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CAN FEEL CAN PATIENTS References: 1. Freeman et al., A prenatal supplement with methylfolate for the treatment and prevention of depression in women trying to conceive EnBrace HR Small Gel Cap and during pregnancy, Annals of Clinical Psychiatry, Feb. 2019 2. Farah et.al, Correlation of Clinical Response with Homocysteine Reduction During Therapy With Reduced B Vitamins in Patients With MDD Who Are Positive for MTHFR C677T or A1298C Polymorphism, Journal of Clinical Psychiatry, May 2016 Ingredients 3. MRC Vitamin Group, Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study, Lancet, 1991 4. Czeizel et al., Periconceptional Folic Acid and Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Con- genital Abnormalities, Clinical and Molecular Teratology, 2008 Rx, All Natural, Unique, Bioactive Prenatal Vitamin Gel Cap 5. FDA, 21 CFR-101.79- Health Claims: Folate and neural tube defects, CFR Text. 2019 6. Kirk E et al., Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study, BMJ, 2004 7. Ufriend et al., The C677T polymorphism of the methelenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage, Obstet- L-Methylfolate Magnesium 5.53mg rics & Gynecology, April 2002 8. MTHFR Living, Preparing for Pregnancy with MTHFR Mutations, Jan. 2014 Folinic Acid 2.5mg 9. Garilli, Bianca ND, MTHFR Mutation: A Missing Piece in the Chronic Disease Puzzle, Huffington Post, Summer, 2012 10. Wald et al, Public health failure in the prevention of neural tube defects: time to abandon the tolerable upper intake level of folate, Folic Acid 1mg Public Health Reviews, 2018 11. Farah et al., The Prevalence and Role of MTHFR Polymorphism in Opiate Dependency, Journal of Addiction and Therapies, Feb. 2018 12. El-Hadidy et al., Methylene tetra hydrofolate reductase C677T Gene Polymorphism in Heroin Dependence, Addiction Research & B12 (Methylcobalamin) 25mcg Therapy, 2015 13. Mararwa et al., Prenatal exposure to SSRIs and SNRIs and risk for pulmonary hypertension of the newborn: a systemic review, me- B12 (Adenosylcobalamin) 25mcg ta-analysis, AJOG, 2018 14. Chambers et al., SSRI and Risk of Persistent Pulmonary Hypertension of the Newborn, The New England Journal of Medicine, 2011 Intrinsic Factor (B12 Vitamin Bioenhancer) 25mg 15. Kieviet et al., Use of antidepressants during pregnancy in The Netherlands: observational study into post-partum interventions, BMC Pregnancy & Childbirth, 2017 B6 (Pyridoxal-5-Phosphate) 25mcg 16. MGH Center for Women’s Health, womensmentalhealth.org, SSRIs and Poor Neonatal Adaptation: How Long do Symptoms Last, 2015 B1 (Thiamine Pyrophosphate) 25mcg 17. Liu et al., Antidepressant Use During Pregnancy and Psychiatric Disorders in Offsprings, BMJ, 2017 18. Lugo-Candelas et al., Association Between Brain Structure and Connectivity in Infants and Exposure to SSRIs During Pregnancy, JAMA B2 (Flavin Adenine Dinucleotide) 25mcg Pediatrics, 2018 19. Berard et al., Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women, BMJ, 2016 B3 (Nicotinamide Adenine Dinucleotide) 25mcg 20. WebMD www.webmd.com, pregnancy-and-antidepressants, 2018 21. FDA A Appendix NIH, Antidepressant Drug Labels for Pregnant and Postpartum Women, 2014 PS-Omega-3 (Phosphatidylserine, EPA, DHA) 23mg 22. EnBrace HR PI, FDS Daily Med, Dec. 2018 23. Turgal et al. MTHFR Polymorphisms and Pregnancy Outcome, PMC 6138472, Sept. 2018 Magnesium Ascorbate 24mg 24. Duprey Robert P. MTHFR Gene Polymorphism positive treatment-resistant depression, Neuropsychiatry 2019 Magnesium L-Threonate 1mg Iron (Ferrous Glycine Cysteinate) 13.6mg Zinc Ascorbate 1mg Betaine 500mcg Citric Acid Monohydrate 1.83mg Sodium Citrate 3.67mg CoQ10 500mcg Bioperine (B Vitamin Bioenhancer) 25mg “EnBrace HR contains 5.53 mg. of L-Methylfolate Magnesium and small quantities of other folate derivatives (1mg. folic acid and 2.5mg of folinic acid) optimal for a depressed population with high rates of MTHFR polymorphism that affect folic acid metabolism and high risk of neural tube defects and other birth defects.” EnBraceHR.com Freeman M. et al: A prenatal Supplement with Methylfolate for the Treatment and Prevention of Depression in Women Trying to Conceive and During Pregnancy, Annals of Clinical Psychiatry, February 2019. 3. 2. 1. Major Therapeutic Benefits Other BirthDefects. for thePrevention ofNTDs and Provides theMostFolate Protection Pregnancy Outcomes. Other Polymorphisms for Adverse Negates theRiskofMTHFRand and afterPregnancy. Treat DepressionBefore,During Clinically Proven toPrevent and EnBrace HR With ClinicalProof Small GelCap Offers 3

1,2 3,4,5 6,7,8,9,11,23,24

EnBraceHR.com EnBraceHR.com A PrenatalEnBrace SupplementA Prenatal Supplement HRwith MethylfolateFor withThe Methylfolate forTreatment the Treatment for the andand Treatment and Prevention ofPrevention Depression of inDepression Women Trying in Women to Conceive Trying toand Conceive During Pregnancyand During Pregnancy Marlene P. Freeman,Marlene MDPrevention1,, P. Gina Freeman, Savella, MD BS1,1, GinaTaylor of Savella, Church, Depression BS BS1, 1Taylor, Lina GoezChurch,-Mogoll BS1, óLinainn, MD, GoezWomen MSc-Mogoll1,2, Alexandraón, MD, Trying MScZ. Sosinsky,1,2, Alexandra BS 1to, Olivia Z. Sosinsky,Conceive B. Noe 1BS, BS,1, Olivia Anjali B. Kaimal Noe 1,3 BS,, Anjali Kaimal3, andMD MAS,During Lee S. Cohen,MD MAS,Pregnancy MD 1Lee S. Cohen, MD1 1Massachusetts General1Massachusetts Hospital, Psychiatry General Department,Hospital, Psychiatry Center Department,for Women’s CenterMental for Health, Women’s Boston, Mental MA; Health, 2Harvard Boston, T.H. Chan MA; School 2Harvard of Public T.H. Chan Health, School Department of Public Health,of Epidemiology, Department of Epidemiology, Marlene P. Freeman,Boston, MA; 3Obstetrics MDBoston, Department,et MA; al, 3Obstetrics Annals Massachusetts Department, of General Clinical Massachusetts Hospital, Boston, Psychiatry,General MA Hospital, Boston, February MA 2019 Abstract Abstract Results Results Results (Cont.) Results (Cont.)

