Putting theory into preliminary practice: neuroinﬂ ... · Putting theory into preliminary practice: neuroinﬂ ammatory models of postpartum depression K Brogan* ... ‘ normal’

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F : Brogan K. Putting theory into preliminary practice: neuroin lammatory models of postpartum depression. OA Alternative Medicine 2013 May 01;1(2):12.

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AbstractIntroduction

Understanding of underlying risk, predisposing factors and effective treatments with high-safety pro ile for breastfeeding mothers with postpar-tum depression continues to evolve. As investigation into neuroin lamma-tory models of depression becomes more the focus of mainstream medi-cine, research into pathological patterns of immune adaptation in late pregnancy and postpartum has begun to emerge in the literature. Alternatives to medication are highly sought after by this patient popula-tion, and natural agents such as pro-biotics, melatonin and tryptophan, omega-3 fatty acids, folate, curcumin and behavioural interventions such as dietary modi ication, exercise, mindfulness meditation, and cranial electrical stimulation present appeal-ing considerations. In lammatory lifestyle factors, appropriate diagnos-tics and environmental modi ication are addressed. This article discusses neuroin lammatory models of post-partum depression.Conclusion

Although exercise, relaxation response and targeted supplementa-tion of the postpartum patient with anti-in lammatory nutrients (such as turmeric, probiotics, folate, omega-3s and melatonin) have not been for-mally studied, they hold promise for low-risk, potentially high-yield inter-ventions of bene it to the mother and the infant.

IntroductionAs with the rising incidence of mental illness and associated disability, post-partum depression rates continue to escalate, commanding the attention of providers who care for women of reproductive age. There is an urgent need to investigate the underlying con-tributors and aetiologies of postpar-tum depression, anxiety and psychosis and to create practice algorithms that guide clinicians in the process of rul-ing out alternative explanations for a patient’s postpartum psychiatric com-plaints and considering non-pharma-ceutical interventions. Treatment data on antidepressant, mood stabilizer, benzodiazepine and antipsychotic medications in lactating women and in the postpartum population gener-ally are lacking, as are longitudinal data. To support this exploration, this article will discuss current theories proclaiming in lammation as a driver of postpartum symptomatology, address proposed biomedical screen-ing for new-onset postpartum mood and anxiety symptoms and discuss as of yet theoretical applications of life-style changes and nutrients that could be applied to buffer in lammatory responses and considered as preven-tive strategies.

DiscussionThe author has referenced some of its own studies in this review. These ref-erenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human sub-jects in these referenced studies gave informed consent to participate in these studies.

Beyond ‘chemical imbalances’Today’s pregnancies are not those of our ancestors. We have ever-in lating incidences of maternal and infant mortality and morbidity, par-ticularly in America. The changes in chronic illness in our paediatric population cannot be accounted for by Mendelian genetics, and we must look to our environment for its role in adverse epigenetic effects. Today’s mother-to-be suffers from a toxic burden through everyday exposures, and there is reason to believe that these largely unstudied exposures are cumulative in their risk. Additives such as dyes and preservatives in pre-natal vitamins, metals and adjuvants in vaccines1 and industrial chemi-cal exposures through cosmetics, furniture, paints, cars, and pollution all bioaccumulate in the very top of the food chain, the foetus. These fac-tors conspire to modulate endocrine and immune responses while simul-taneously rendering the body less capable of managing and supporting metabolic processes of detoxi ication. This is known as oxidative stress, or the inability of the products of aero-bic respiration to be effectively neu-tralized by endogenous antioxidant agents prior to causing damage to cellular machinery and membranes.

What are these toxins?Environmental toxic exposures include pesticides, most notably glyphosate; industrial chemicals such as polybrominated diphenyl ether (PDBE) lame retardants, pthalates, bisphenol A (BPA); neurotoxic met-als such as mercury and aluminium; and carcinogens such as dioxins. With 80,000 registered agents in the Toxic Substances Inventory, a mere 200 have been studied for human safety

Putting theory into preliminary practice: neuroinfl ammatory models of postpartum depression

K Brogan*

*Corresponding authorEmail: [email protected]

New York University/Bellevue Hospital Center, 280 Madison Avenue, Suite 702, New York, NY 10016, USA

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parameters. An important case series supported by the Environmental Working Group and the Red Cross examined umbilical cords, identi-fying 287 toxic chemicals, 217 of which are known neurotoxins. PDBE and BPA have been associated with adverse cognitive, endocrine and motor outcomes in children2, and while ubiquitous, may represent a modi iable exposure in our immedi-ate environment.

