brain regions Involved with hippocampal neurogenesis via upregulation of BDNF Modifies N-methyl-D-aspartate (NMDA) and glutamate activity Zinc modulates the hypothalmic-pituitary adrenal axis, and has been shown to be neuroprotective in animal models Zinc supplementation has been found to attenuate inflammation via inhibition of TNF-alpha, and IL-1beta Low zinc serum level is associated with depression risk, and correlated with an increase in the activation immune system biomarkers, suggesting that this effect may result in part from a depression-related alteration in the immune-inflammatory system (Lai et al. 2010)
Emerging evidence of zinc (20mg-30mg per day) for depression Beneficial as an adjunct to antidepressant treatment Or in cases of deficiency and/or comorbid low immune system Two key 12-week RCTs have examined the effects of zinc (25mg/d) monotherapy supplementation as an adjunct with antidepressants for depressed adults non-responsive to medication Found that zinc significantly lowered depressive symptom scores of depressed patients (pooled standard mean difference over placebo on HAM-D of -2.84 points, p<0.001) (Lai et al. 2010) Dose 25-30mg per day (use amino acid or picolinate form)
Sarris, Schweitzer, Stough, Bousman, Berk, Byrne, Ng, Mischoulon 2013
Sarris, Schweitzer, Stough, Bousman, Berk, Byrne, Ng, Mischoulon 2013
Sarris, Schweitzer, Stough, Bousman, Berk, Byrne, Ng, Mischoulon 2013 NHMRC Project Grant: APP 1048222 8 week double-blind RCT SAMe vs. Combination Nutraceutical vs. Placebo for adults with current MDD who are taking an SSRI/SNRI and are non-responsive (MADRS >18) MADRS primary outcome + biomarkers (including pharmacogenomics)
Aims and Design: 3-year study, 3-arm double-blind RCT using two nutraceuticalinterventions as adjunctive treatment of 300 depressed SSRI non-responders (100 per arm) Group A: SAMe(800mg/day) Group B:Enhanced SAMecombination nutraceutical(cn) formulation consisting of SAMe(800mg/day), Ethyl-EPA (1000mg/day), 5-HTP (200mg/day), folinic acid: 500mcg/day), zinc picolinate(30 mg/day) + cofactors Group C: Matching placebo Primary outcomes will be the Montgomery-Asberg Depression Rating Scale Blood sample will be collected at baseline to analyse SNPs: COMT, MTHFR, TPH1, SLC6A4, SLC39A8, SLC39A12, FADS1, FADS2, CBS, BHMT, MTR, TCN2 We will measure levels of BDNF, homocysteine, zinc, folate, EFA levels This study will be conducted at The Melbourne Clinic (Melbourne University) & Royal Brisbane Women s Hospital, Herston(University of Queensland)
Sexual dysfunction commonly presents with SSRIs Several nutrients and plant medicines have been trialled to ameliorate symptoms Some evidence exists for: Maca (Lepidium meyenii) Current evidence does not support Ginkgo biloba Other evidence in general ED for: L-Arginine Panax ginseng
Mitochondrial Dysfunction and Bipolar Disorder Evidence points to a critical role for mitochondrial dysfunction in BD Far higher prevalence of both BD and depression in people with mitochondrial abnormalities than in the general population Changes in brain energy levels and markers of energy metabolism are altered in depression and BD, also implicating the role of mitochondrial changes in these illnesses Mounting evidence showing genetic links between BD and mitochondrial dysfunction Impaired energy metabolism triggers pro-apoptotic signalling, oxidative damage, excitotoxicity, impeding mitochondrial replication and function
Sources of Oxidative Stress Glutamate excitotoxicity Glutathione depletion Altered gene expression - electron transport chain complexes Dopamine Calcium Mitochondria l Dysfunction 6-OHDA Bax p53 ROS Cyt. C/ Caspase DNA DAMAGE APOPTOSIS LIPID PEROXIDATION PROTEIN CARBONYLATION Berk TIPS 2008