Background: Women often seekBackgroundalternativesFIGURE: Womento standardoften antidepressantsseek alternatives 2.fortomajor standardMADRSdepressiveantidepressantsdisorder for major Scoresdepressive disorder Demographicsby Group and PregnancyDemographics Characteristics and Pregnancy Characteristics Adverse Events Adverse Events (MDD) during pregnancy. In this(MDD)preliminaryduring pregnancystudy, EnBrace. In thisHR,preliminarya prenatalstudy,supplementEnBrace containingHR, a prenatal supplement containingTABLE 1 Subject characteristics of subjectsTABLE 1 who Subject received characteristics medication of (N=19) subjects who received medication (N=19) Adverse Events Reported Adverse Events Reported methylfolate, was investigated inmethylfolate,pregnant womenwas investigatedor women planningin pregnantpregnancywomenforor women(1) depressiveplanningrelapsepregnancy for (Demographic1) depressive characteristicsrelapse N (%), unless otherwiseDemographic noted characteristics N (%), unless otherwise noted Adverse Event Adverse Event # of patients experienced # of patients experienced prevention and for (2) the acute preventiontreatment ofandMDDfor.(2) the acute treatment of MDD. Age (years), mean ± SD Age (years), mean ± SD 32.8 ± 3.0 32.8 ± 3.0 Nausea Nausea 3 (15.8%) 3 (15.8%) 25 Race Race Constipation Constipation 3 (15.8%) 3 (15.8%) White/Caucasian White/Caucasian 16 (84.2%) 16 (84.2%) Cough and nasal# congestion Cough and nasal congestion 2 (10.5%) 2 (10.5%) Methods: This 12-week open-labelMethodsstudy: Thisincluded12-weekwomenopenwith-labelhistoriesstudy includedof MDDwomenwho werewith planninghistories of MDD who were planning Black/African American Black/African American1 (5.3%) 1 (5.3%) Difficulty concentrating Difficulty concentrating 2 (10.5%) 2 (10.5%) pregnancy or pregnant <28 weekspregnancy. Group 1orparticipantspregnant 50% andfiveone(83improving.3%) improving33.3%>.50One% andadverseone20improvingevent occurred,33.3%a. Onehospitalizationadverse eventfor occurred, a hospitalization for Some high school Some high school 0 0 Mild weight gain Mild weight gain 1 (5.3%) 1 (5.3%) depression. depression. High school or received GED High school or received0 GED 0 Chest tightness Chest tightness 1 (5.3%) 1 (5.3%) Some college or Associate Degree Some college or Associate1 (5.3%) Degree 1 (5.3%) Total Adverse Events: 26; Unique Adverse Events:Total Adverse 17 Events: 26; Unique Adverse Events: 17 Graduated college (BA, BS) Graduated college (BA, 4BS) (21.1%) 4 (21.1%) Conclusions: Results suggest EnBraceConclusionsHR is: Resultsa well-toleratedsuggest EnBraceinterventionHR iswitha wellpotential-toleratedefficacyinterventionfor the with potential efficacy for the Master's Degree Master's Degree 11 (57.9%) 11 (57.9%) prevention and treatment of perinatalpreventiondepressionand treatment. Larger controlledof perinataltrialsdepressionare necessary. Larger. controlled trials are necessary. Doctoral Degree (PhD, MD, etc.) Doctoral Degree (PhD, MD,3 (15.8%) etc.) 3 (15.8%) Employment status Employment status Discussion and ConclusionsDiscussion and Conclusions Full-or part-time work Full-or part-time work 17* (89.5%) 17* (89.5%) Homemaker Homemaker 2* (10.5%) 2* (10.5%) Results Summary Results Summary Introduction Introduction Student Student 2* (10.5%) 2* (10.5%) Pregnancy characteristics Pregnancy characteristics • We assessed EnBrace HR in two• samplesWe assessed of women EnBrace planning HR in two pregnancy samples or of during women early planning pregnancy, pregnancy to or during early pregnancy, to Major Depressive Disorder (MDD)Major and DepressiveMajor Depressive Disorder Episodes (MDD) and(MDEs) Major in Women: Depressive Episodes (MDEs) in Women: Pregnancy status Pregnancy status obtain data regarding: obtain data regarding: • MDD occurs approximately twice• MDD as often occurs in womenapproximately compared twice to asmen. often1,2 in women compared to men.1,2 Planning pregnancy/Trying to conceive Planning pregnancy/Trying12 (63.2%) to conceive 12 (63.2%) • 1) Prevention of depressive relapse• 1) Prevention in women withof depressive histories relapseof MDD in women with histories of MDD Pregnant at enrollment Pregnant at enrollment7 (36.9%) 7 (36.9%) 3 3 • 2) Acute treatment of MDD in• women2) Acute who treatment were depressed of MDD andin women wanted who to avoid were thedepressed use of an and wanted to avoid the use of an • There is high risk for MDEs during• There pregnancy is high andrisk thefor MDEspostpartum during period. pregnancy and the postpartum period. Assisted Reproductive Technology (ART) Assisted Reproductive Technology (ART) • Pregnant women often discontinue• Pregnant standard women antidepressant often discontinue medications standard prior antidepressant to or during pregnancy medications prior to or during pregnancy Use for conception/attempted conception Use for conception/attempted5 (26.3%) conception 5 (26.3%) antidepressant or did not want toantidepressant increase the dose or did of not one want that tothey increase were already the dose taking. of one that they were already taking. because of safety concerns.4-8 because of safety concerns.4-8 15 No use of ART No use of ART 14 (73.7%) 14 (73.7%) • Three of 11 women in Group 1• whoThree reduced of 11 womenor discontinued in Group their 1 who antidepressants reduced or discontinued and who were their well antidepressants at and who were well at Pregnancy events during trial Pregnancy events during trial • There are few evidence-based• alternativesThere are fewto antidepressant evidence-based medications alternatives for to the antidepressant treatment and medications prevention for the treatment and prevention baseline experienced a relapse tobaseline an MDE experienced (27.3%), a rate a relapse lower tothan an expectedMDE (27.3%), when a compared rate lower to than expected when compared to Became pregnant Became pregnant 4 (21.1%) 4 (21.1%) historical controls who discontinuedhistorical antidepressants controls who for discontinued pregnancy (67.7%). antidepressants3 for pregnancy (67.7%).3 of MDD during pregnancy, leavingof pregnant MDD during women pregnancy, and clinicians leaving with pregnant the clinical women dilemma and clinicians of weighing