Perinatal Mental Health Conference Fairmont Hot Springs, Montana October 2018 Connecting Pathways and Building Bridges An Integrative Approach for Treating Perinatal Mood and Anxiety Disorders Christine White Deeble, ND Psycho-Gastro-Neuro-Endo- Immuno Putting it all together. • This isn’t about who I work for or what I profit from. I work for myself and I’m not selling anything or profiting from this other than I have received some payment for my time. • I believe in the body’s inherent capacity to heal itself. My • I do not believe that illness, of any kind, manifests without clues being present. My job, our job as Disclaimers: health care providers, is to identify those clues. • I believe people have a basic right to be offered all their options, and that our jobs are to facilitate their process in making those choices, and to help them re-evaluate along their journey towards their own optimal health. • I am a full-time clinician, not a researcher. I am not regularly on the lecture circuit. Which means I do not have hours to search the archives of medicine for multitudes of studies to cite. • I do rely on those who have the time to condense information and my sources will be sources that you Who am I? can learn from beyond today. • I don’t mean to be disrespectful to any profession of type of treatment, but I do expect I will say some things that some of you might be uncomfortable with because it will challenge your paradigm. • Participants will be able to identify and understand the relevance of several clinical signs and symptoms, through testing and intake, which can guide treatment decisions for women experiencing a PMAD to allow for a more Objectives comprehensive care plan. • Participants will leave with an understanding of treatment plan options that include a range of integrative medicine options such as diet, lifestyle, nutrients, and . • Women, by nature, are built to be resilient and strong, healthy, in harmony while fluctuations occur, and to have balance. We are built to carry and raise children. We are complex systems with natural synchronization. Homeostasis, • Pregnancy and birth are fundamentally understood to be huge shift in the physiology and biochemistry. Seeking These are understood to have significant impact on how the brain functions and our moods. It touches Balance women at the deepest of all levels. • When balance is lost, the results can be devastating. Helping correct that balance in a manner that doesn’t respect all the pathways involved will result in an unstable condition that will have a tendency to want to fall out of balance. • Bridges must be built with solid footings and anchored on a firm foundation. Connecting • Pathways are routes we follow to get from one place to another. pathways and building • Let’s build bridges between disciplines and make obvious the pathways that are bridges responsible for the underlying or root causes of PMAD. • Psycho—life and relationship changes, stress, trauma • Neuro—brain chemistry changes • Endo—rapid hormone fluctuations, steroid and Multi-factoral thyroid…and age and stress levels play a huge role in this element. • Immuno—inflammatory • “In recent years various neuroendocrine and psycho neuro immunological involvements in the onset of postpartum depression have been reported. The leading idea behind this is that labor, delivery, and postpartum periods induce multiple inflammatory responses in women, which, in a subset of women could be intensified by genetic predisposition, preexisting inflammatory status, and specific vulnerability The leading to depressive symptomatology. Additionally, nutritional status is essential for proper functioning of the hypothalamic- pituitary-adrenal (HPA) axis and adequate immune reactions in Interconnected the body. During pregnancy due to higher demands for certain nutrients, deficiencies are more likely to occur, leading to Pathways dysregulation of immune mechanisms, deprivation of regular cellular mechanisms, and consequently, depressive symptomatology.” • “Reduced monoamine levels (serotonin, dopamine, and norepinephrine) in the brain have been proposed as factors contributing to the neurotransmitter insufficiency responsible for the onset of depressive disorders.” • Changes in the HPA axis are well documented with depression; elevated cortisol is linked with depression; stress results in HPA axis changes; and stress impacts gut immunity and gut barrier integrity. • It is well understood and documented that commensal gut microbes produce serotonin, melatonin, GABA, catecholamines, histamine and acetylcholine. These NTs don’t necessarily cross the BBB to a large degree, the Cont’d likely impact visceral reactions that impact the CNS. And for example, Lactobacilli alters tryptophan metabolism. The SCFAs in the gut produced by commensal microbes and this is likely one of the communication pathways. Research has shown that Butyrate, a SCFA, can produce impact on the frontal cortex and result in an antidepressant effect. • We are in an age of medicine where we can no longer chose to ignore epigenetics, the gut brain axis, the impact of food quality on health, and the relationship of stress and disease • We are the sum total of our experiences, pregnancy and postpartum aren’t some sort of reset button which negates who women were before they became pregnant, gave birth, or transitioned into motherhood. And when we do consider pre-pregnancy health, we aren’t just talking about Paradigm Shift diagnosed mental health issues or frank physical pathology. • This is the heart of naturopathic or . Understanding whole health, understanding that we can be well based upon conventional standards but ill if we consider a functional perspective. • We don’t necessarily need new treatments that haven’t been invented, we need to use what we know already and apply it in the appropriate way to this population. We need to honor the obvious pathways at play.

