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Mood Supporting Supplements and Complementary Treatments in Pregnancy

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Mood Supporting Supplements and Complementary Treatments in Pregnancy Mood Supporting Supplements and Complementary Treatments in Pregnancy Juan Francisco López, M.D. Associate Professor, Dept. of Psychiatry & Comprehensive Depression Center Co-Director, Perinatal Psychiatry Clinic, Associate Research Professor, Molecular and Behavioral Neuroscience Institute “Integrative” Psychiatry Genes Medications & Psychotherapy Stress Light Medical Illness Exercise Alcohol & other drugs Nutrition Judicious use of Supplements Juan F. López, MD On my Soapbox! (Rate limiting) COOHOH COOH Tryptophan hydroxylase C NH2 C NH2 N N In diet. Active Tryptophan CNS transport 5-Hydroxytryptophan 5-OH Tryptophan decarboxylase C COOH OH H N C NH2 5-Hydroxy Indole N Acetic Acid 5-OH Indole Acetaldehyde 5-Hydroxytryptamine Neurotransmitter Depletion Studies SSRI NRI Normal Responders Responders Subjects 5-HT NE 5-HT NE 5-HT NE Depletion Depletion Depletion Depletion Depletion Depletion No No No No Symptoms Symptoms Symptoms Symptoms Symptoms Symptoms Return Return Return Return Appear Appear Delgado PL, Miller HL, Salomon RM, et al. Biol Psychiatry 1999;46:212-220. Delgado PL, Moreno FA, Potter R, et al.. In: Briley M, ed. Antidepressant therapy at the dawn of the third millennium. London: Martin Dudnitz, Ltd, 1997:141-163. Complementary and Alternative Medicine Therapies Approximately 40% of U.S. adults use CAM treatment each year (NIH). Consumer Reports: 54% of Americans take a supplement once/day. In a UK study, more than one-quarter of women reported use of CAM during pregnancy (Complement Ther Med, 19 : 303) Complementary and alternative medicine therapies for perinatal depression A number of these treatments may be reasonable to consider for women during pregnancy or postpartum, but the safety and efficacy of these relative to standard treatments must still be systematically determined. Knowing What’s in Your Supplements Private Supplement Watchdog Groups Clinical Case A 25 y/o G1P0 female 24 weeks of gestation with a history of Bipolar II Disorder presents with new symptoms of MDD of one month duration. Patient had been stable with a combination of lamotrogine 200 mg daily and Seroquel 100 mg at bedtime, with no symptoms of depression, mania, or hypomania for the past two years. Patient had elected to continue on the current combination and dose of medication when she became pregnant. Recent attempts to increase Seroquel resulted in significant sedation. Patient’s medical history is positive for recent episodes of bronchitis, and a possible diagnosis of alveolitis. What could you do (pharmacologically) to treat this depressive episode? Clinical Trials of N-acetylcysteine in Psychiatry and Neurology: A Systematic Review. (Neurosci Biobehav Rev. 2015, 55:294-321 Several controlled and uncontrolled studies examined NAC use for symptom treatment and prevention during bipolar disorder’s maintenance phase. Findings and recommendations have been mixed, but often positive. Some studies finding patient’s depressive symptoms improved but frequency of mania unchanged. Published case studies have been 100% favorable. NAC may offer a special advantage to bipolar patients with medical comorbidities over those without medical comorbidities. A large study showed robust improvement in depression, functioning, and quality of life when NAC was prescribed as add-on to usual treatment. N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder—A Double-Blind Randomized Placebo-Controlled Trial Berk et al. Biological Psychiatry 64:468 Clinical Trials of N-acetylcysteine in Pregnancy Patients with history of recurrent unexplained miscarriage (n = 80) were treated with N-acetyl cysteine 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of patients treated with folic acid alone (n = 86). 600 mg N-Acetyl cysteine boosts the chances of pregnancy continuing past 20 weeks by 190%. (Reprod Biomed Online 17:122) N-acetyl cysteine boosts pregnancy rates by 40% and lowers miscarriage odds by 60% in clomiphene-resistant PCOS women (Reprod Biomed Online 20:403) Omega-3 fatty acids Omega-3 fatty acids are among the most commonly used CAM treatments in the USA. Well-established health benefits and particular benefits for obstetrical outcomes and infant development (Lancet, 369: 578; Obstet Gynecol Surv, 56: S1). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) Omega-3 fatty acids Association between low omega-3 intake from seafood and increased risk of depressive symptoms during pregnancy (Epidemiology 20:598-603). Women with no n-3 PUFA intake from seafood were more likely to have high levels of anxiety (OR 1.53; 1.25-1.87) compared with those with intake of >1.5 grams/week (Plos One 8:e67671, 2013). Omega-3 fatty acids To optimize pregnancy outcomes and fetal health, consensus guidelines have recommended that pregnant women consume at least 200 mg of DHA per day. Despite increased demand for omega-3 fatty acids during pregnancy, dietary intake by perinatal women in the US and UK has been noted as deficient. Omega-3 fatty acids Meta-analyses of RCT demonstrate a statistically significant antidepressant benefit of omega-3 fatty acids in mood disorders overall. Two meta-analyses show that EPA is the effective component (J Am College of Nutrition 28:525; J Clin Psych 72:1577). Effective dose is in the 1000 mg range, or 60% of EPA > DHA Recent Review and Meta-Analysis of CAM on Maternal Depression and Anxiety (Smith et al J Affect Disord 2019) Found no evidence for an effect for Omega 3 in reducing antenatal depression. Included three RTC studies: Freeman et al., 2008 Mozurkewich et al., 2013 Su et al., 2008 Study Study design N Omega-3 dose Length of trial Outcome Freeman et al. (2006b) Open-label, flexible-dose 12 EPA and DHA, flexible- Mean participation 40.9% mean decrease in for MDD in pregnancy dose; mean final dose 8.3weeks (protocol allowed depressive symptoms on 1.9g/day for variable duration) the EPDS Freeman et al. (2006c) Randomized dose-ranging 16 EPA and DHA, 0.5g, 1.4g, 8 weeks Mean % decreases on the trial for postpartum MDD or 2.8g/day EPDS and HRSD 51.5% and 48.8%, respectively (no significant differences between groups) Su et al. (2008) Double-blind, placebo- 36 EPA and DHA, 3.4g/day 8 weeks Significantly higher controlled trial MDD in response, remission rates pregnancy in omega-3 group Freeman et al. (2008) Double-blind, placebo- 59 EPA and DHA, 1.9 g/day 8 weeks No significant difference controlled trial for MDD in between omega-3 fatty pregnant and postpartum acids and placebo women (all received supportive psychotherapy) Rees et al. (2008) Double-blind, placebo- 26 6 weeks 6 g fish oil per day; No significant difference controlled trial for MDD in provided 1.6 g DHA; 0.4 g between omega-3 fatty pregnant and postpartum EPA (2 g DHA and EPA) acids and placebo women More recent RCT Omega 3 Studies (Makrides et al. JAMA 2010) 2399 pregnant women during the last half of pregnancy were randomised to supplementation with fish oil (800 mg/d DHA and 100 mg/d EPA) or vegetable oil (placebo). Depressive symptoms, measured by the EPDS at 6 weeks and 6 months postnatally, did not differ between groups More recent RCT Omega 3 Studies (Mozurkewich et al. Am J Obstet Gyn 2013) 126 pregnant women at risk for depression randomly assigned EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA), or soy oil placebo. EPA-rich fish oil and DHA-rich fish oil supplementation did not prevent depressive symptoms during pregnancy or postpartum. BUT depressive symptoms were low, and improved in all groups. More recent RCT Omega 3 Studies (Mozurkewich et al. Am J Obstet Gyn 2013) EPA-rich fish DHA-rich fish Placebo (n = Parameter Significance oil (n = 39) oil (n = 38) 41) Mean BDI visit 8.7(4.2) 7.0(4.6) 6.3(3.9) .051a 2, n (SD) Mean BDI visit 8.2(5.7) 6.9(6.3) 7.4(5.5) .81a 3, n (SD) Mean BDI visit 6.6(5.2) 5.7(4.8) 5.9(6.1) .78a 5, n (SD) MDD visit 2, n 4(10) 4(11) 0(0) >.16b (%) MDD visit 3, n 2(5) 4(11) 3(7) (%) MDD visit 5, n 3 (8) 2 (5) 2 (5) (%) Started 6(15) 7(18) 4(10) .56c antidepressant, n (%) On lowest 3(50) 7(100) 3(75) [1 .07c antidepressant unknown dose] dose, n (%) Omega-3 Fatty acids as Monotherapy in Treating MDD in Pregnant Women: a Meta- Analysis of RCT (Wei-Hong et al. Iran J Pharm Res 2017) Did not include Mozurkewich et al Found a beneficial effect of the omega- 3 fatty acids for pregnant women with MDD. Omega-3 fatty acids BOTTOM LINE: On the basis of positive findings from RCTs and meta-analyses in non-perinatal depression: I suggest to pregnant patients with depression to consume at least 1.5 g EPA daily I advice to post-partum patients to consume at least 1 g EPA daily Folate It is recommended that women of reproductive age consume 0.4–1 mg folic acid daily to reduce the risk of neural tube birth defects. In a large UK prospective cohort study of non-pregnant women, less than 6% of women who became pregnant during the observation period reported daily folic acid supplementation of 0.4 mg/day or more (BMJ, 338: b481) Folate Most, but not all, studies report an association of low folate levels and an increased risk of depression. Low blood folate has been associated with a poorer response to treatment with antidepressants in MDD. Folate In a placebo–controlled trial as adjunctive treatment to fluoxetine, a significantly greater improvement in the folate group, a difference most pronounced in women (J Affect Disord, 60:121) Two multicenter, placebo-controlled RCTs trials examining the use of L-methylfolate with on-going antidepressant therapy for MDD; improvement was found with 15 mg but not the 7.5 mg dose.
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