with the clinical dilemma of weighing Pregnancy Loss Pregnancy Loss 2 (10.5%) 2 (10.5%) risks of fetal exposure to medicationrisks against of fetal impactexposure of untreatedto medication maternal against depression. impact of untreated maternal depression. Delivered Delivered 1 (5.3%) 1 (5.3%) • All participants in Group 2, who• wereAll participants depressed in at Group baseline, 2, who experienced were depressed remission at baseline,by the end experienced of the remission by the end of the Table 1. Demographics are listed for all 19 womenTablewho1. Demographicsinitiated studyaredruglisted. Twoforwomenall 19 womenin Groupwho1, whoinitiatedwerestudytryingdrugto .conceive,Two womenintendedin Groupto discontinue1, who were trying to conceive,study,intended and to5 ofdiscontinue 6 (83.3%) experiencedstudy, over and a5 50%of 6 (83.3%)improvement experienced on the overMADRS a 50% from improvement baseline. One on patient the MADRS from baseline. One patient antidepressants upon becoming pregnant, but didantidepressantsnot conceive duringupon becomingthe trial. Thesepregnant,womenbutthusdid notdidconceivenot reduceduringor discontinuethe trial. Theseantidepressantswomen thusduringdid notthereduceacute or discontinue antidepressants during the acute L-Methylfolate and Folate-RelatedL-Methylfolate Therapies: and Folate-Related Therapies: treatment phase, and were not included in analysestreatment. phase, and were not included in analyses. in Group 2 remitted, then relapsed,in Group then again2 remitted, remitted then prior relapsed, to completing then again the remitted study. prior to completing the study. • We found EnBrace HR was well• -toleratedWe found in EnBrace this sample. HR was One well serious-tolerated adverse in Groupthis event sample. occurred; One 1seriousa woman adverse in event occurred; a woman in • Evidence suggests various folate• Evidenceforms including suggests folic various acid, folinicfolate formsacid, and including methylfolate folic acid, may folinic haveacid, and methylfolate may have Figure 1. Mood and QualityFigure of 1.Life Mood Outcomes and Quality of Life Outcomes antidepressant effects.9-12 These antidepressantinterconvertible effects. folate 9forms-12 These constitute interconvertible the one-carbon folate forms cycle andconstitute are the one-carbon cycle and are Group 1 experienced a relapse ofGroup depression 1 experienced and was ahospitalized. relapse of depression and was hospitalized. postulated to exert an antidepressantpostulated effect to by exert impacting an antidepressant neurotransmitter effect synthesis. by impacting13 neurotransmitter synthesis.13 Group 1 – Relapse PreventionGroup Group; 1 – RelapseWell at Baseline Prevention Group; Well at Baseline Strengths Strengths • Because folate must be converted• Because to its active folate form, must methylfolate, be converted forto itsuse active in the form, body, methylfolate, polymorphisms for use in the body, polymorphisms25 25 70 70 Group 2 impairing folate methylation mayimpairing limit the folateefficacy methylation of folate as may an intervention limit the efficacy targeting of folate MDD. as9 -an16 intervention targeting MDD.9-16 • We assessed a novel nutritional• supplementWe assessed for a novel MDD nutritionalprevention supplement and treatment for inMDD women prevention in the antenataland treatment in women in the antenatal • Methylfolate may be more readily• Methylfolate absorbed in may the bebrain more than readily folate, absorbed and methylfolate in the brain has than potential folate, as and a methylfolate has potential as a 65 period, a critical65 goal among womenperiod, seeking a critical to avoid goal antidepressantsamong women seeking during pregnancy.to avoid antidepressants during pregnancy. 20 20 non-psychotropic treatment for MDD.non-psychotropic17-18 treatment for MDD.1017-18 • Other strengths include the rigorous• Other assessments strengths include of history the ofrigorous MDEs andassessments the diagnosis of history of MDD of MDEsand the and the diagnosis of MDD and the • L-methylfolate treatment in early• L -trialsmethylfolate has been treatment found to inducein early significant trials has beenimprovement found to ininduce depressive significant improvement in depressive 60 validation of MDE60 status at each validationstudy visit of using MDE the status MINI. at We each collected study visit biomarkers using the for MINI. assessment We collected of biomarkers for assessment of symptoms both when used as ansymptoms adjunct to both antidepressant when used therapyas an adjunct and when to antidepressant used as a monotherapy. therapy and19- 24when used as a monotherapy.15 19-24 15 exploratory variables. exploratory variables. SR, EPDS Score SR, EPDS Score SF Score SF Score - - • Folate-related compounds reduce• Folate rates-related of neural compounds tube defects reduce and ratesimprove of neural child neurodevelopmental tube defects and improve child neurodevelopmental 55 - 55 - 25-28 25-28 Limitations Limitations outcomes, conferring benefits andoutcomes, minimizing conferring potential benefits risks of and antidepressants minimizing potential during pregnancy. risks of antidepressants during pregnancy.10 10 QLESQ QLESQ 50 • The most important50 limitation• is Thethe lackmost of important a placebo limitation arm. We drawis the fromlack ofhistorical a placebo controls arm. We assessing draw from historical controls assessing MADRS, QIDS MADRS, QIDS MADRS, depressive relapse and symptomdepressive burden3. Concurrent relapse and parallel symptom comparison burden3. groupsConcurrent were parallel not available. comparison groups were not available. EnBrace HR: EnBrace HR: 5 5 • EnBrace HR is a prescription prenatal/postnatal• EnBrace HR is a dietaryprescription management prenatal/postnatal product that dietary contains management 5.53 mg L- product that contains 5.53 mg L- 45 • Another major45 limitation is the• smallAnother number major of limitation subjects overall is the small and in number each group. of subjects overall and in each group. methylfolate and other folate derivativesmethylfolate (1 mg and folic other acid, folate and 2.2derivatives mg folinic (1 acid),mg folic optimal acid, andfor a 2.2 population mg folinic acid), optimal for a population • Our sample is largely composed• ofOur women sample who is largely are white, composed non-Hispanic, of women married, who are and white, highly non educated.