Regarding previous slide

The predisposing, pregnancy and CUMS factors that contribute to PPD, both directly and via “baby blues” induce TDO and IDO, increasing TRYCATs, including KYNA and QUIN, as well as increasing PiCs and O&NS.

Notes: Such increased immuno-inflammation drives down serotonin, melatonin, and á7nAChr, whilst increasing autoimmunity, somatization, and relative amygdalae–cortex activity. Along with decreased omega-3 polyunsaturated fatty acids, this increases PPD. Treatments include psychotherapy and antidepressants. Estrogen can enhance the efficacy of SSRIs, whilst melatonin may provide a safer treatment for both mother and child. Some antidepressants are not recommended if breastfeeding, including those where no relevant data exist.

Abbreviations: á7nAChr, alpha 7 nicotinic acetylcholine receptor; CUMS, chronic unpredictable mild stress; E2, estradiol; EDO, indoleamine 2,3-dioxygenase; kyn, kynurenine; KYNA, kynurenic acid; MDD, major depressive disorder; O&NS, oxidative and nitrosative stress; PIC, proinflammatory cytokine; PPD, postpartum depression; QUIN, quinolinic acid; SES, socioeconomic status; SSI, selective serotonin reuptake inhibitor; T3, thyroid hormone; TDO, tryptophan 2,3-dioxygenase; TRYCAT, tryptophan catabolite.

Anderson G, Maes M. Postpartum depression: psychoneuroimmunological underpinnings and treatment. Neuropsychiatric Disease and Treatment. 2013;9:277-287. doi:10.2147/NDT.S25320. • Progesterone is produced in the ovaries, adrenals and CNS and has many metabolites. • It can induce anxiety (anxiogenic), it can reduce anxiety (anxiolytic) and can enhance sleep. • In the CNS the majority of the effects of Progesterone progesterone are by the metabolites and Brain Allopregnanolone and Pregnenolone. • Allopregnanolone is the most neuro-active and is a major GABA agonist. This results in action on GABA Chemistry receptors that are important in regulating stress, anxiety, vigilance, alertness and seizures. The result can be calming and supportive of sleep, it can also result in anxiety and depressive moods. • When allopregnanolone interacts with the GABA receptor, it changes it and makes it less reactive to further stimulation and this can then result in decreased GABA-mediated inhibition centrally. This can then translate into anxiety and depression (the Allopregnenolone, theory being if GABA levels are innately to low). GABA and • Additionally, progesterone results in reduced serotonin action by deceasing platelet uptake of Serotonin serotonin and thus mood impact or increased anxiety. • Additionally, progesterone also lowers serotonin levels by increasing MAO which is the enzyme that breaks down serotonin.

