Psychopharmacology and Pregnancy: Treatment Efficacy, Risks, and Guidelines 2014

13. Complements and Alternatives to Psychopharmacology During Pregnancy

Kelly Brogan 

(1)

Faculty Member NYU/Bellevue Hospital Center, New York, NY 10016, USA

Kelly Brogan

Email: drbrogan@kellybroganmd.com

13.1 Bright Light Therapy

13.2 SAMe

13.3 Cranial Electrical Stimulation

13.4 Essential Fatty Acids

13.5 Folate/Folic Acid/L-methylfolate

13.6 Vitamin D

13.7 Oxidative Stress

13.8 Conclusion

References

Abstract

A discussion of pharmacologic and non-pharmacologic management of mental disorders in the pregnant woman is presented, with a focus on alternative health approaches and putative environmental/lifestyle contributors to depression and anxiety. The chapter explores some considerations of “modifiable risk factors” thought to play a role in epigenetic manifestations of infant and child illness. Several case examples illustrate the potential for integrative medicine in patients of reproductive age. Non-pharmacologic treatments reviewed include Bright Light Therapy, S-adenosylmethionine (SAMe), Cranial Electrical Stimulator, Essential Fatty Acids, Folate/L-methylfolate, Vitamin D, Diet, Exercise, Mindfulness.

Keywords

Alternative medicineIntegrative psychiatryFish oilB vitaminsBright light therapyDietExerciseMeditation

Board certified in Psychiatry, Psychosomatic Medicine, and Integrative and Holistic Medicine

Women of reproductive age represent a population whose treatment demands expert consideration of a complex web of risks and benefits. Between 10 and 18 % of women suffer from depression and anxiety at a time in their lives when expectations are high for stability and wellness (Heron et al. 2004). A comprehensive approach to patient care endeavors to identify root causes of illness (digestive, nutrient, hormonal, and fatty acid imbalances) and to provide patients with tools for self-care that extend beyond compliance with a prescription and for alternatives to medication when that preference is expressed.

Kate: Discontinuation of medication

Kate is a 32-year-old woman with a history of dysthymia and one depressive episode in college following a romantic disappointment. Her doctor has treated her since with sertraline. She married and seeks a consultation regarding discontinuation of her medication prior to attempting conception.

This patient represents an ideal candidate for a trial off medication and consideration of alternatives that may be more consistent with her preferences. During or after a taper of medication, risks and benefits of treatment with bright light therapy, S-adenosylmethionine (SAMe), and cranial electrical stimulation (CES) can be explored.

13.1 Bright Light Therapy

Often viewed as an evidence-based intervention for seasonal depression, bright light therapy continues to accrue data for treatment in the pregnant patient. In an open study on antenatal Major Depression, 60 min daily at 10,000 lux for 3 weeks resulted in a 49 % improvement as measured by the Hamilton Rating Scale for Depression (HAM-D) (Oren et al. 2002), and a 10-week, double-blind, randomized, placebo-controlled trial of 7,000 versus 500 lux demonstrated an effect size of 0.43 for the 7,000 lux group after 5 weeks, which could be considered comparable to antidepressant treatment (Epperson et al. 2004). In a study of patients with antepartum Major Depressive Disorder treated with 7,000 lux light therapy, there was an 81 % response rate with 69 % achieving remission (Wirz-Justice et al. 2011). A typical recommendation is for patients to get 30 min of morning exposure to a UV-filtered, 10,000 lux lamp, at the appropriate distance, with the lamp shining down on the face. Risk considerations include headache and activation in patients with a history of Bipolar Disorder.

13.2 SAMe

SAMe is a naturally occurring methyl donor in the human body that participates in a variety of synthetic reactions, including the formation of neurochemicals, methylation of phospholipids, glutathione synthesis, myelination, coenzyme q10, carnitine, creatine synthesis, and DNA transcription. To date, 48 clinical trials have been completed including head-to-head studies with traditional medications and randomized, placebo-controlled trials (Brown et al. 2002).