-Hispanic, It married,is and highly educated. It is 0 0 40 not clear if our40 findings are generalizablenot clear toif ourthe findingslarger population are generalizable of reproductive to the larger-aged population women. of reproductive-aged women. with high rates of polymorphismswith that high affect rates folic of acid polymorphisms metabolism. that affect folic acid metabolism. Week 0 Week 2 Week 4 Week 0 Week 6 Week 2 Week 8 Week 4 Week 10 Week 6 Week 12 Week 8 Week 10 Week 12 Conclusions and Future DirectionsConclusions and Future Directions Methods Methods • Study results suggest EnBrace• HRStudy is a novel results and suggest well tolerated EnBrace interventionHR is a novel with and potentialwell tolerated efficacy intervention for the with potential efficacy for the 5 prevention and treatment of depressionprevention among and womentreatment planning of depression pregnancy among and womenwho are planning pregnant pregnancy and who are pregnant Group 1: Well at Baseline; Group 1: Well at Baseline;Group 2: Depressed at Baseline;Group 2: Depressed at Baseline; MADRS QIDS-SRMADRS EPDSQIDS-SR QLESQ-SF EPDS • LargerQLESQ controlled-SF trials are necessary• Larger to controlled definitively trials determine are necessary efficacy to and definitively its role in determine the armamentarium efficacy and its role in the armamentarium Relapse Prevention Group DEPRESSION SCALE Relapse Prevention GroupAcute Treatment Group Acute Treatment Group of treatments for antenatal depression.of treatments for antenatal depression. Inclusion Criteria: Inclusion Criteria: Inclusion Criteria: Inclusion Criteria: • Age >18 • Age >18 • Age SEVERE WELL MILD MODERATE >18 • Age >18 Group 2 – Acute Treatment GroupGroup; 2 Depressed – Acute Treatment at Baseline Group; Depressed at BaselineReferences References • MDD as primary diagnosis • MDD as primary diagnosis• MDD as primary diagnosis • MDD as primary diagnosis 25 25 70 70

• Have prescribing clinician • Have prescribing clinician• Have prescribing clinician • Have prescribing clinician 1. Kessler, R.C., Epidemiology of women and depression.1. J Kessler,Affect Disord R.C., Epidemiology, 2003. 74(1): p.of 5women-13. and depression. J Affect Disord, 2003. 74(1): p. 5-13. 65 65 • Planning to conceive or <28 weeks• Planning pregnant to conceiveat or <28 weeks20 pregnant at 20 2. Noble, R.E., Depression in women. Metabolism, 2005.2. 54(5Noble, Suppl R.E.,1): Depression p. 49-52. in women. Metabolism, 2005. 54(5 Suppl 1): p. 49-52. • Planning to conceive or <28 weeks• Planning pregnant to conceiveat or <28 weeks pregnant at 3. Cohen, L.S., et al., Relapse of major depression during3. pregnancyCohen, L.S., in etwomen al., Relapse who maintain of major or depression discontinue during antidepressant pregnancy treatmein womennt. whoJama, maintain 2006. 295(5): or discontinue p. 499-507. antidepressant treatment. Jama, 2006. 295(5): p. 499-507. enrollment enrollment enrollment enrollment 4. Andrade, S.E., et al., Use of antidepressant medications4. Andrade,during pregnancy: S.E., et al., a Usemultisite of antidepressant study. Am J Obstet medicationsGynecol during, 2008. pregnancy: 198(2): p. a194 multisite e1-5. study. Am J Obstet Gynecol, 2008. 198(2): p. 194 e1-5. 60 5. Lupattelli, A., et al., Self-reported60 perinatal depressive5. symptomsLupattelli, andA., et postnatal al., Self- symptomreported perinatalseverity after depressive treatment symptoms with antidepressants and postnatal symptomin pregnancy: severity a cross after-sectional treatment study with across antidepressants 12 in pregnancy: a cross-sectional study across 12 • Planning to discontinue antidepressants• Planning or to discontinue• No antidepressantsdose increase of orcurrent antidepressant• No dose increase or of current antidepressant15 or 15 European countries using the Edinburgh Postnatal DepressionEuropean Scale. countries Clin Epidemiol, using the 2018. Edinburgh 10: p. Postnatal655-669. Depression Scale. Clin Epidemiol, 2018. 10: p. 655-669. recently tapered off antidepressantsrecently tapered off antidepressantsstart of new antidepressant medicationstart of new antidepressant medication 6. Uguz, F., Maternal Antidepressant Use During Pregnancy6. Uguz and, theF., Maternal Risk of Attention Antidepressant-Deficit/Hyperactivity Use During Pregnancy Disorder and in Children: the Risk Aof Syste Attentionmatic- Deficit/HyperactivityReview of the Current Disorder Literature. in Children: J Clin A Systematic Review of the Current Literature. J Clin SR, EPDS Score SR, EPDS Score SF Score SF Score

- - Psychopharmacol, 2018. 38(3): p. 254-259. Psychopharmacol, 2018. 38(3): p. 254-259. 55 - 55 - • No current major depressive episode• No current on MINI major depressive• Currently episode depressed, on MINI as verified• byCurrently MINI depressed, as verified by MINI 7. Morales, D.R., et al., Antidepressant use during pregnancy7. Morales, and risk D.R., of autismet al., Antidepressant spectrum disorder use andduring attention pregnancy deficit and hyperac risk of tivautismity disorder: spectrum systematic disorder reviewand attention of observational deficit hyperac studiestiv ityand disorder: systematic review of observational studies and

10 10 QLESQ methodological considerations. BMCQLESQ Med, 2018. 16(1): methodologicalp. 6. considerations. BMC Med, 2018. 16(1): p. 6. • “Depressed”; baseline MADRS •score“Depressed”; > 15 baseline MADRS score > 15 8. Prady, S.L., et al., A systematic review of maternal antidepressant8. Prady, S.L., use et al.,in pregnancy A systematic and review short -ofand maternal long-term antidepressant offspring's outcomes. use in pregnancy Arch Womens and shortMent- andHealth, long- term2018. offspring's 21(2): p. 127 outcomes.-140. Arch Womens Ment Health, 2018. 21(2): p. 127-140. • “Well”; baseline MADRS score •<10“Well”; baseline MADRS score <100 50 50