Brexanolone “Pregnancy causes a dramatic rise in the reproductive hormones estrogen and progesterone. It also produces a spike in brain levels of a steroid called allopregnanolone, which normally activates receptors for GABA—a neurochemical that signals brain cells to stop firing. GABA receptors go dormant during pregnancy to avoid overactivation by allopregnanolone; otherwise a pregnant woman would become virtually anesthetized. Immediately following birth, estrogen, progesterone and allopregnanolone drop back to normal levels, after which GABA receptor levels rebound quickly. But in some new mothers, this rebound takes longer, which may result in postpartum depression. The new drug, developed by Sage Therapeutics, works by elevating allopregnanolone. Doing so activates GABA receptors and keeps the neurochemical at a healthy level. In one of Meltzer-Brody’s studies, a phase II clinical trial of 21 severely depressed postpartum women, 70 percent of those who received the drug went into remission. Most important, the effect occurred immediately after it was administered, and benefits persisted for 30 days. Sage Therapeutics has since conducted two phase III trials with a combined 226 postpartum women, and preliminary reports are promising. The drug, called brexanolone, is now under review by the U.S. Food and Drug Administration.” • Do we need a new drug, or do we need a new way of thinking about PMADs? • What if we simply begin to use what we know and cease with a mechanistic approach to health and healing and instead follow the known pathways and utilize the known Paradigm mechanisms of action. • Research has shown the administration of oral shift….. pregnenolone increases allopregnanolone levels. • Assessing and the augmenting progesterone levels is also a likely mechanism to address allopregnanolone levels. • “Genetic vulnerability predisposes subgroups of women to develop perinatal depression. Yet it is the epigenetics that plays a pivotal role in the development of a majority of illnesses, perinatal Another depression included. Various external factors influence either triggering or preventing an consideration: illness in a predisposed person. Environmental toxins are abundant in our lives and frequently Genetics vs cause oxidative stress, which translates into the inability of the organism to effectively neutralize Epigenetics metabolic products of aerobic oxygenation, leading to different cellular and neuronal damages.” • Integrative Therapies for Depression, Chpt 28 Integrative Approaches to Perinatal Depression, Vesna Pirec, MD and Kelly Brogan MD, pg 424 • HPA Axis Dysfunction and relevance for PMAD The pathways, • The Gut-Brain Axis the testing • The role of hormones and neurotransmittes and what to • Testing: Conventional, Functional, Interpreting • Treatment Options do • Resources • After 36 weeks of gestational age, estrogen and progesterone levels drastically increase compared to the pre-pregnancy baseline and so does CRH which regulates the HPA axis. CRH also increases dramatically due to its secretion Interconnected from the placenta so that its level may increase Pathways: HPA up to 100 times at 6-8 weeks prior to delivery. • Thus, cortisol levels increase significantly. Axis and PMAD • After birth, Estrogens, Progesterone, CRH and Cortisol drop rapidly. For some women, this transition is not temporary and predispose them to PMAD. • The hypothalamus-pituitary-adrenal (HPA) axis is the endocrine response to stressors producing adrenocorticotropic hormone (ACTH) from the pituitary gland with measurable changes in levels of plasma cortisol and salivary cortisol as produced in the adrenal cortex. The HPA Axis sympathetic-adrenal-medullary system produces epinephrine and norepinephrine and measurable changes in heart rate are seen. • These systems work together to generate the “stress response”. • HPA axis dysfunction, or adrenal dysfunction/ is an alteration of the stress response resulting in a dysregulation of stress hormones – mainly an alteration in the Adrenal quantity and/or diurnal pattern of adrenal hormone secretion (cortisol and DHEA). Dysfunction/ • Those experiencing HPA axis dysregulation Adrenal Fatigue commonly complain of fatigue but may also experience sleep disruptions, weight changes, salt and/or sugar cravings, heightened allergies, anxiousness, nervousness, blood pressure alterations and numerous other symptoms • “Through several factors like microbial balance, gut barrier integrity, immune stimulation, and altered systemic inflammatory load, the health of the gut is increasingly being seen as vital to mental health.” Integrative Therapies for Depression, Chapter 3, The Gut-Brain Axis, The Role of the Gut in Brain Health,. Greenblatt and Brogan.2016 • Population-based studies have shown that individuals consuming a “traditional” diet consisting of vegetables, fruits, and lean, non-processed meats have a decreased likelihood of anxiety. Conversely, individuals consuming a “Western diet,” high in processed meats, pizza, chocolates, sweets, soft drinks, margarine, French fries, beer, coffee, cake and ice cream, have Gut-Brain Axis been shown to have a significantly increased likelihood of anxiety. • There appears to be a higher prevalence of SAD [Social Anxiety Disorder] in individuals who have celiac disease or a sensitivity to gluten. Greater rates of anxiety are also seen in people suffering from irritable bowel syndrome (IBS), a condition that has also been linked to food allergies/sensitivities. Therefore, ruling out the possibility of food allergies and intolerances is a reasonable step to take when investigating underlying causes of SAD.” NDNR March 11, 2015 • “In the CNS, serotonin is involved primarily in regulating emotions and stress, sleep, and appetite. In the GI tract, serotonin modulates intestinal secretions, GI motility, and other critical functions. Changes to the gut microbiome have been shown to profoundly Serotonin and influence neurotransmission of serotonin in both the PNS and CNS. Probiotics could the gut potentially improve CNS symptoms by promoting the production of free tryptophan, which then serves to increase the availability of serotonin.” THE MICROBIOTA-GUT-BRAIN AXIS: THE BIOLOGICAL & CLINICAL BASIS FOR USING PROBIOTICS IN MENTAL HEALTH DISORDERS March 2, 2018 Jeremy Appleton, ND Serotonin, tryptophan metabolism and the brain-gut-microbiome axis S.M. O’Mahonya,b,1, G. Clarkea,c, ,1, Y.E. Borrea, T.G. Dinana,c, J.F. Cryana,b

∗

Abstract

Gut microbiota-brain axis is the two-way information communication network between intestinal microbiota and brain, whose composition includes gut microbes and their metabolite, intestinal tract, enteric nervous system and the sympathetic and parasympathetic branch of the autonomic nervous system, neural immune system, neuroendocrine system and central nervous system. Gut microbiota-brain axis has become one of the hotspots in the field of neuroscience. A growing body of evidences have revealed that gut microbes not only play an important role in maintaining normal healthy homeostasis, but also can affect the individual’s mental health through inflammation, immune system, stress reaction and HPA axis. Dietary changes gut microbes associated with the risk of suffering from mood disorders. Probiotics supplementation not only plays an important role in the treatment of mental disease and regulating gut microbes, but also is a valuable therapy pathway for developing the new treatment methods to treat the brain disorder.