In a population of postpartum patients with subjective reports of depressive symptoms, doses of SAMe up to 1,600 mg achieved a 75 % reduction of symptoms in 30 days (50 % in 10 days) relative to placebo (Cerutti et al. 1993). There are eight studies (n = ~150) looking at the use of SAMe in the pregnant population for the treatment of cholestasis, which support its safety (Hardy et al 2003). SAMe is generally well tolerated with potential side effects including insomnia, anxiety, and gastrointestinal upset. Dosing is typically 400–2,400 mg depending on severity and tolerance.

13.3 Cranial Electrical Stimulation

Cranial electrical stimulators are FDA-approved patient-administered devices. They are indicated for the treatment of anxiety, depression, and insomnia. A low-intensity alternating current is transmitted across the skull for 20 min once-twice daily to promote alpha wave activity and to modulate neurotransmitters, endorphins, and cortisol (Gunther and Phillips 2010).

The five meta-analyses include 67 human studies (n = 2,910) and demonstrate the efficacy of the devices without report of adverse events (Smith 2008). There are no perinatal studies of the device; however, given the relative safety of electroconvulsive treatments in the pregnant population, adverse effects are unlikely. This device may represent a first-line option for women given that is it noninvasive with a low-side-effect profile.

Kate’s therapy

After serial introduction of both light box therapy for 30 minutes in the morning, and cranial electrical stimulation for 20 minutes twice daily, Kate was successfully tapered off of her SSRI and went on to conceive 4 months later. She maintained this treatment throughout her pregnancy.

Tasha: Polypharmacy to monotherapy

Tasha is a 30-year-old woman with a history of recurrent depression, panic disorder, and generalized anxiety, currently treated with citalopram and prn lorazepam. She has been hospitalized twice for passive suicidality. She is at 8 weeks gestation and is not in a supportive relationship. She follows a vegan diet and exercises several times a week.

The goal in this patient is to optimize medication treatment towards monotherapy, as there is sparse evidence supporting the safety of polypharmacy. Augmenting or complementing her treatment with low risk, potentially high yield, choices might be a consideration. Essential fatty acids, vitamin D, L-methylfolate, and mindfulness meditation/breathing exercises would all be considerations.

13.4 Essential Fatty Acids

Phospholipids, free fatty acids, and triglycerides provide sources of energy and storage, structural support for membrane receptors, peptides, channels, and nuanced signaling systems as eicosanoid precursors.

Omega-3 fatty acids come under the umbrella of essential polyunsaturated fatty acids, which refers to their dietary requirement, and to their carbon/hydrogen structure. The best-studied representatives are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). EPA is a relatively minor structural component of nerve cell membranes influencing fluidity, but a major prostaglandin precursor, and DHA is a primary component of brain gray matter. Humans are assumed to be relatively inefficient at converting essential linoleic acid and alpha-linolenic acid precursors into the highly unsaturated fats and eicosanoids such as the omega-6 fatty acids dihomogammalinolenic acid (DGLA) and arachidonic acid (AA) and the omega-3 fatty acid EPA derived primarily from fish and pastured meat. A high carbohydrate diet and associated elevation in insulin and glucose levels may upregulate phospholipase A2 that cleaves fatty acids from phospholipids, disturbing membrane structure. Given the prevalence of refined vegetable oils in the American diet, some researchers posit that omega 6 fatty acids dominate dietary sources of omega-3s (a point of question is whether these vegetable oils in commercial foods represent trans or distorted fats when incorporated into human phospholipids). The anti-inflammatory effect of omega-3 fatty acids may be related to their interference with key inflammatory cytokines and competitive inhibition of the cyclo-oxygenase pathway, but there may also be a role in neurotrophic growth, genetic expression, and neurotransmitter production and function.