MADRS, QIDS MADRS, QIDS MADRS, 9. Alpert, J.E., et al., Folinic acid (Leucovorin) as an adjunctive9. Alpert, treatment J.E., et al.,for FolinicSSRI-refractoryacid (Leucovorin) depression. as anAnn adjunctive Clin Psychiatry, treatment 2002. for 14(1): SSRI- p.refractory 33-8. depression. Ann Clin Psychiatry, 2002. 14(1): p. 33-8. 10.Coppen, A. and J. Bailey, Enhancement of the antidepressant10.Coppen action, A. and of fluoxetine J. Bailey, Enhancement by folic acid: aof randomised the antidepressant, placebo action controlled of fluoxetine trial. J Affect by folic Disord acid:, 2000. a randomised 60(2): p., 121placebo-30. controlled trial. J Affect Disord, 2000. 60(2): p. 121-30. • Primary Outcome: To obtain preliminary• Primary Outcome:data on To obtain preliminary5 data on 5 11.Farah, A., The role of L-methylfolate in depressive disorders.11.Farah, CNS A., spectrums,The role of 2009.L-methylfolate 14(S2): p. in 2 -depressive7. disorders. CNS spectrums, 2009. 14(S2): p. 2-7. • Primary Outcome: To obtain preliminary• Primary Outcome:data on To obtain preliminary data on 45 12.Fava, M. and D. Mischoulon45, Folate in depression: efficacy,12.Fava, safety, M. and differences D. Mischoulon in formulations,, Folate in depression:and clinical issues.efficacy, Journal safety, of differences Clinical Psychiatry, in formulations, 2009. 70(S5): and clinical p. 12 -issues.17. Journal of Clinical Psychiatry, 2009. 70(S5): p. 12-17. the efficacy of EnBrace HR for depressivethe efficacy relapse of EnBrace efficacy HR for of depressive EnBrace HR relapse for treatment efficacy ofVisit acute of EnBrace MDEs 1 HR for treatment Visit of acute MDEs 2 Visit 3 Visit 4 Visit 5 13. Sarris, J., Visitet al., Adjunctive Nutraceuticals 6 for Depression: 13. Sarris, A SystematicVisit J., et al., ReviewAdjunctive and 7 NutraceuticalsMeta-Analyses. forAm Depression: J Psychiatry, A Systematic2016. 173(6): Review p. 575 and-87. Meta-Analyses. Am J Psychiatry, 2016. 173(6): p. 575-87. 14.Papakostas, G.I., C.F. Cassiello, and N. Iovieno, Folates14. andPapakostas S-adenosylmethionine, G.I., C.F. Cassiello for major, and N.depressive Iovieno, Folatesdisorder. andCan S -Jadenosylmethionine Psychiatry, 2012. 57 for(7): major p. 406 depressive-13. disorder. Can J Psychiatry, 2012. 57(7): p. 406-13. prevention in women who discontinueprevention in womenin who women discontinue who opt to avoid startingin women an who opt to avoid starting an0 0 40 15.Nahas, R. and O. Sheikh, Complementary40 and alternative15.Nahas medicine, R. and for O.the Sheikh, treatment Complementary of major depressive and alternative disorder. medicineCanadian for Family the treatment Physician, of 2011. major 57 depressive(6): p. 659 -disorder.663. Canadian Family Physician, 2011. 57(6): p. 659-663. Week 0 Week 2 Week 4 Week 0 Week 6 Week 2 Week 8 Week 4 Week 10 Week 6 Week 12 Week 8 Week 10 16.Melong Week, J. and D.12 Gardner, Women with depression should16.Melong be offered, J. and folic D. Gardner, acid. Canadian Women Family with depression Physician, 2011.should 57 be(9): offered p. 993 folic-996. acid. Canadian Family Physician, 2011. 57(9): p. 993-996. antidepressants while trying to conceiveantidepressants or during while antidepressant trying to conceive or increasing or during the antidepressantdose of a current or increasing the dose of a current 17.Kelly, C.B., et al., The MTHFR C677T polymorphism is 17.associatedKelly, C.B., with et al.,depressive The MTHFR episodes C677T in polymorphismpatients from Northernis associated Ireland. withJournal depressive of Psychopharmacology, episodes in patients from2004. Northern 18(4): p. Ireland.567-571.Journal of Psychopharmacology, 2004. 18(4): p. 567-571. early pregnancy early pregnancy antidepressant while trying to conceiveantidepressant or during while trying to conceive or during 18.Mischoulon, D. and M.F. Raab, The role of folate in depression18.Mischoulon and dementia., D. and M.F.The Raab Journal, The of role clinical of folate psychiatry, in depression 2006. 68 and: p. dementia. 28-33. The Journal of clinical psychiatry, 2006. 68: p. 28-33. 19.Papakostas, G.I., et al., L-methylfolate as adjunctive therapy19.Papakostas for SSRI, -G.I.,resistant et al., major L-methylfolate depression: as resultsadjunctive of two therapy randomized, for SSRI -doubleresistant-blind, major parallel depression:-sequential results trials. of twoAm randomized, J Psychiatry, double2012. -blind, parallel-sequential trials. Am J Psychiatry, 2012. early pregnancy. early pregnancy. Figure 1. The aim for Group 1 was toFigureprevent1. depressionThe aim forrelapse,Group 1andwastheto aimpreventfor Groupdepression2 wasrelapse,to improveand thedepressionaim for Group 2 was 169to (12):improve p. 1267-74.depression 169(12): p. 1267-74. Group l(Blue Graph)-Relapsesymptoms, measured through several moodsymptoms,Preventionand qualitymeasuredof lifethroughquestionnairesseveral mood. Trendsandshownqualityby ofgroupGroup,life questionnairesfor the primary. Trendsmood shown by groupat20.Di forPalma, the C.,baseline primaryet al., Is methylfolatemood effective in relieving20. majorDi Palma, depression C., et al., in“well,” Is chronic methylfolate alcoholics? effective A hypothesis in relieving of treatment.major depressionCurrent that in therapeutic chronic alcoholics? research, A 1994.hypothesis 55(5): of p. treatment. 559-568. Current therapeutic research, 1994. 55(5): p. 559-568. 21.Godfrey, P., et al., Enhancement of recovery from psychiatric21.Godfrey, illness P., byet al.,methylfolate. EnhancementThe ofLancet, recovery 1990. from 336 psychiatric(8712): p. illness392-395. by methylfolate. The Lancet, 1990. 336(8712): p. 392-395. outcome measure, the MADRS (Montgomeryoutcome-Asbergmeasure,Depressionthe MADRSRating(MontgomeryScale) in dark-Asbergblue; Depressionfor secondaryRatingmoodScale)measures,in dark blue; for secondary22.Guaraldi,mood G.P., et al.,measures, An open trial of methyltetrahydrofolate22.Guaraldi,in elderly G.P., etdepressed al., An open patients. trial ofAnnals methyltetrahydrofolate of clinical psychiatry,in elderly1993. 5 depressed(2): p. 101 patients.-105. Annals of clinical psychiatry, 1993. 