Hongxing Wang and Yuping Wang. “Gut Microbiota-Brain Axis and Mental Health”. EC Psychology and Psychiatry 1.2 (2016): 55-60. Gut Microbiota-Brain Axis

Gut microbiota-brain axis refers to two-way information flow network between gut microbiotia and brain, with its components including gut microbiota and their metabolic products, enteric nervous system, sympathetic and parasympathetic branch within autonomic nervous system, neural immune system, neuroendocrine system and central nervous system.

Through this network, the brain affects gut movement, sensory and secretion function. On the contrary, viscera information from the gut also affects brain function. For example, incoming and outgoing branches of vagus nerve allow information to transfer in and out of gut. Activation of the vagus nerve has anti-inflammatory effect. Positive effects of many gut microbiota and probiotics on brain function are dependent on the activity of vagus nerve. But other independent mechanism also plays a role.

Hongxing Wang and Yuping Wang. “Gut Microbiota-Brain Axis and Mental Health”. EC Psychology and Psychiatry 1.2 (2016): 55-60. Gut, inflammation and immune system

Development of gut immune system depends on gut microbiota. Segmented filamentous bacterium in gut can restore the full functions of gut B and T lymphocytes. Bacteria communicate with the host through a variety of ways, and the receptor-TLRs of host cell plays a key role in this communication between bacteria and host. These receptors are the first step to produce cytokine reaction and is also widely distributed on neurons. So, intestinal epithelial cells can transport microbial composition or metabolites into inner environment, and the nervous system also interacts with these bacterial and viral components. The balance of gut microbiota may change the regulation of inflammatory response and this mechanism may also get involved in the regulation of emotion and behavior.

Hongxing Wang and Yuping Wang. “Gut Microbiota-Brain Axis and Mental Health”. EC Psychology and Psychiatry 1.2 (2016): 55-60. Gut, stress reaction and HPA axis

Depressive disorder involves inflammation and HPA. Gut microbiota affect the hypothalamus function via pro-inflammatory factors and anti-inflammatory factors. Among them, pro-inflammatory factors stimulate release of corticotrophin releasing hormone (CRH) which is the main polypeptide regulator of HPA axis. HPA stimulates the adrenal glands to release adreno-cortico-tropic-hormone (ACTH), and ACTH is necessary component to the normal stress. However, over-expression of CRH promotes stress over-reaction. The system disorder is associated with depression and anxiety. The germ-free mice study indicates that the symbiotic microbiota plays a key role of healthy and balanced immune system.

Damage of gut microbiota stimulates HPA activities to release stress hormones, and exogenous stress source direct stimulates HPA. At the same time, HPA also has devastating effects on gut microbiome. Stress leads to changes of intestinal motility and secretion function, which have negative effect on regeneration ability of intestinal mucosa and gut microbiota. Stress reaction releases neuro- transmitters and pro-inflammatory factors, and these neuro-transmitters and pro-inflammatory factors affect intestinal physiology.