Between the years 1948 and 1971, treatment of pregnant women treated with a synthetic oestrogen, diethyl-stilbestrol (DES), demonstrated epigenetically driven reproductive effects two generations later, leading to its ban in 1971. Similarly, Skinner et al. have looked at germ cell inher-itance of chronic disease phenotypes (tumours, kidney disease, immune dysfunction) in fourth-generation rats born of pesticide-exposed ances-tors3, demonstrating that these non-DNA-sequence-related phenotypes could be passed down. This research serves to sound the alarm on under-studied environmental toxins and their role in consideration of preg-nancy exposures.

A recent report on the poten-tial harm associated with the most ubiquitously applied pesticide, glypho-sate, typically applied to ‘roundup-ready’ genetically modi ied crops (soy, corn, sugar beets etc.) discusses the potential role of this chemical in depleting tryptophan and altering gut lora functioning related to the pesticide’s bactericidal effects on gut microbiota4. Alteration of microbes in gut ecology may have deleterious effects independent of the depletion of this essential amino acid. The role of healthy gut microbial balance will be discussed in the following, but the integrity of colonic enterocytes rely on healthy balance of bacteria and fungi for nutrient absorption, vitamin production and immune protection.

These exposures may be driving in lammatory responses and per-turbations of the antenatal immune

system in ways that deleteriously affect the foetus and put the mother at greater risk for postpartum mood pathology.

The greatest defence compromisedThe experience of pregnancy is one that draws heavily on a woman’s native nutrient stores and involves luctuations in hormone levels and

immunologic parameters. The ana-bolic state of pregnancy demands a synergy of nutrients not only to nourish the growing foetus but also to support the tissues of reproduc-tion (mammary, placental) and metabolism. Some theorize that the relative de iciencies of certain criti-cal nutrients may make some women more vulnerable to postpartum psy-chiatric symptoms. A study of preg-nant American women found that the majority were consuming below recommended amounts of iron, zinc, calcium, magnesium, folate and vita-mins D and E5 and that selenium sup-plementation may protect against the development of postpartum depression6.

In addition, elements of our modern diet, including high sugar (fructose) content and trans fats rendered from heat-labile vegeta-ble oils, contribute to free radical production and a drive on behalf of the body, to manage these perceived sources of in lammation. Two stud-ies have raised questions about the role of foods such as gluten and dairy in the development of postpartum depression and psychosis, inding that plasma/cerebrospinal luid mor-phine-like fragments derived from casein and gluten may have an asso-ciation with maternal psychopathol-ogy7 and, potentially, mental illness in the child8.

In lammatory underpinningsSeveral years of preliminary work9

have focused on the premise that these affected women experience

suppression of the hypothalamic-pituitary axis (free cortisol- and corticotrophin-releasing hormone) more severely and extensively than ‘ normal’ controls and that post-partum blues may represent the activation of in lammatory response system10. In states of relative hypo-cortisolemia (or low hypothalamic activity), in lammation, infection and autoimmunity are more likely. Speci ically, studies have noted that macrophages are activated and TH1 cells are suppressed, suggesting that this aberrant immune response may be a signi icant driving force in the presentation of altered mood states11.

A relatively recent discovery is the psychoneuroimmunologic bridge—the kynurenine pathway. In animal and clinical research, the kynurenine:tryptophan ratio has been used as a marker of in lam-mation correlated with postpar-tum depressive behaviours and states. In lammatory messengers, or cytokines IL6 and TNF-alpha, have been demonstrated to be elevated in the cerebrospinal luid of women at the time of their childbirth, who then presented with depression at 6 weeks postpartum12. Similarly, elevated levels of IL-1B predicted depressive symptoms at 1 month postpartum9. In the non-pregnant population, in lammatory underpin-nings of depressive illness (cytokines, chemokines, reactive proteins, adhe-sion molecules) have been well-established, and anti-in lammatory interventions have been explored13. Among other disruptive effects, these in lammatory agents induce the enzyme indoleamine 2,3-dioxygenase (IDO), which ‘steals’ tryptophan in the production of kynurenine, result-ing in a net decrease of serotonin. Cortical cells appear to speci ically convert kynurenine to kynurenic acid, which acts to decrease activity through acetylcholine antagonism. Meanwhile, in the amygdala, primi-tive impulses may go unchecked secondary to N-methyl-D-aspartate

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(NMDA) receptor agonism by qui-nolinic acid. A brilliant review of this theory proposes that this sequence of unfortunate events may account for the intrusive violent images and impulses that often accompany postpartum mental pathology14 (Figure 1).