5(2): p. 101-105. Exclusion Criteria for Both Groups:Exclusion Criteria for Both Groups: the QIDS–SR (Quick Inventory of Depressivethe QIDSSymptomatology–SR (Quick Inventory-Self Report)of Depressivein orangeSymptomatologyand the EPDS-(EdinburghSelf Report)Postnatalin orange and the EPDS23.Passen(Edinburgh, M., et al., OralPostnatal 5′-methyltetrahydrofolic acid 23.in senilePassen organic, M., et mental al., Oral disorders 5′-methyltetrahydrofolic with depression: acidresults in senileof a double organic-blind mental multicenter disorders stu withdy. Agingdepression: Clinical results and Experimental of a double-blind multicenter study. Aging Clinical and Experimental Depression Scale) in light blue; and forDepressiona quality ofScale)life outcome,in light bluethe;QLESQand for-SFa quality(QualityofoflifeLifeoutcome,EnjoymenttheandQLESQSatisfaction-SF (Quality of Life EnjoymentResearch, and1993. 5Satisfaction(1): p. 63-71. Research, 1993. 5(1): p. 63-71. • Significant risk for self-harm or• harmSignificant to others; risk for self-harm or harm to others; 24.Shelton, R.C., et al., Assessing effects of l-methylfolate24. inShelton, depression R.C., management: et al., Assessing results effects of aof real l-methylfolate-world patient in depression experience management: trial. The primary results care of companion a real-world for patient CNS disorders, experience 2013. trial. The primary care companion for CNS disorders, 2013. discontinued drug antidepressantsQuestionnaire – Short Form) in green. GroupQuestionnaire1 experienced– ShortnoForm) significantandin greenchanges. Groupin 1anyexperiencedreplacedof the fournomeasures,significantandchangesGroupin2any of thewithfour measures, and GroupEnBrace2 HR. The goal • Diagnosis of schizophrenia or bipolar• Diagnosis disorder; of schizophrenia psychotic symptoms; or bipolar active disorder; eating psychotic disorder; symptoms; a cognitive active eating disorder; a cognitive 15(4). 15(4). experienced significant improvementsexperiencedin the moodsignificantquestionnairesimprovementsbut not thein thequalitymoodofquestionnaireslife questionnairebut. AllnotANOVAsthe quality of life questionnaire25.Roffman, J.L., Neuroprotective. All ANOVAs Effects of Prenatal Folic25. AcidRoffman, Supplementation: J.L., Neuroprotective Why Timing Effects Matters. of PrenatalJAMA Folic Psychiatry, Acid Supplementation: 2018. 75(7): p. 747 Why-748. Timing Matters. JAMA Psychiatry, 2018. 75(7): p. 747-748. disorder; an active substance and/ordisorder; alcohol an abuseactive disordersubstance (within and/or 6 alcoholmonths abuse of screening); disorder (within 6 months of screening); 26.Obeid, R., W. Holzgreve, and K. Pietrzik, Is 5-methyltetrahydrofolate26.Obeid, R., W. an Holzgreve alternative, and to K. folic Pietrzik acid ,for Is 5the-methyltetrahydrofolate prevention of neural tube an alternative defects? J Perinatto folic acidMed, for 2013. the prevention41(5): p. 469 of- neural83. tube defects? J Perinat Med, 2013. 41(5): p. 469-83. indicating significance are reported in Tableindicating3. significance are reported in Table 3. 27.Greene, N.D. and A.J. Copp, Neural tube defects. Annu27.RevGreene, Neurosci N.D., and2014. A.J. 37 Copp: p. 221, Neural-42. tube defects. Annu Rev Neurosci, 2014. 37: p. 221-42. • Pernicious anemia; gastric bypass• Pernicious surgery; a anemia; seizure gastricdisorder bypass and/or surgery; anticonvulsant a seizure medication disorder and/or use; anticonvulsant medication use; 28.Wolff, T., et al., Folic acid supplementation for the prevention28.Wolff, of T., neural et al., tubeFolic defects:acid supplementation an update of the for evidencethe prevention for the of U.S. neural Preventive tube defects: Services anTask update Force. of theAnn evidence Intern Med, for the 2009. U.S. 150 Preventive(9): p. Services Task Force. Ann Intern Med, 2009. 150(9): p. • Allergy to study drug, inactive was•ingredients,Allergy to studybeeswax, todrug, soy, inactive fish,prevent nuts, ingredients, peanuts, beeswax, egg, wheat, soy, milk, fish, relapse. nuts,or shellfish. peanuts, egg, wheat, milk, orResults: shellfish. Group 1 experienced632-9. lower632-9. rates of relapse Measures Measures Study Design Study Design Group Group MADRS EPDS MADRS QIDS-SR EPDS QLESQ-SFQIDS-SR FinancialQLESQ-SF Disclosures/SupportFinancial Disclosures/Support rates, 9%, compared to1 F(6,54)=1.13the p=0.357CohenF(6,54)=1.831 F(6,54)=1.13p=0.111 Studyp=0.357F(6,54)=1.58F(6,54)=1.83p=0.171 p=0.111historicalF(2,17)=1.06F(6,54)=1.58p=0.368p=0.171 F(2,17)=1.06 relapsep=0.368 rate comparator Marlene P. Freeman: National Pregnancy RegistryMarlene for P. Atypical Freeman Antipsychotics: National Pregnancy Research Registry Support: for Alkermes Atypical AntipsychoticsBiopharmaceuticals, Research Forest/Actavis Support: Alkermes Biopharmaceuticals, Forest/Actavis Seen at CWMH: Seen at CWMH: • Clinician-rated scales (MADRS, • Clinician-rated scales (MADRS, consult for consult for 2 F(6,29)=5.16 p=0.001 F(6,29)=4.312 F(6,29)=5.16p=0.003p=0.001F(6,29)=6.49F(6,29)=4.31p=0.0002p=0.003F(2,9)=2.88F(6,29)=6.49p=0.108p=0.0002 Pharmaceuticals,F(2,9)=2.88 Otsukap=0.108 Pharmaceuticals, SunovionPharmaceuticals,Pharmaceuticals, Otsuka Pharmaceuticals, Inc., Teva Pharmaceutical Sunovion Pharmaceuticals,Industries; Other Inc.,Research Teva PharmaceuticalSupport: JayMac Industries; Other Research Support: JayMac MINI mood section) MINI mood section) Pharmaceuticals, SAGE Therapeutics; As an Pharmaceuticals,employee of MGH, SAGE Dr. FreemanTherapeutics; works As with an employee the MGH CTNI,of MGH, which Dr. Freemanhas had research works with fundin theg MGH from CTNI, which has had research funding from pregnancy/ ofpregnancy/ 68%, • Subject-report Group questionnaires • Subject -report2(Red questionnaires Graph)-Acute treatment of depression, at baseline multiple pharmaceutical companies and NIMH;multiple Advisory/Consulting: pharmaceutical companies Janssen (Johnson and NIMH; & Johnson), Advisory/Consulting: SAGE Therapeutics; Janssen Speaking/Hon (Johnson & Johnson),oraria: None; SAGE Therapeutics; Speaking/Honoraria: None; planning planning (QLESQ, QIDS-SR, EPDS) (QLESQ, QIDS-SR, EPDS) Table 2. F-statistics for ANOVA tests andTablecorresponding2. F-statisticsp-forvaluesANOVA. Statisticaltests andsignificancecorrespondingwas establishedp-values. Statisticalat the α =significance0.05 level was establishedRoyalty/patent,at the α other= 0.05 income:level