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

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Juan F. López, MD On my Soapbox! (Rate limiting) COOHOH COOH Tryptophan hydroxylase C NH2 C NH2

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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

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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. (Am J Psychiatry, 169:1267) No studies of folate augmentation or monotherapy for perinatal depression. Folate BOTTOM LINE: On the basis of the potential decrease in birth defects and RCT data that modestly support an antidepressant effect of augmentation with folate (i.e. folic acid 0.4– 5 mg/day or folinic acid 15–30 mg/day), we recommend folate as an important adjunctive strategy for perinatal unipolar depression, as it carries little risk and may be particularly effective in women with low serum folate levels. Vitamin D

It has been estimated that over one billion people have either vitamin D insufficiency or deficiency. The best assessment of vitamin D is by a serum 25-hyroxyvitamin D (25-OH D) level. Vitamin D deficiency is defined as a level less than 20 ng/mL and vitamin D insufficiency is a level less than 30 ng/mL. Vitamin D may have an impact on disorders such as cancer, osteoporosis, cardiovascular disease, and diabetes. Vitamin D Low Vitamin D linked to depression in young women of reproductive age (Pscyh Res 277:46) Low Vitamin D levels associated with perinatal depression (Arch Womens Ment Health 17:213) Effect of light therapy may be mediated by Vitamin D. Vitamin D

Meta-analysis of RTC of Vit D supplementation in Depression failed to show an effect (J Clin Endo Metab, 99:757-767) However, many of the studies focus on individuals with relatively low levels of depression and sufficient (not deficient) serum vitamin D levels at baseline. In addition, the studies used varying vitamin D doses and durations of treatment. Vitamin D A meta-analysis of all studies “without flaws” demonstrated a statistically significant improvement in depression with Vitamin D supplements (+0.78 CI +0.24, +1.27) (Nutrients 2014 6:1501- 1518)

Distribution of the Vitamin D receptor and 1α-hydroxylase in human brain (J Chemical Neuroanatomy 29:21-30) Vitamin D Women who take high doses of vitamin D during pregnancy have reduced risk of complications, including gestational diabetes, preterm birth, and infection. (J Steroid Biochem Mol Biol. 2013 136: 313) Women in the study who took 4,000 IU of the vitamin daily in their second and third trimesters showed no evidence of harm. Maternal delivery 25(OH)D was inversely associated with any comorbidity of pregnancy, with fewer events as 25(OH)D increased. Vitamin D BOTTOM LINE: Of course treat Vitamin D deficiency in pregnant and post-partum women, even if it may not have a psychotropic effect. Trace Elements (Metals)

Credible links between nutrient deficiency and mood have been reported for calcium, iron, selenium, magnesium, zinc (reviewed in J American Dietetic Association, 109:1566)

During pregnancy and lactation, nutritional requirements are increased so that fetal and infant growth are adequately supported, as well as maternal metabolic needs specific to reproduction. Trace Elements (Metals)

There is no need to screen pregnant women routinely for trace element status, except to monitor hemoglobin and hematocrit as an indicator of iron status. The best indicators that a woman's trace element status may be at risk is a history of poor food selections, a clinical disorder that alters trace element use or excretion, or prior residence in a region of the world where the trace element content of the soil is low. MODERN FARMING IS BAD FOR SOIL Overall Good Nutrition is Very Important! An example: A potential protective role of the Mediterranean Diet Pattern in preventing depressive disorders (Arch Gen Psych 66:1090) Diets higher on the glycemic index, are associated with greater odds of depression in the Women’s Health Initiative Observational Study (Gangwisch et al. Am J Nutrition 2015) Avon Longitudinal Study of Parents and Children Br J Psychiatry. 2013; 203: 417–421

During gestation, higher depressive symptoms were related to lower levels of healthy nutrition and higher levels of unhealthy nutrition Both depression and poor nutrition were prospectively associated with reduced cognitive function in children assessed at age 8. A direct and indirect (via nutritional environment) prenatal maternal depression effect! Web MD Recommendations (Is it enough?)

Look for a prenatal vitamin that includes: 400 micrograms (mcg) of folic acid, 400 IU of vitamin D. 200 to 300 milligrams (mg) of calcium, 70 mg of vitamin C. 3 mg of thiamine, 2 mg of riboflavin, 20 mg of niacin. 6 mcg of vitamin B12, 10 mg of vitamin E. 15 mg of zinc, 17 mg of iron. 150 micrograms of iodine In some cases, your doctor will give you a prescription for a certain type of prenatal vitamin. Exercise Several trials have shown that aerobic exercise reduces depressive symptoms. Epidemiological data suggest that regular exercise is associated with decreased risk of depressive symptoms. Studies of both antenatal aerobic exercise and general physical activity in women without MDD showed that exercise or physical activity was associated with fewer depressive symptoms in pregnancy (summarized in Best Pract Res Clin Obstet Gyn 28:85) Exercise during pregnancy attenuates prenatal depression: a randomized controlled trial. Perales et al. Eval Health Prof. 2015;38:59-72

Supervised exercise three times/week during most of pregnancy (n = 167) 90 were allocated to exercise (EG) and 77 to the control group (CG). Significant differences were found between groups in CES-D scores (EG: 7.67 ± 6.30 vs. CG: 11.34 ± 9.74, p = .005) and in percentages of pregnant women depressed (EG: n =12.2% vs. CG: n = 24.7%, p = .04) Exercise Postpartum

Two RCTs comparing a 12-week intervention of exercise with a control situation in postnatal women with an EPDS score of 10 or greater (suggestive of postnatal depression, but in itself not diagnostic) showed significantly greater reduction in EPDS (Birth 35:60; Int J Ment Health Nurs, 12:130)

One study indicated that exercise can reduce physical fatigue in postnatal depressed women (Ann Behav Med, 35:179) Exercise

BOTTOM LINE: Well…duh Massage Therapy (Outside Pregnancy) A meta-analysis of 17 RCTs of massage therapy in depressed people (perinatal studies were excluded) concluded that massage therapy is significantly associated with reduced depressive symptoms (J Clin Psychiatry, 71: 894) Massage Therapy (In Pregnancy) Antenatal massage therapy is efficacious in reducing antenatal and postnatal depressive symptoms; decreasing urinary levels of cortisol; and increasing urinary levels of serotonin and dopamine (reviewed in Deligiannidis and Freeman, Best Pract Res Clin Obstet Gyn 28:85). Antenatal massage has also been associated with reduced rates of prematurity and low birth weight. Combining massage therapy with group interpersonal psychotherapy in women with antenatal depression has been shown to reduce depressive symptomatology and cortisol levels greater than group psychotherapy alone (J Body Mov Ther, 13:297–303) Other promising “alternative” treatments in pregnancy that need further studies: Acupuncture reduced depressive symptoms in a RCT of 150 pregnant women (Manber et al., 2010) A small study (n = 27) found a positive effect for Bright Light Therapy (Wirz- Justice et al., 2011) Nutritional psychiatry: Your brain on food

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Alcohol & other drugs Nutrition Judicious use of Supplements Juan F. Lopez, MD WIMH Clinic 2019 Mens sana in corpore sano Stepping Off My Soapbox