Hongxing Wang and Yuping Wang. “Gut Microbiota-Brain Axis and Mental Health”. EC Psychology and Psychiatry 1.2 (2016): 55- 60. • Nutrition and exercise matter; • A history with using exercise to manage mental We are what health and stress is key to understand; • Less than ideal diets high in carbohydrates, we eat: what processed foods, or if women are not eating regularly due to parenting an infant will impact to consider health and mental health. about diet and • A lack of actual nutrients and elevated stress hormones means nutrient depletion. B exercise vitamins, magnesium and quality protein are key to brain chemistry. • Studies are showing that bacterial/microbiome imbalances are related to higher levels of perceived psychological stress as measured by standardized testing and that the introduction Stress, of probiotics resulted in decreased levels of exercise and urinary cortisol levels. • Increased levels of activity and exercise have probiotics shown positive impact on the microbiome. • We all need movement and exercise. But also consider the new mother who is used to be very active and is now become sedentary as she cares for an impact. There is a real physiologic impact. Estrogen, Progesterone, DHEA, Testosterone Steroid Hormones • Estrone (E1)-5-10% of total estrogen, greater than 10x weaker than E2 • Estradiol (E2)—The most abundant estrogen and women’s brain estrogen receptors are specific to this form. • Estriol (E3)—produced in large quantities in pregnancy. Estrogens • There is vast evidence to prove women’s moods are strongly linked to shifts in E levels. • Multiple studies have shown rapid improvement in PMAD with E2 treatment. • Nearly every neural pathway is impacted by estrogen. • Produced by the ovaries, adrenal glands, and the CNS. • It exerts neuropsychological and neuroprotective effects. • It can increase anxiety and induce sleep. • It can be low in women with a history of Progesterone miscarriages and that deficiency can translate into postpartum resulting in impacts on the HPA Axis and menstrual cycles. • It is implicated in PMS and PMDD. • In short, progesterone can be part of the solution and part of the problem. • DHEA is the most abundant steroid hormone in the body. • In later stage HPA Axis dysfunction, DHEA levels will drop along with the cortisol. It is an indicator of the degree of dysfunction. DHEA and • It is a precursor to testosterone and the Testosterone estrogens. • It has been shown in studies to positively impact depression in men and women. • Testosterone-May or may not play a role in PMAD but can have an impact on quality of life; imbalance with Estrogens can lead to acne. • Serotonin, GABA, Dopamine, Norepinephrine, Epinephrine (Adrenaline), Glutamate, Glycine, Neurotransmitters Histamine and PEA • SEROTONIN is a key neurotransmitter that is involved in the regulation of sleep, appetite and aggression. Serotonin imbalance is a common contributor to mood problems, and pharmacologic agents that alter serotonin levels are among the most commonly used class of drugs prescribed for anxiety and depression. Serotonin • High stress, insufficient nutrients, fluctuating hormones and the use of stimulant medications or caffeine can all contribute to the depletion of serotonin over time. When serotonin is out of range, depression, anxiety, worry, obsessive thoughts and behaviors, carbohydrate cravings, PMS, difficulty with pain control, and sleep cycle disturbances can result • GABA is the major inhibitory neurotransmitter found in the CNS and is important for balancing excitatory action of other neurotransmitters. High levels can result in a ‘calming’ action that may contribute to sluggish , feelings of sedation, and foggy thinking. Low GABA levels are associated with dysregulation of the adrenal GABA stress response. Without the inhibiting function of GABA, people can become anxious and/or reactive and those symptoms can extend from poor impulse control to seizure disorders. Alcohol as well as benzodiazepine drugs act on GABA receptors and imitate the effects of GABA. • DOPAMINE is largely responsible for regulating the pleasure reward pathway, memory and motor control. Its creates both inhibitory and excitatory action depending on the dopaminergic receptor it binds to. Memory issues are common with both elevations and depressions in dopamine levels. Caffeine and other