Nutraceutical Compounds A number of pharmacological treatments and nutritional supplements have previously been used in individuals with conventional mitochondrial disorders Antioxidants (co-enzyme Q10, idebenone, vitamin C, vitamin E and menadione), agents that specifically improve lactic acidosis (dichloroacetate and dimethylglycine) Agents that correct secondary biochemical deficiencies (carnitine, creatine), respiratory chain co-factors (nicotinamide, thiamine, riboflavin, pantothenic acid, pyridoxine and Co Q10) The addition of the antioxidant, glutathione modulating nutrient NAC may also provide a very potent intervention in the novel formulation of a BD combination nutraceutical
N-Acetyl Cysteine (NAC) The N-acetyl derivative of cysteine Less reactive, less toxic and less susceptible to oxidation than cysteine, as well as being more soluble in water When taken orally NAC is readily absorbed via digestive system, then converted in liver almost entirely to cysteine and used for glutathione (GSH) synthesis Cysteine that is not converted to GSH is capable of crossing the blood-brain barrier by means of sodiumdependent transport systems Neuroprotective antioxidant properties, and from the sulfur protein supporting glutathione production
Dean, et al. (2011) J Psychiatry Neurosci; 36: 78-86 N-Acetyl Cysteine (NAC)
NAC Bipolar Disorder Pilot Study Berk and colleagues 2008 published the results A 24-week RCT using 1g bid of NAC versus placebo in a sample of 75 participants stable on medication or therapy with DSM-IV-TR diagnosed BD type I or BD type II Results revealed that NAC significantly reduced bipolar depression levels with a strong effect size No significant effect was found on mania outcomes Recommended Dosage: 500mg bid titrated to 1000-1500mg bid
NAC in Bipolar Depression: Study End-points 16 14 12 10 8 6 4 2 0 P=0.002 P=0.012 MADRS BDRS LIFE-RIFT NAC Placebo Berk Biological Psychiatry, 2008
NAC in Bipolar II Disorder: Remission rates Chi 2 = 4.67, p=0.031 Berk Journal of Affective disorders 2010
N-Acetyl Cysteine vs. Mitochondrial Nutraceutical Combination vs. Placebo for BD I/II: 16-week double-blind blind RCT Berk, Mahli, Dean, Sarris, et al. 2012 ARM 1: [N-Acetyl Cysteine] Two 500mg capsules BID (2gm/day) ARM 3: [Matching Placebo] ARM 2: [NAC + Combination] N-Acetyl Cysteine + Coenzyme Q10 Alpha Lipoic acid Acetyl L carnitine B Vitamins Vit E, Vit A, Vit D, Biotin 1 capsule of each BID Supplier: Bioceuticals
NAC for the Treatment of OCD Obsessive-compulsive disorder (OCD) is a disabling mental disorder that affects 1% to 2% of the population, and treatments are inadequate Dysfunction of glutamatergic neurotransmission is implicated in OCD Glutamate modulating agents are potentially efficacious N-acetylcysteine (NAC) is an amino acid based nutraceutical, and is another readily available agent that has been found to attenuate the synaptic release of glutamate in subcortical brain regions NAC restores the extracellular glutamate concentration in the nucleus accumbens offering a critical pharmacological action in reducing compulsive behaviour
N-Acetly Cysteine (NAC) in the Treatment of OCD: A Double-Blind Placebo-Controlled Study Aims 16-week RCT assessing the efficacy of NAC in reducing OCD symptoms To evaluate the safety of NAC compared to placebo Primary outcome is the Y-BOCS (target sample 50 people over 14 mths) Who is eligible? Male/Female outpatients aged 18-65 with diagnosis of OCD Currently experiencing OCD symptoms (YBOCS >18) Be on any stable treatment regimen for a minimum of four weeks of current treatment (can also be receiving no other treatment)
What is involved? Participants are randomised to 3 gm of NAC/day or matching placebo They take the study tablets (and continue other treatment as usual) How long is the study? Study length is 16 weeks with clinic visits at weeks 0,4,8,12,16
Information for Referring Patients NUTRACEUTICAL MDD STUDY Please contact: Erica Hannagan Phone: 3487 4748 Email: NAT-Dstudy@unimelb.edu.au (or the Prof Unit) MITO-NAC Bipolar Disorder Study Please contact: Nathan Dowling Phone: 9420 9255 Email: ndowling@unimelb.edu.au OCD NAC STUDY Please contact: Gina Oliver Phone: 0422 529 432 Email: georginao@student.unimelb.edu.au
Thank You References and Publications Available Upon Request