Currently, the only means of assessing individual fatty acid needs is through erythrocyte analysis, and the optimal dietary ratio ranges from 4:1 to 1:1 omega 6:3 depending on the source consulted. Disparity in benefit with omega-3 supplementation may relate to a lack of individual assessment of need. There is a risk that chronic oversupplementation of omega-3 from flax and/or fish oil may impair the production of omega-6 highly unsaturated fatty acids such as gamma linolenic acid (GLA), DGLA, and AA (precursors to prostaglandin E1 and prostacyclin) and contribute to imbalance through competitive inhibition of desaturase enzymes (Niculescu et al. 2013). The effect of GLA administration can be simplistically attributed to structural membrane support and production of the eicosanoid DGLA that serves to regulate AA (promoting its retention in the membrane) through its conversion to PGE1. At least three randomized, placebo-controlled trials of evening primrose oil (0.5–2 mg) in premenstrual syndrome suggest that GLA is an effective intervention potentially related to its potentiation of PGE1 and attenuation of prolactin sensitivity at the receptor site in the membrane (Horrobin 1983). The importance of the individual biochemical profile is an essential consideration.

Epidemiologic data suggests that prevalence of perinatal depression is inversely associated with fish consumption (Hibbeln 2002) and breast milk levels of DHA (Golding et al. 2009). A prospective cohort study of 54,000 women found that the lowest fish intake during pregnancy raised the likelihood of treatment with an antidepressant for up to 1 year postpartum (Strøm et al. 2009). Since this data emerged, four placebo-controlled, double-blind interventional trials have been done to assess the link between omega-3 fatty acids and perinatal depression, one of which has shown an association between supplementation and decrease in depressive symptoms (Su et al. 2008; Freeman 2009; Mozurkewich et al. 2013). These studies were limited by short duration (6–8 weeks), inconsistency in assessment for indication of supplementation, timing of intervention, confirmation of serum fatty acid response, high placebo response, and small size. A recent randomized trial of EPA, DHA, or soy-oil placebo demonstrated an inverse relationship between DHA supplementation/serum levels and Beck Depression Inventory (BDI) score for at-risk women (based on history and initial BDI score) in the third trimester, but improvement did not reach significance (Mozurkewich et al. 2013). Recent meta-analyses support dosing of a 3:2 EPA:DHA, 1–3 g daily supplement relative to placebo (Sublette et al. 2011). Given data that supports mitigation of risk for preterm birth, preeclampsia, and even behavioral development, supplementation is thought to represent a low risk, high yield option. It may be advisable to balance such supplementation with GLA from evening primrose given the limited duration of these studies and the aforementioned impact on omega-3 and omega-6 metabolism with omega-3 supplementation.

In the postpartum period, there is concern for the maternal reservoir of essential nutrients having been largely depleted by the needs of the growing fetus. Without appropriate repletion, these deficits may represent an underlying etiology of postpartum depression and anxiety. Immediately following delivery, omega-3 fatty acids are lower and omega 6:3 ratios higher in women who develop depressive symptoms at 6–10 months postpartum (De Vriese et al. 2003). One study demonstrated that recovery of maternal DHA levels at 32 weeks postpartum was slower in women with postpartum depressive symptoms (Otto et al. 2003), potentially reflecting reduced membrane fluidity. A prospective cohort study demonstrated that women with dietary ratios of omega-6 to omega-3 fats greater than 9:1 (unclear if adequate control for trans fat intake) had a higher incidence of postpartum depression as assessed by the Edinburgh Postnatal Depression Scale (EPDS). Given concerns over pollutants and mercury contamination of marine sources, many patients may benefit from considering a molecularly distilled, third party checked supplement.

13.5 Folate/Folic Acid/L-methylfolate

Folate (B9) is found in leafy greens, lentils, broccoli, and sunflower seeds and is an important cofactor in the synthesis of monoamines, reduction of homocysteine, and slowing brain breakdown of tryptophan. The relationship between folate and depression has been explored in studies linking low serum levels to poor treatment response, elevated homocysteine, to depression incidence (Folstein et al. 2007), and augmentation to increased likelihood of remission (Coppen and Bailey 2000). There are four transformation steps required to render folic acid a biologically available form of folate that can cross the blood–brain barrier to participate in the production of neurochemicals. One of these metabolites, 5-MTHF or L-methylfolate, is required for the production of biopterin, a cofactor for neurotransmitter production, and of methionine/SAMe from homocysteine (with B12 as a cofactor), influencing the production and function of neurotransmitters, DNA, and enzymes. Recent literature has focused on the role of genetic polymorphism for MTHFR in the metabolism of folate and associations with depressive illness (Gilbody et al. 2007).