stimulants, such as medications for ADD/ADHD, often improve focus by increasing dopamine release, although continual stimulation of this release can deplete dopamine over time. • Common symptoms associated with low dopamine levels include loss of motor control, cravings, compulsions, loss of Dopamine satisfaction and addictive behaviors including: drug and alcohol use, smoking cigarettes, gambling, and overeating. These actions often result from an unconscious attempt to self- medicate, looking for the satisfaction that is not occurring naturally in the body. • Elevated dopamine levels may contribute to hyperactivity or anxiety and have been observed in patients with schizophrenia. High dopamine may also be related to autism, mood swings, psychosis and attention disorders. L-DOPA is a precursor to dopamine, and is used therapeutically for low dopamine conditions such as Parkinson’s disease. These medications can cause elevations in dopamine. • NOREPINEPHRINE, also called noradrenaline, is an excitatory neurotransmitter produced in the CNS, as well as a stress hormone produced in the adrenal medulla. Norepinephrine is involved in a wide variety of actions including attention, focus, regulating heart rate, affecting blood flow, and suppressing inflammation. Involved in arousal, it prepares the body for action by relaying messages in Norepinephrine the sympathetic nervous system as part of the autonomic nervous system’s fight-or-flight response. High levels of norepinephrine are often linked to anxiety, stress, elevated blood pressure, and hyperactivity, whereas low levels are associated with lack of energy, focus, and motivation. • EPINEPHRINE, often better known as adrenaline, is synthesized from norepinephrine in both the CNS and the adrenal medulla. Much like norepinephrine, this excitatory neurotransmitter helps regulate muscle contraction, heart rate, glycogen breakdown, blood pressure and more, and is heavily involved in a stress response. Elevated levels of epinephrine are Epinephrine often associated with hyperactivity, ADHD, anxiety, sleep issues, and low adrenal function. Over time, chronic stress and stimulation can deplete epinephrine stores leading to difficulty concentrating, fatigue, depression, insufficient cortisol production, chronic stress, poor recovery from illness, dizziness and more. • GLUTAMATE is an excitatory neurotransmitter and is considered to be the most abundant neurotransmitter in the nervous system. Glutamate is involved in most aspects of normal brain function including cognition, memory and learning, although high levels of glutamate can cause excitotoxicity, a process where nerve cells are damaged by excessive stimulation. Elevated glutamate levels are commonly associated with panic attacks, anxiety, difficulty concentrating, OCD and depression, whereas low glutamate levels may result in agitation, memory loss, sleeplessness, low energy Glutamate levels and depression. and Glycine • GLYCINE is inhibitory and plays dual roles as both a neurotransmitter and an amino acid that serves as a building block of proteins. Glycine improves sleep quality, calms aggression, and serves as an anti-inflammatory agent. Glycine has been shown to boost mental performance and memory. Elevated glycine levels may be associated with compromised cognitive processing. Low levels of glycine may contribute to poor sleep, poor cognitive function, and issues with memory. • HISTAMINE is an excitatory neurotransmitter involved in the sleep/wake cycle and inflammatory response. Histamine plays a dual role in the body as both a neurotransmitter and immunomodulator increasing metabolism, promoting wakefulness, attention, circadian rhythms, learning, and memory. Elevated levels may be associated with allergy-like symptoms, gastro-intestinal concerns, and inflammation. Elevated histamine can contribute to Histamine and insomnia. Low histamine may affect digestion and appetite control, learning, memory, and mood, and may result in drowsiness. PEA • PEA (PHENETHYLAMINE) promotes energy, elevates mood, regulates attention and aggression, and serves as a biomarker for ADHD. Elevated PEA may contribute to anxiety, with very high levels having amphetamine-like effects. Elevated PEA levels may be associated with higher cortisol levels. Low PEA may be associated with ADHD, depression, Parkinson’s disease and bipolar disorder.