In addition, an excellent review of the literature highlights seven studies examining postpartum depression and its association with in lamma-tory modulators, the best studied of which are IL1, IL6, c-reactive protein (CRP), TNF-alpha, further supporting the association between mood states and in lammation15. Macrophage-driven cytokine production is an area of ongoing investigation in this population.

ScreeningThese models remain theoretical, and so are serotonergic theories of depression; hence, the considera-tion of individualized screening and low-risk interventions is appropri-ate. The monoamine hypothesis of depression and anxiety and associ-ated pharmacologic interventions

have fallen short of expected treat-ment responses and one reason for this may be the underlying aetiology continues largely unabated in treated patients. Assessing for individual parameters of a highly heterogeneous diagnosis serves to optimize bene it and minimize risk. Screening for the following markers is recommended to assess for drivers of in lammation:

• Homocysteine• CRP• Fasting insulin/glucose• HgA1C• Vitamin D 25 OH and 1,25• Methylmalonic acid• TSH, free T3, free T4 and

thyroid antibodies• Celiac panel• Methylenetetrahydrofolate

reductase (MTHFR) genetic pro ile.

Consideration of alternative treat-ment and non-medication alterna-tives is discussed in a review by this author16; however, the following will focus on theoretical anti-in lamma-tory interventions.

Looking to nature for supportTargeted lifestyle recommendations around minimization of personal care products, home, and food-based toxins as well as a focus on whole, organic, unprocessed food may serve to protect the interests of the mother and the growing infant. It is recom-mended that women

• ilter their air and water• purchase products free of

known carcinogens and endocrine disruptors such as parabens, TEA, fragrance (pthalates), sodium lauryl/laureth sulphate and triclosan

• eat organic produce, pastured meat/dairy

• make their own cleaning products from household vinegar, baking soda, tea tree oil or purchase similarly simple products

• avoid eating or drinking from heated plastics

• avoid cell phone use• avoid processed foods and

sugar, consume low-mercury ish

• carefully consider the risks and bene its of any elective medical interventions.

ProbioticsOur most important interface between self and the environment is the gut. The vagus nerve appears to be the primary conduit between the 200 to 600 million nerve cells in our enteric or intestinal nervous system and our central nervous system. Stimulation and function of these cells is directly affected by the population of bacteria that nourish the enterocytes, promote immune tolerance and alert us of dan-ger. While our intestinal microbiome is determined by our mode of birth delivery (c-section vs vaginal birth), whether we were breastfed and early exposures through environment and diet, it is ever modi iable through macro- and micro-nutrients, stress

5-Hydroxytryptophan

Serotonin

NMDA receptor

IFN-yTNF-a

IDO

Kynurenic acid

Tryptophan

TDO

Kynurenine

3-Hydroxykynurenine

Quinolinic acid

Nicotinamid

+

Figure 1: Metabolism of Tryptophan Is Skewed By Stress and In lammation

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and supplementation. In fact, clini-cal investigation into the bene icial effects of probiotics (lactobacillus and bi idobacterium) on mood and anxiety have suggested that probiot-ics may promote anti-in lammatory responses through IL10 activation and alleviate anxiety17.

Melatonin and tryptophanAn area of innovative speculation is looking at the role of melatonin as a treatment intervention in the third trimester and postpartum18. If serotonin is compromised by in lam-mation or dietary insuf iciency of tryptophan, melatonin will be as well. Melatonin plays a pivotal role in sleep onset and maintenance, but perhaps of equal importance, as a powerful antioxidant line of defence.

Tryptophan has been studied in the general population as an antide-pressant and augmentation strategy with sleep-promoting and anxiolytic properties. One study investigated its ef icacy for hormonally related pathol-ogy in luteal phase dysphoria and suggests it may have a role in postpar-tum states of progesterone suppres-sion19. As it relates to the kynurenine catabolism pathway, it has also been noted that women with depression and anxiety in early peurperium have higher kynurenine:tryptophan ratios indicating tryptophan degradation secondary to in lammatory stimuli.