For individuals with variants in one of two known genes C677T and 1298C, efficiency of conversion of folate or folic acid to L-methylfolate is compromised to varying extents. Bioavailability of folate and its metabolites can theoretically impact homocysteine and neurotransmitter levels as well as global DNA methylation, including placental methylation. Maternal MTHFR polymorphisms are associated with antenatal depression and may influence the fetal programming of serotonin transporter methylation and future functioning (Devlin et al. 2010). A recent study in the postpartum population demonstrated benefit with regard to EPDS scores at 21 months postpartum for women with C677TT polymorphism who supplemented with folic acid during pregnancy (Lewis et al. 2012). Bypassing this enzymatic conversion with supplementation of bioactive folate appears to be a potentially important treatment option. Thus, it is important to assess individual risk factors in terms of dietary/supplement intake in the first trimester and biomarkers for methylation.

13.6 Vitamin D

Our growing insight into the myriad of immune modulating, bone supporting, and mood modifying actions of vitamin D, a steroid hormone, has served to reveal its complexity. Several studies have suggested a relationship between low serum vitamin D (25OH) levels and depression, particularly in women, and in premenstrual dysphoria and seasonal depression. A recent study of 178 pregnant African-American women demonstrated a relationship between low first trimester 25-hydroxyvitamin D serum levels and second trimester antenatal depression diagnosed by the CES-D (Cassidy-Bushrow et al. 2012). Optimizing levels during pregnancy and postpartum likely represents a high yield intervention given the limitations of its endogenous production. While small amounts of vitamin D may be obtained through fish, eggs, and cod liver oil, sunlight has historically been the primary source. Monitoring levels with consideration of higher dosing ranges may be a reasonable approach; particularly given data suggests that doses of 4,000 IU in the second and third trimester may minimize risk of pregnancy complications such as gestational diabetes and preeclampsia. Supplementation to achieve a serum level above 40 ng/ml, which has been found to be the lower threshold required to optimize 1,25(OH)2D levels, often requires more than the recommended 400 IU daily, even up to 4,000 IU daily (Wagner et al. 2012). An Amsterdam birth cohort demonstrated that deficiency/insufficiency of vitamin D, as demonstrated by serum levels at 13 weeks gestation, was associated with significant depressive symptoms at 16 weeks of gestation (Brandenbarg et al. 2012). Postpartum serum levels less than 32 ng/ml have been correlated with increased incidence of depressive symptoms as quantified by the EPDS (Murphy et al. 2010).

Tasha’s therapy

After an assessment of her vitamin D status, homocysteine, and MTHFR genetic profile, Tasha decided to focus on dietary changes including incorporating wild salmon and sardines twice a week, sunflower seeds, walnuts, pumpkin seeds, and pastured eggs and poultry. She obtained daily sun exposure of approximately 20 minutes from the hours of 10 to 2. These efforts, along with an established breathing practice helped to eliminate her need for additional benzodiazepine throughout her pregnancy.

Maggie: Postpartum mood disorder

Maggie is a 34-year-old woman with a history of treatment with venlafaxine in the past and several failed trials of SSRIs. She is now 4 months postpartum with tearfulness, forgetfulness, weight gain, amotivation, fatigue, and mood flatness. She describes a diet consisting primarily of refined carbohydrates and sweet snacks.

Consideration of medication treatment in a breastfeeding mother is one that relies on technical case report/series data about maternal/fetal serum levels of drugs, protein binding, and peaks and troughs. Based on the work of lactation specialists and pharmacologists such as Thomas Hale, a collective assumption is made among providers that an infant serum level of less than 10 % of the maternal dose is considered a clinically insignificant exposure.