Testing • Conventional vs Functional • Blood, Urine and Saliva Options • Interpretation and Perinatal Considerations • Conventional testing generally refers to serum testing vs functional which can also include saliva or urine. • Functional testing refers to testing that seeks to show what might be called sub-clinical levels or which utilizes methodology not considered conventional or standard of care. Conventional • Functional also refers to the ranges used to interpret lab results. • Functional testing includes urine hormone and neurotransmitter testing, for example, and salivary hormones. It also includes vs digestive health stool testing which measures a far more comprehensive set of markers than conventional stool testing. Functional • With the perinatal population, you will need to interpret lab values in the context of the ssx she is presenting with, pre-pregnancy values if they exist, pregnancy values if within a few weeks to a few months of birth, and in the context of her menstrual cycle if cycles have resumed. If she is taking hormonal contraception or psychoactive medications, those too much be taken into account. • Look for extreme values within the normal ranges, use third trimester ranges for comparison, compare with pre-pregnancy levels if possible. Listen to her symptoms, take a good history and then use that to guide your Testing interpretation. • Medicine is a practice, there is art to treating the whole person. • This choice may be dictated by time or financial resources. Insurance sometimes covers these tests. • Blood, urine and saliva each provide unique information. • Establish a relationship with a lab company or Blood, Saliva another practitioner who can help you with interpreting labs. Functional lab companies and Urine have staff dedicated to helping clinicians with interpretation. • If you are going to consider doing testing other than conventional serum testing, you will need to have test kits on hand. • Use for the basics, and thyroid, consider other testing methods for other hormones. • It provides a snap shot which will not show daily fluctuations and with some hormones that is critical Blood (Serum) • Generally shows only total hormones, not free Testing or unbound. • Should at least run a SHBG to assess this binding protein to understand free vs total hormones. • And, if it is all you can do, then get the levels, but you have to interpret in the context of her symptoms. • CMP, lipids, CBC with auto diff—look for what is in the high or low end of the ranges. • Ferritin, Iron, and TIBC –impacts energy levels, thyroid and dopamine production. Blood Testing- • HCRP-high sensitivity C reactive protein— inflammatory marker. the basics • Thyroid-TSH, Free T3 and T4, Reverse T3, Anti- thyroid anti-bodies, Anti-peroxidase antibody • Consider Celiac testing, pregnancy is a known stressor that can trigger the onset of active celiac disease • Copper levels rise with pregnancy and should drop rapidly postpartum; previous pregnancies can result in rising levels in women who don’t clear it well. Excess copper in the brain alters the balance of dopamine and norepinephrine Copper, which both regulate mood. Copper toxicity with elevated estrogen (such as with HRT or oral contraceptives) can consider in further complicate the picture. Ideally, run serum copper and ceruloplasmin to get a free copper level. multiparas • Total serum copper normal range = 10-22 umol/L (63.7-140 ug/dL) women and • Total serum copper high-normal = 17.5 – 20.0 umol/L (110 – 125 ug/dL) PPP • Total serum copper high = >20 umol/L (125 ug/dL) • Percentage free copper above 20% is classified as elevated. • Has been shown to indicate higher than physiological levels of hormones in people using transdermal hormones. • Saliva testing cannot show metabolites, which can be very helpful in understanding complex cases. Saliva Testing • Any oral supplementation will skew results and cross-reactivity occurs. • In the context of postpartum women, it is best for circadian patters for free cortisol. Often paired with DHEA which can also be useful. • Also helpful for cycle mapping. • When to consider and not to consider. • Hormones • 24 hr urine • DUTCH-Dried Urine Testing for Urine Testing Comprehensive Testing • Neurotransmitters • Urine testing is easy and provides good insight into overall levels • 24-hr urine is a reliable method of assessing active hormones and their metabolites (and metabolites have physiologic activity). • Show total daily production, anabolic to catabolic Urine Testing: activity, all sex and adrenal hormones, and some labs will also do a Free T3 and Free T4 which can be 24-hr used with serum testing to further evaluate complex cases. collection and • Are done at home which makes them convenient and can capture a ideally less stressful or more DUTCH representative day in a woman’s life. • Gives greater information to assess low adrenal function status as an element of or reason for depressive symptom picture. • Salivary • 4-point cortisol (serum AM cortisol is NOT helpful except in severe cases) • Estrogens, Progesterone, however best for cycle Hormone mapping Testing: • Urine • Steroid hormones (if available, can be more useful Cortisol, DHEA, than blood levels due to metabolites and levels of free hormone, vs bound) Estrone, • Melatonin (measured during the night) Estradiol, • Neurotransmitters (Serotonin, GABA, Epinephrine, Norepinephrine, Dopamine); no need to stop any Progesterone psychoactive medications for this testing; supplements may interfere, follow lab recommendations. • Urine testing provides indirect information regarding levels through analytes in urine. • Some are produced in the brain and cross the BBB, and some are produced in the periphery. Neurotransmitter The kidneys filter them into the urine. Some measurements represent what is in the CNS and Levels for others it represents what is made in the periphery. • Overall it represents the systemic neurotransmitter tone and allows guidance for treatment decisions. • Food-Diet—Let food be your medicine and medicine be your food. • Lifestyle-movement and mindfulness • Getting outside • Walking • Change of scenery Treatment • Mind-body practices • Talking, connecting, acknowledging—take away the guilt. Yes they Options are tired, its OK to say it, they aren’t whining and the aren’t weak. • HRT • Not really “replacement”. Is about augmenting current levels, it is about physiologic dosing and bioidentical composition. • Rx—short term, long term, complementary with other approaches • Supplements • D3—Vitamin D Council • https://www.vitamindcouncil.org/i-tested- my-vitamin-d-level-what-do-my-results- mean/ • Folate vs folic acid Nutrients • Magnesium—chelates are more absorbable. Some combined with B6, B12, methylfolate, and malic acid to improve absorption. • B’s—B complex, verify folate, not folic acid. • PUFAs—fish oil, omega 3-6-9 blends • Protein, Protein, Protein—meat, plant, powders • People with darker skin. People who spend a lot of time indoors during the day. For example, if you’re housebound, work nights or are in hospital for a long time. • People who cover their skin all of the time. For example, if you wear sunscreen or if your skin is covered with clothes. • People that live in the North of the United States or Canada. Vitamin D • Older people have thinner skin than younger people and this Deficiency may mean that they can’t produce as much vitamin D. • Infants that are breastfed and aren’t given a vitamin D supplement. If you’re feeding your baby on breast milk alone, and you don’t give your baby a vitamin D supplement or take a supplement yourself, your baby is more likely to be deficient in vitamin D. • Pregnant women. • People who are very overweight (obese) • Vegetables, Fruit and Protein- • Meat or protein powders • Organic if possible—EWG.org • Fats • Water and electrolytes Food • Limit grains, especially refined • Caution with dairy • Limit the refined sugar • Limit the coffee or soda/caffeine • Limit nuts and legumes, they can just become to dominant Glyphosate has been linked to the depletion of the serotonin precursor, tryptophan. It has also been shown to negatively impact the gut micro biome (gut bugs) which then impacts the Food, Mood, absorption of nutrients and thus negatively impacts the formation of and the value of elements necessary and critical for non-GMO and maintaining mood stability, such as neurotransmitters. This harm to cell-to- organic food cell communication is referred to as endocrine-disruption.