Omega-3 fatty acidsOmega-3 fatty acids come under the umbrella of essential polyunsatu-rated fatty acids, which refers to their dietary requirement and to their unique carbon/hydrogen structure. The best-studied representatives are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). EPA is a relatively minor structural compo-nent of nerve cell membranes in lu-encing luidity but a major prosta-glandin precursor, whereas DHA is a primary component of brain grey matter. Humans are assumed to be relatively inef icient at converting

essential linoleic acid and alpha-linolenic acid precursors into 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, which is derived primarily from ish and pas-tured meat. A high-carbohydrate diet and associated elevation in insulin and glucose levels may upregulate phopholipase A2, which cleaves fatty acids from phospholipids, disturb-ing membrane structure. Given the prevalence of re ined vegetable oils in the American diet, some researchers posit that omega-6 fatty acids domi-nate 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 phos-pholipids). The anti-in lammatory effect of omega-3 fatty acids may be related to their interference with key in lammatory cytokines and competi-tive 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 omega-6:omega-3 ratio ranges from 4:1 to 1:1, depend-ing on the source consulted. Disparity in bene it with omega-3 supple-mentation may relate to a lack of individual assessment for need. There is a risk that chronic oversupplemen-tation of omega-3 from lax and/or ish 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 [PGE1] and pros-tacyclin) and contribute to imbal-ance through competitive inhibition of desaturase enzymes20. The effect of GLA administration can be sim-plistically attributed to structural membrane support and production of eicosanoid DGLA, which serves to

regulate AA (promoting its retention in the membrane) through its con-version to PGE1. At least three ran-domized, 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 prolac-tin sensitivity at the receptor site in the membrane21. The importance of individual biochemical pro ile is an essential consideration.

Epidemiologic data suggest that prevalence of perinatal depression is inversely associated with ish con-sumption22 and breast milk levels of DHA23.

In the postpartum period, there is concern for the maternal reservoir of essential nutrients having been largely depleted by the needs of grow-ing foetus. Without appropriate reple-tion, these de icits may represent an underlying aetiology of postpartum depression and anxiety. Immediately following delivery, omega-3 fatty acids are lower and omega-6:omega-3 ratios higher in women who develop depressive symptoms at 6 to 10 months postpartum24. One study demonstrated that recovery of mater-nal DHA levels at 32 weeks post-partum was slower in women with postpartum depressive symptoms25, potentially re lecting reduced mem-brane luidity. A prospective cohort study demonstrated that women with dietary ratios of omega-6:omega-3 fats greater than 9:1 (unclear whether adequate control for trans fat intake) had a higher incidence of postpar-tum depression as assessed by the Edinburgh Postnatal Depression Scale (EPDS). Given concerns over pollut-ants and mercury contamination of marine sources, many patients may bene it from considering a molecu-larly distilled, third-party-checked supplement.

FolateFolate (B9) is found in leafy greens, lentils, broccoli and sun lower seeds

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and is an important cofactor in the synthesis of monoamines, reduction of homocysteine and slowing brain breakdown of tryptophan. The rela-tionship between folate and depres-sion has been explored in studies linking low serum levels to poor treatment response, elevated homo-cysteine, depression incidence26 and augmentation to increased likeli-hood of remission27. There are four transformation steps required to render folic acid a biologically avail-able 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/S-adenosylmethionine from homocysteine (with B12 as a cofactor), in luencing the production and function of neurotransmitters, DNA and enzymes. Recent literature has focused on the role of genetic pol-ymorphism for MTHFR in the metab-olism of folate and associations with depressive illness28.

For individuals with variants in one of the two known genes, C677T and 1298C, ef iciency of conversion of folate or folic acid to l- methylfolate is compromised to varying extents. Maternal MTHFR polymorphisms are associated with antenatal depression and may in luence the foetal programming of serotonin transporter methylation and future functioning29. A recent study in the postpartum population demon-strated bene it with regard to EPDS scores at 21 months postpartum for women with C677TT polymorphism who supplemented with folic acid during pregnancy30. Bypassing this enzymatic conversion with supple-mentation of bioactive folate appears to be a potentially important treat-ment option. Thus, it is important to assess individual risk factors in terms of dietary/supplement intake in the irst trimester and biomarkers for methylation.