Medical editing:Royalty/patent, GOED Newsletter; other income: Independent Medical Data editing: Monitoring GOED Committee:Newsletter; JanssenIndependent (Johnson Data & Monitoring Johnson) Committee: Janssen (Johnson & Johnson) If If Blood drawIf (V1, V4, V7): folate, If Blood draw (V1, V4, V7): folate, Consent & • Consent & • Referred to study Phone eligibleReferred to studyeligible PhoneB12, homocysteine,eligible IL-6, CRP eligible B12, homocysteine, IL-6, CRP for all analyses. Group 1 experiencedforno allsignificantanalysesdifferences. Group 1 experiencedon any of thenoquestionnaires,significant differencesas anticipatedon any inof hypothesesthe questionnaires,. as anticipated in hypotheses. clinician clinician Lee S. Cohen: National Pregnancy Registry forLee Atypical S. Cohen: Antipsychotics National Pregnancy Research Registry Support: for Alkermes Atypical AntipsychoticsBiopharmaceuticals, Research Forest/Actavis Support: Alkermes Biopharmaceuticals, Forest/Actavis from community Screen from community ScreenGenetic testing (V1): MTHFR Genetic testing (V1): MTHFR Group 2 experienced significant improvementsGroup 2 inexperiencedmood, butsignificantnot in qualityimprovementsof life as measuredin mood,bybutthesenotfourin qualityinstrumentsof life as. measured by these four instruments. thatinterview were• interviewin a• • severeAssessments depressive• Assessments state, aim was improvementPharmaceuticals, Otsuka Pharmaceuticals, SunovionPharmaceuticals,Pharmaceuticals, Otsukawith Pharmaceuticals, Inc., Teva Pharmaceuticals; Sunovion EnBracePharmaceuticals, Other research support:Inc., Teva Brain Pharmaceuticals; & Behavior Other research support: Brain & Behavior polymorphisms polymorphismsmonthly by monthly by Research Foundation, JayMac Pharmaceuticals,Research National Foundation, Institute JayMacon Aging,Pharmaceuticals, National Institutes National of Health, Institute SAGE on Therapeutics; Aging, National Advisory/Consulting: Institutes of Health, SAGE Therapeutics; Advisory/Consulting: Advertising and Advertising and • Subject meets with clinician to • Subjectphone meets with clinician to phone Relapse Rates Relapse Rates Alkermes Biopharmaceuticals (through MGHAlkermes Clinical TrialsBiopharmaceuticals Network Initiative); (through Praxis MGH Precision Clinical Medicines, Trials Network Inc.; Honoraria:Initiative); PraxisNone; Precision Royalty/patent, Medicines, Inc.; Honoraria: None; Royalty/patent, flyers flyers plan tapering schedule if still on plan tapering schedule if still on other income: None other income: None HR. Results:antidepressants in Group 1 Groupantidepressants in Group 1 2 experiencedGroup 1 Relapse 100% Rates Group 1 Relapseremittance Rates with a mean MADRS • EnBrace prenatal supplement • EnBrace prenatal supplement Gina Savella, Taylor Church, Lina Goez-MogollónGina ,Savella Alexandra, Taylor Z. Sosinsky, Church, LinaOlivia Goez B. Noe,-Mogollón Anjali, Kaimal Alexandra: Nothing Z. Sosinsky, to disclose Olivia B. Noe, Anjali Kaimal: Nothing to disclose dispensed dispensed Major Depressive Episode ExperiencedMajor Depressive Within 12- EpisodeObserved Experienced WithinExpected* 12- Observedp-value Expected* p-value week ActiveFull Phase Study week Included Active Phase in Pocket reduction of 17.33 points. Yes Yes 3 7.4 3 7.4 Week: 0 2 4 6 Week:8 010 2 12 Mo: 4 1 6 8 6 10 12 Mo: 1 6 0.005 Acknowledgments0.005 Acknowledgments No No 8 3.6 8 3.6 Visit: 1 2 3 4 5Visit: 16 2 7 3 4 5 6 7 Continuation Continuation This study was completed at MassachusettsThis study General was Hospital completed and at funded Massachusetts by an investigator General -Hospitalinitiated and grant funded from JayMacby an investigator-initiated grant from JayMac Phase Phase Pharmaceuticals, LLC., who provided thePharmaceuticals, study supplement, LLC., but who had provided no role thein study study design, supplement, implementation, but had no data role analysis,in study design,or implementation, data analysis, or Recruitment/Screening Recruitment/ScreeningAcute Treatment Phase Acute Treatment Phase Table 3: *Chi Square analysis (binaryTablevariable3: ;*Chirelapse/noSquare relapse)analysis was(binaryperformedvariable;torelapse/nocompare Grouprelapse)1 wasMDDperformedrelapse ratesto compare Group 1 MDD relapse rates (Optional) (Optional) manuscript preparation. The Massachusettsmanuscript General preparation. Hospital Translational The Massachusetts and Clinical General Research Hospital Center Translational provided resourcesand Clinical for Research blood Center provided resources for blood (23.1%) to historical controls who had relapse(23.1%)ratesto historicalof 67.7%controlsfor antidepressantwho had relapsemedicationrates ofdiscontinuation67.7% for antidepressantfor pregnancymedication.3 discontinuation for pregnancy.3 Conclusion: Study results suggest EnBraceprocessing. HRprocessing. is a novel and well tolerated intervention with efficacy for the prevention and treatment of depression among women planning pregnancy and who are pregnant. 60% ofallwomen nationallyhave anMTHFRPolymorphism glutathione, andSAM-Eproduction. intracellularly are:increasedhomocysteine, reducedneurotransmitter, of theenzymethatconverts folateintomethylfolate. The biochemical results MTHFR Polymorphisms areminorgeneticmutationsthatprevent theproduction 80% plusofdepressedoraddictedwomen have anMTHFRSNP 50% offolaterelatedNTDsareexplainedby thisgeneticvariant MTHFR Polymorphisms forthese aredocumentedriskfactors EnBrace HRnegatestheriskof Uterine Blood Clotting Uterine BloodClotting Pre-Eclampsia Pre-Term Delivery Miscarriage Homocysteine Levels (umol/L)atBaselineand Week 8 30% REDUCTION INHOMOCYSTEINE LEVELS for Adverse Pregnancy Outcomes. MTHFR andotherPolymorphisms Homocysteine Level, Mean umol/L 12 10 0 2 4 6 8 Baseline Week 8 Compared to Placebo Placebo (n=123) EnBrace HR(n=159) Adverse Pregnancy Outcomes Benefit full Psychiatry, May 2016, Farah Andrew etal. Journal ofClinical 30%, comparedtotheplacebo group. an MTHFRvariant tolower homocysteine Randomized Control Trial inpatientswith 5.53 mg.,andisproven ina330patient EnBrace HRhasthemostmethylfolate, 6,7,8,9 6,7,8,9 study in pocket Faulty Epigenetics Infertility Post-Partum Depression Perinatal Depression # 2 6,7,8,9,11,12,23,24 2,22 6,9,11 6,7,8,11 6,7,8,9,11,12,23,24