Prior to the consideration of medication treatment for new-onset postpartum depression, anxiety, and/or often comorbid obsessive/compulsive symptoms, a thorough evaluation for root cause etiology must be performed. The experience of pregnancy is one that draws heavily on a woman’s native nutrient stores, and involves fluctuations in hormone levels and immunologic parameters. The anabolic state of pregnancy demands a synergy of nutrients not only to nourish the growing fetus, but also to support the tissues of reproduction (mammary, placental). Some theorize that the relative deficiencies of certain critical nutrients may make some women more vulnerable to postpartum psychiatric symptoms. A study of pregnant American women found that the majority were consuming below recommended amounts of iron, zinc, calcium, magnesium, folate, and vitamins D and E (Giddens et al. 2000) and that selenium supplementation may protect against the development of postpartum depression (Mokhber et al. 2011). Screening for serum levels of B12/methylmalonic acid, copper, chromium, magnesium, and zinc is indicated.

Immune modulation in the postpartum contributes to conservative estimates of a 10 % incidence of postpartum thyroiditis. Up to one-third of women experience thyroiditis with insomnia, anxiety, palpitations, irritability, and weight loss occurring 1–4 months postpartum, followed by hypothyroidism which may present 4–8 months postpartum and continue for 9–12 months. These symptoms may include weight fluctuations, constipation, hair and skin changes, depression, psychomotor slowing, and fatigue. While many cases spontaneously resolve within 1 year from onset, treatment is often indicated. Of 31 inpatient women with a diagnosis of postpartum psychosis, 19 % had detectable thyroid autoantibodies and 67 % of these women developed thyroid dysfunction by 6 months as compared to 20 % in the controls (Bergink et al. 2011). TSH at delivery has been shown to be a predictor of postpartum depression at 6 months postpartum (Sylvén et al. 2013). Screening for thyroid autoantibodies, levels of free hormone (T3 & T4), and TSH is the appropriate method of assessment.

For women with diagnosed hypothyroidism on T4 monotherapy, T3 may represent an appealing option for augmentation prior to consideration of antidepressant treatment (Nygaard et al. 2009). Given an established history in psychiatry of T3 augmentation, the support of active thyroid hormone is likely to improve mood and wellness parameters based on limited central nervous system conversion of T4 to T3, a nutrient-dependent process impeded by elevated cortisol (Cooke et al. 1992).

Maggie’s Therapy

After serum screening, it was noted that Maggie had values consistent with B12 deficiency and hypothyroidism. Her symptoms resolved after 3 weeks on replacement therapy.

13.7 Oxidative Stress

Oxidative stress refers to an imbalance between the oxidant substances produced by mitochondrial metabolism and antioxidant neutralization through superoxide dismutase and glutathione peroxidase, vitamin E, flavonoids, copper, vitamin C, zinc, and selenium. Reactive oxygen species or free radicals that are not neutralized may then compromise the mitochondrial machinery, DNA, and the delicate polyunsaturated fats in cell membranes, rendering the cell unstable.

Specific inflammatory cytokines such as IL1B have been identified as potential early warning indicators of postpartum depression developing at 1 month (Corwin et al. 2008). Biochemical individuality, in concert with limited access to nutrient-dense foods and the metabolic demands placed on us by our chemical exposures, leads to a vulnerability that can be mitigated with some attention to these areas.

Studies are being published, demonstrating that whole food diets exert a protective effect with regard to depressive incidence and diets consisting of commercial and processed foods confer a dose-dependent risk (Sánchez-Villegas et al. 2012). Sugar and trans fats (hydrogenated and heated/processed vegetable oils) are implicated as an element of the modern diet that spurs pro-inflammatory cytokines and oxidative stress. One of the biomarkers of this biochemical stress is elevated homocysteine; another is preferential formation of quinolinic acid which ‘steals’ tryptophan from serotonin formation thought to occur in pro-inflammatory states associated with postpartum depression (Maes et al. 2002). Some experts theorize that processing of foods has rendered certain molecules inflammatory/neuroactive when undigested and absorbed through the gut wall. Two studies have raised questions about the role of foods such as gluten and dairy in the development of postpartum depression and psychosis, finding that plasma/cerebrospinal fluid morphine-like fragments derived from casein and gluten may have an association with maternal psychopathology (Lindström et al. 1984) and potentially mental illness in the child.