TurmericTaking the multiple potential path-ways to postpartum depression and anxiety into account—hypothalamic-pituitary-adrenal axis, dysregulated in lammatory pathways, increased oxidative stress, mitochondrial dys-function, nutrient depletion—the multi-modal effects of cucumin, the principal cucuminoid of the Indian spice turmeric are very appealing. Although much of the data are ani-mal-based at this point31, curcumin has demonstrated anti-in lammatory modulation of cytokines, including COX-2 inhibition, and inhibition of IDO expression, neurotransmitter-supportive through monoamine oxi-dase (MAO) inhibition mechanisms, and protective against oxidative stress on a mitochondrial and tissue level32. When used as a culinary spice or as a concentrated curcumin sup-plement, absorption is enhanced with pepper (Figure 2).

Cranial electrical stimulationCranial electrical stimulators are FDA-approved patient-administered devices. They are indicated for the

treatment of anxiety, depression and insomnia. A low-intensity alternat-ing current is transmitted across the skull for 20 minutes once or twice daily to promote alpha-wave activity and to modulate neurotransmitters, endorphins and cortisol33.

The ive meta-analyses include 67 human studies (n = 2,910) and dem-onstrate the ef icacy of devices with-out report of adverse events34. 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 repre-sent a irst-line option for women, given that it is non-invasive with a low-side-effect pro ile.

ExercisePerhaps the most potent health elixir, exercise is never more important than in our sedentary, technology-driven societies. It has been dem-onstrated to have resonant clinical bene its, such as those evidenced by a controlled trial that looked at 3 hours of weekly exercise in depressed post-partum women and found that they

TH17-inducing cytokines

COX2IDO

PGE2

Nitric oxideOxidative damage

Serotonin

Curcumin Neuroprotective

Anti-inflammatory

Antioxidant

Neurochemical

BDNFQuinolinate

Mitochondrial protection

DopamineNerepinephineCortisol modulation

Figure 2: Mechanisms of Action of Curcumin

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improved signi icantly relative to controls35. Perhaps one of the puta-tive mechanisms of this improve-ment is the effect of exercise on in lammatory cytokines, such as those demonstrated in the Treatment with Exercise Augmentation for Depression (TREAD) study, where depressed patients, partially treated with an antidepressant were found to have clinical improvement that corre-lated with decrease in THF-alpha.

Yoga and mindfulnessAs was demonstrated in a pilot study looking at mindfulness-based yoga practice in an antenatally depressed population, interventions that are based on ancient practices of parasym-pathetic nervous system support may also present a feasible option for non-medication treatment36. The practice of yoga has been demonstrated in the general and chronically ill population to have a favourable impact on cor-tisol, endorphins and in lammatory cytokines such as IL6 and TNF-alpha in as short a time as 10 days37. A recent study examined the immediate and long-term epigenetic effects of medi-tation inding that within 15 minutes of relaxation response practice, genomic bene its were apparent at centres thought to be responsible for in lammatory control (downregula-tion of NF-KB), insulin release and mitochondrial function38.

Stress and breastfeedingIt is now appreciated that science has not been able to replicate the com-plexity of breast milk and the myriad essential bene its it confers to an infant and baby and that formula feed-ing may have negative repercussions for the mother as well. An interesting exploration of this topic discusses the protective effect on mother’s mood and perceptions of stress when breast-feeding as well as the attenuation of cortisol in response to stressors during suckling. Immune support is conferred to mother and baby during exclusive breastfeeding39. A concern related to

the aforementioned toxic exposures is the accumulation of environmental contaminants in breast milk. Chlorella, a fresh water algae, has been studied as a means of promoting excretion of environmental dioxin exposure and enhancement of immune support through elevated levels of IgA40 and may represent a low-risk intervention when exposures are suspected.

ConclusionAlthough exercise, relaxation response and targeted supplementation of postpartum patient with anti-in lam-matory nutrients (such as turmeric, probiotics, folate, omega-3s and mela-tonin) have not been formally stud-ied, they hold promise for low-risk, potentially high-yield interventions of bene it to the mother and the infant. Promoting immune system balance through minimization of lifestyle-related sources of in lammation (i.e. sugar, trans fats, stress, poor sleep, sedentariness, toxic chemical expo-sures) represents a powerful com-monsense tool for health and wellness in the reproductive years and beyond. For the patient at risk for postpartum depression (based on personal, family history or sociodemographics), imple-mentation of lifestyle modi ication as prophylaxis would be bene icial. In the setting of active symptoms, the patient who elects not to take psychiatric medication should be offered alterna-tives in addition to psychotherapy and group support.

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