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<ul><li><p>Review</p><p>Page 1 of 7</p><p>Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)</p><p>F : Brogan K. Putting theory into preliminary practice: neuroin lammatory models of postpartum depression. OA Alternative Medicine 2013 May 01;1(2):12.</p><p>Natu</p><p>ropa</p><p>thy</p><p>Com</p><p>pe n</p><p>g in</p><p>tere</p><p>sts:</p><p> non</p><p>e de</p><p>clar</p><p>ed. C</p><p>onfl i</p><p>ct o</p><p>f int</p><p>eres</p><p>ts: n</p><p>one </p><p>decl</p><p>ared</p><p>.A</p><p>ll au</p><p>thor</p><p>s co</p><p>ntrib</p><p>uted</p><p> to th</p><p>e co</p><p>ncep</p><p>t on,</p><p> des</p><p>ign,</p><p> and</p><p> pre</p><p>para</p><p> on </p><p>of th</p><p>e m</p><p>anus</p><p>crip</p><p>t, a</p><p>s w</p><p>ell a</p><p>s re</p><p>ad a</p><p>nd a</p><p>ppro</p><p>ved </p><p>the fi n</p><p>al m</p><p>anus</p><p>crip</p><p>t.A</p><p>ll au</p><p>thor</p><p>s ab</p><p>ide </p><p>by th</p><p>e A</p><p>ssoc</p><p>ia o</p><p>n fo</p><p>r Med</p><p>ical</p><p> Eth</p><p>ics </p><p>(AM</p><p>E) e</p><p>thic</p><p>al ru</p><p>les </p><p>of d</p><p>iscl</p><p>osur</p><p>e.</p><p>AbstractIntroductionUnderstanding 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.ConclusionAlthough 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.</p><p>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 patients 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.</p><p>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.</p><p>Beyond chemical imbalancesTodays 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. Todays 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.</p><p>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 </p><p>Putting theory into preliminary practice: neuroinfl ammatory models of postpartum depression</p><p>K Brogan*</p><p>*Corresponding authorEmail: drbrogan@kellybroganmd.com</p><p>New York University/Bellevue Hospital Center, 280 Madison Avenue, Suite 702, New York, NY 10016, USA</p></li><li><p>Page 2 of 7</p><p>Review</p><p>Com</p><p>pe n</p><p>g in</p><p>tere</p><p>sts:</p><p> non</p><p>e de</p><p>clar</p><p>ed. C</p><p>onfl i</p><p>ct o</p><p>f int</p><p>eres</p><p>ts: n</p><p>one </p><p>decl</p><p>ared</p><p>.A</p><p>ll au</p><p>thor</p><p>s co</p><p>ntrib</p><p>uted</p><p> to th</p><p>e co</p><p>ncep</p><p>t on,</p><p> des</p><p>ign,</p><p> and</p><p> pre</p><p>para</p><p> on </p><p>of th</p><p>e m</p><p>anus</p><p>crip</p><p>t, a</p><p>s w</p><p>ell a</p><p>s re</p><p>ad a</p><p>nd a</p><p>ppro</p><p>ved </p><p>the fi n</p><p>al m</p><p>anus</p><p>crip</p><p>t.A</p><p>ll au</p><p>thor</p><p>s ab</p><p>ide </p><p>by th</p><p>e A</p><p>ssoc</p><p>ia o</p><p>n fo</p><p>r Med</p><p>ical</p><p> Eth</p><p>ics </p><p>(AM</p><p>E) e</p><p>thic</p><p>al ru</p><p>les </p><p>of d</p><p>iscl</p><p>osur</p><p>e.</p><p>Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)</p><p>F : Brogan K. Putting theory into preliminary practice: neuroin lammatory models of postpartum depression. OA Alternative Medicine 2013 May 01;1(2):12.</p><p>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.</p><p>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.</p><p>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 pesticides 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.</p><p>These exposures may be driving in lammatory responses and per-turbations of the antenatal immune </p><p>system in ways that deleteriously affect the foetus and put the mother at greater risk for postpartum mood pathology.</p><p>The greatest defence compromisedThe experience of pregnancy is one that draws heavily on a womans native nutrient stores and involves luctuations in hormone levels and </p><p>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.</p><p>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.</p><p>In lammatory underpinningsSeveral years of preliminary work9 have focused on the premise that these affected women experience </p><p>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.</p><p>A relatively recent discovery is the psychoneuroimmunologic bridgethe 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 </p></li><li><p>Page 3 of 7</p><p>Review</p><p>Com</p><p>pe n</p><p>g in</p><p>tere</p><p>sts:</p><p> non</p><p>e de</p><p>clar</p><p>ed. C</p><p>onfl i</p><p>ct o</p><p>f int</p><p>eres</p><p>ts: n</p><p>one </p><p>decl</p><p>ared</p><p>.A</p><p>ll au</p><p>thor</p><p>s co</p><p>ntrib</p><p>uted</p><p> to th</p><p>e co</p><p>ncep</p><p>t on,</p><p> des</p><p>ign,</p><p> and</p><p> pre</p><p>para</p><p> on </p><p>of th</p><p>e m</p><p>anus</p><p>crip</p><p>t, a</p><p>s w</p><p>ell a</p><p>s re</p><p>ad a</p><p>nd a</p><p>ppro</p><p>ved </p><p>the fi n</p><p>al m</p><p>anus</p><p>crip</p><p>t.A</p><p>ll au</p><p>thor</p><p>s ab</p><p>ide </p><p>by th</p><p>e A</p><p>ssoc</p><p>ia o</p><p>n fo</p><p>r Med</p><p>ical</p><p> Eth</p><p>ics </p><p>(AM</p><p>E) e</p><p>thic</p><p>al ru</p><p>les </p><p>of d</p><p>iscl</p><p>osur</p><p>e.</p><p>Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)</p><p>F : Brogan K. Putting theory into preliminary practice: neuroin lammatory models of postpartum depression. OA Alternative Medicine 2013 May 01;1(2):12.</p><p>(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). </p><p>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.</p><p>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 </p><p>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:</p><p> Homocysteine CRP Fasting insulin/glucose HgA1C Vitamin D 25 OH and 1,25 Methylmalonic acid TSH, free T3, free T4 and </p><p> thyroid antibodies Celiac panel Methylenetetrahydrofolate </p><p>reductase (MTHFR) genetic pro ile.</p><p>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.</p><p>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</p><p> ilter their air and water purchase products free of </p><p>known carcinogens and endocrine disruptors such as parabens, TEA, fragrance (pthalates), sodium lauryl/laureth sulphate and triclosan</p><p> eat organic produce, pastured meat/dairy</p><p> make their own cleaning products from household vinegar, baking soda, tea tree oil or purchase similarly simple products</p><p> avoid eating or drinking from heated plastics</p><p> avoid cell phone use avoid processed foods and </p><p>sugar, consume low-mercury ish</p><p> carefully consider the risks and bene its of any elective medical interventions.</p><p>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, pro...</p></li></ul>