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EnBrace HR has the most folatethe most has HR EnBrace protection for the prevention of prevention for the protection Birth Defect Protection for ALL pregnant patients! Birth Defect Protection for maximum endogenous SAM-E for epigenetic normalcy! maximum endogenous SAM-E for epigenetic Health Claims: Folate and Health Claims: Folate strongest NTDs states, “The evidence for full folate andprotection from NTDs other birth defects comes study from an intervention the Medical Research by The Council of UK and Hungarian Intervention Trial.” 70% by an NTD reduced the recurrence risk by affected by pregnancy daily. taking 4mg. of folic acid or equivalency folic acid, reproductive health, or cancer even at high doses over 5mg. at high doses over health, or cancer even folic acid, reproductive EnBrace HR contains the amounts of folate needed for 170% NTD/ HR contains the amounts of folate needed EnBrace EnBrace HR contains the exact vitamin coenzymes needed to provide needed to provide HR contains the exact vitamin coenzymes EnBrace The Hungarian RCT found 100% reduction in risk of first occurrence The The FDA 21 CFR: 101.79- FDA The with a previous history of a MRC, RCT found that women The The National Academy of Sciences found no evidence of harm from of Sciences found no evidence Academy National The • of an NTD with 1mg. of folic acid. • • • EnBraceHR.com• • References: 1. Freeman et al., A prenatal supplement with methylfolate for the treatment and prevention of depression in women trying to conceive EnBrace HR Small Gel Cap and during pregnancy, Annals of Clinical Psychiatry, Feb. 2019 2. Farah et.al, Correlation of Clinical Response with Homocysteine Reduction During Therapy With Reduced B Vitamins in Patients With MDD Who Are Positive for MTHFR C677T or A1298C Polymorphism, Journal of Clinical Psychiatry, May 2016 Ingredients 3. MRC Vitamin Group, Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study, Lancet, 1991 4. Czeizel et al., Periconceptional Folic Acid and Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Con- genital Abnormalities, Clinical and Molecular Teratology, 2008 Rx, All Natural, Unique, Bioactive Prenatal Vitamin Gel Cap 5. FDA, 21 CFR-101.79- Health Claims: Folate and neural tube defects, CFR Text. 2019 6. Kirk E et al., Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study, BMJ, 2004 7. Ufriend et al., The C677T polymorphism of the methelenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage, Obstet- L-Methylfolate Magnesium 5.53mg rics & Gynecology, April 2002 8. MTHFR Living, Preparing for Pregnancy with MTHFR Mutations, Jan. 2014 Folinic Acid 2.5mg 9. Garilli, Bianca ND, MTHFR Mutation: A Missing Piece in the Chronic Disease Puzzle, Huffington Post, Summer, 2012 10. Wald et al, Public health failure in the prevention of neural tube defects: time to abandon the tolerable upper intake level of folate, Folic Acid 1mg Public Health Reviews, 2018 11. Farah et al., The Prevalence and Role of MTHFR Polymorphism in Opiate Dependency, Journal of Addiction and Therapies, Feb. 2018 12. El-Hadidy et al., Methylene tetra hydrofolate reductase C677T Gene Polymorphism in Heroin Dependence, Addiction Research & B12 (Methylcobalamin) 25mcg Therapy, 2015 13. Mararwa et al., Prenatal exposure to SSRIs and SNRIs and risk for pulmonary hypertension of the newborn: a systemic review, me- B12 (Adenosylcobalamin) 25mcg ta-analysis, AJOG, 2018 14. Chambers et al., SSRI and Risk of Persistent Pulmonary Hypertension of the Newborn, The New England Journal of Medicine, 2011 Intrinsic Factor (B12 Vitamin Bioenhancer) 25mg 15. Kieviet et al., Use of antidepressants during pregnancy in The Netherlands: observational study into post-partum interventions, BMC Pregnancy & Childbirth, 2017 B6 (Pyridoxal-5-Phosphate) 25mcg 16. MGH Center for Women’s Health, womensmentalhealth.org, SSRIs and Poor Neonatal Adaptation: How Long do Symptoms Last, 2015 B1 (Thiamine Pyrophosphate) 25mcg 17. Liu et al., Antidepressant Use During Pregnancy and Psychiatric Disorders in Offsprings, BMJ, 2017 18. Lugo-Candelas et al., Association Between Brain Structure and Connectivity in Infants and Exposure to SSRIs During Pregnancy, JAMA B2 (Flavin Adenine Dinucleotide) 25mcg Pediatrics, 2018 19. Berard et al., Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women, BMJ, 2016 B3 (Nicotinamide Adenine Dinucleotide) 25mcg 20. WebMD www.webmd.com, pregnancy-and-antidepressants, 2018 21. FDA A Appendix NIH, Antidepressant Drug Labels for Pregnant and Postpartum Women, 2014 PS-Omega-3 (Phosphatidylserine, EPA, DHA) 23mg 22. EnBrace HR PI, FDS Daily Med, Dec. 2018 23. Turgal et al. MTHFR Polymorphisms and Pregnancy Outcome, PMC 6138472, Sept. 2018 Magnesium Ascorbate 24mg 24. Duprey Robert P. MTHFR Gene Polymorphism positive treatment-resistant depression, Neuropsychiatry 2019 Magnesium L-Threonate 1mg Iron (Ferrous Glycine Cysteinate) 13.6mg Zinc Ascorbate 1mg Betaine 500mcg PATIENTS Citric Acid Monohydrate 1.83mg CAN FEEL Sodium Citrate 3.67mg COMPLETELY SAFE CoQ10 500mcg

Bioperine (B Vitamin Bioenhancer) 25mg Possible Side Effects EnBrace HR SSRI’s SNRI’s “EnBrace HR contains 5.53 mg. of L-Methylfolate Magnesium and Weight Gain No! Yes Yes Loss of Libido, difficulty achieving erections, No! Yes Yes small quantities of other folate derivatives (1mg. folic acid and 2.5mg inability to reach orgasm of folinic acid) optimal for a depressed population with high rates of Increased thoughts of suicide and No! Yes Yes aggression in adolescents & adults MTHFR polymorphism that affect folic acid metabolism and high risk Drowsiness or Confusion No! Yes Yes of neural tube defects and other birth defects.” Nervousness & Agitation No! Yes Yes EnBraceHR.com Freeman M. et al: A prenatal Supplement with Methylfolate for the Treatment and Prevention of Depression in Women Trying Adapted from: Consumer Reports Best Buy Drugs. Using antidepressants to treat depression: comparing efficacy, safety and price. 2012 to Conceive and During Pregnancy, Annals of Clinical Psychiatry, February 2019.

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