Generationally transferred alterations in microbial flora resultant from surgical birth, formula feeding (Song et al. 2013), antibiotics, medications such as proton pump inhibitors, and dietary exposures may account for intestinal dysbiosis and attendant psychiatric and immunologic sequelae. Preliminary investigation into the anxiolytic properties of probiotics is based on the bidirectional communication between the enteric and central nervous system through the vagus nerve (Messaoudi et al. 2011). With altered flora comes poor enterocyte health, poor micronutrient production by native bacteria, poor absorption and digestion (particularly of peptides) with zonulin-mediated intestinal permeability (Fasano 2012), and production by pathogenic bacteria and fungi of inflammatory cytokines (Campbell-McBride 2010). Congenital heart defects, preterm birth, and psychiatric pathology in the offspring are all outcomes that have been examined in the study of the impact of antenatal depression and antidepressant treatment in pregnancy. We may mitigate a third path of influence by promoting a diet devoid of trans fat, refined carbohydrates, and minimized in inflammatory sugars and associated advanced glycation end products.

Other sources of oxidative stress include environmental exposures to chemicals that place a metabolic burden on the system. With 80,000 registered agents in the Toxic Substances Inventory, a mere 200 have been studied for human safety parameters. An important case series supported by the Environmental Working Group and the Red Cross examined umbilical cords, identifying 287 toxic chemicals, 217 of which are known neurotoxins. Polybrominated diphenyl ethers (PDBE) flame retardants, pthalates, and bisphenol A (BPA) have been associated with adverse cognitive, endocrine, and motor outcomes in children (Jurewicz and Hanke 2011), and while environmentally ubiquitous, represent a modifiable exposure in our immediate environment.

Treatment between 1948 and 1971 of pregnant women with a synthetic estrogen, diethylstilbestrol, demonstrated epigenetically driven reproductive effects two generations later, leading to its subsequent ban. Intergenerational epigenetic changes may also be influencing the pregnancies we are working so hard to take into treatment consideration. Examination of germ cell inheritance of chronic disease phenotypes (tumors, kidney disease, immune dysfunction) in fourth-generation rats born of pesticide exposed ancestors has demonstrated, once again, that these non-DNA-sequence-related phenotypes could be passed down (Anway and Skinner 2006). This research serves to sound the alarm on understudied environmental toxins and their role in consideration of pregnancy exposures.

Given the myriad of epigenetic variables that are just now being explored in the literature, the most prudent approach appears to be one that advocates for an organic, whole foods, low-glycemic diet, awareness of environmental chemical exposures, focus on stress management behaviors and techniques, and a personally tailored treatment plan that reflects patient preference for evidence-based alternatives to medication and/or medications with a history of treatment benefit in the patient.

13.8 Conclusion

When a woman is planning a pregnancy, is pregnant, or postpartum, she may reach out to a mental health provider for expertise in this developing field of study. Each patient’s history and current symptoms will inform the risk/benefit analysis around medication treatment during this sensitive period. After an informed consent and review of current psychotropic literature, the patient’s preferences should play an integral role in the treatment plan. Complementary and alternative medicine offers an improved capacity to individualize treatment rather than providing a “yes” or “no” to a given prescription. Whether optimizing underlying nutritional factors associated with depression such as folate, essential fatty acids, and vitamin D or using targeted therapies such as SAMe, cranial electrical stimulation, and bright light therapy, options for intervention multiply. Consideration of health and wellness parameters such as education around a whole food diet and minimization of environmental toxic exposures will also support a healthy pregnancy and postpartum experience for mother and baby.

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