Samsel, A and Seneff S. 2013. Glyphosate’s suppression of cytochrome P450 enzymes and amino acid biosynthesis by the gut microbiome: Pathways to modern diseases. Entropy. 15(4):1416-1463. • Sugar isn’t just sugar. • HFCS (high-fructose corn syrup, natural corn syrup, isolated fructose, maize syrup, glucose/fructose syrup and tapioca syrup) is a damaging sugar by the nature of how it impacts your gut enzymes, is made Food, Mood, from crops treated with glyphosate, and is Deficiencies processed in the liver and turned into fat. • Fats, trans fats, hydrogenated oils—”Natural” fats and “sugar” are generally healthier. • As study done in 2000 showed that pregnant women in the US tend to consume inadequate levels of essential nutrients such as calcium, magnesium, iron, zinc, vitamin D, and folate. • Rice Cooker or One Pot • Frozen vegetables and fruit • Prepare ahead, like hard boiled eggs Food and Diet • Soup, miso, canned—it needs to be easy. Strategies • Bone broth—store bought, in powders • Greens powders • There needs to be choice and it needs to be easy, whatever these mean for individual women. Probiotic supplementation and safety

• https://ndnr.com/pain-medicine/probiotics-and-gastrointestinal- health/ • Other resources • Do your research, make specific recommendations. • Melatonin is a normal component of human milk which is synthesized from the amino acid tryptophan. • A study with lactating women showed laughter raised melatonin levels. • Mothers are recommended to nurse in the dark at night so preserve melatonin levels and help preserve sleep rhythms in infants. • “In studies in which exogenous oral melatonin was given to women, the resulting serum melatonin was variable, but peak serum concentrations ranged from 1.1 to 2.6 mcg/L for each 1 Melatonin mg administered. This would result in an average increase in breastmilk melatonin concentration from 0.4 to 1 mcg/L for each 1 mg administered to the mother… resulting concentrations would be higher than the typical physiologic peak milk concentrations of 0.02 mcg/L, it would present a considerably lower dose to the infant than the 10 mg/kg dosages of melatonin that have been safely administered to neonates in clinical studies.” • Delivery matters, oral doses are approx. 15% bioavailable. Sublingual delivery allows for greater bioavailability. Ideal dosing, sublingual 1-3 mg at bedtime. Homocysteine and Serotonin: Association with Postpartum Depression • Postpartum depression (PPD) is a disorder of multifactorial origin with significant consequences on both maternal and child health. One of the biological factors implicated is perturbed methionine–homocysteine metabolism. Since this metabolic pathway plays a significant role in myelination of nerve fibers, the growth and development of the child would also be adversely affected. We carried out this study in 103 women (58 with PPD and 45 without PPD) who delivered their child in our institute from December 2010 to November 2011. The study group was evaluated for PPD using Edinburgh postnatal depression scale with a cut-off score of 10. Assessment of fetal well being was done by APGAR score assessed immediately after birth. Serum folic acid, vitamin B12, homocysteine and serotonin was done by ELISA. We found significantly elevated levels of homocysteine in women with PPD as compared to those without PPD, both at 24–48 h as well as six weeks after delivery, although no associations were found with folate and vitamin B12 levels. Also, there was a significant negative correlation between serum homocysteine and serotonin levels in the postpartum depression group with a significant negative correlation between homocysteine and serotonin. Our study showed a significantly lower APGAR score in the infants born to mothers with PPD. Our study also shows that homocysteinemia is associated with PPD whether at the first week or sixth week, while low serum serotonin may play a role in depression during the first week, but may not have a role in depression status at the sixth week. Also, PPD in the mother is related to a low APGAR score in infants born to these mothers emphasizing the significance of both mental as well as nutritional status of the mother.

• (http://dx.doi.org/10.1016/j.ajp.2013.05.007) Asian Journal of Psychiatry • Anti-inflammatory which addresses IL-1 and H- CRP • No GI irritation as Rx and OTC medications can cause. • Loose stools and belching common side effects. Fish Oil • These side effects can be ameliorated by taking frozen or with a digestive enzyme or apple cider vinegar. • 1200-2400 mg EPA/DHA typical and safe starting dose. J Affect Disord. 2018 May 16;238:47-61. doi: 10.1016/j.jad.2018.05.018. [Epub ahead of print] Omega-3 polyunsaturated fatty acid supplementation in prevention and treatment of maternal depression: Putative mechanism and recommendation.

Omega-3 fatty acid deficiency, due to inadequate intake, fast depletion during pregnancy and lactation, is one of the risk factors of PPD. Associations between neuroinflammation (elevated pro-inflammatory cytokines) and aberrant neurotransmission (low serotonergic transmission activity) and risk of PPD have also been reported by numerous studies. Supplementation with eicosapentaenoic acid (EPA)-rich oil can effectively reduce depression during pregnancy and PPD after childbirth. Long term treatment with docosahexaenoic acid (DHA)-rich oil can be effective in reducing the risk of PPD in healthy women, but not in lactating women. Supplementation of DHA-rich oil to women begun at pregnancy and continued after childbirth exerts no beneficial effect on depression. • L-tryptophan Amino Acid • 5 HTP • L-tyrosine Support for • GABA and phenibut Neurotransmitters • L-theanine • Magnesium, types for better absorption Magnesium • Companion nutrients and other • Electrolytes and electrolyte supplementation minerals • Calcium • Selenium • Adaptogens Herbal • Anti Inflammatory • Nervine Medicine • Phytohormonal • Herbs used to strengthen the bodies immune response and help the body cope with physical and mental stress. Adaptogens • They are used as tonics and their MOA is unlike pharmaceuticals in that they do not target specific organs or systems. • They impact the HPA axis. • Effects upon the Central Nervous System: • The systematic study of the pharmacological effects of R. rosea, begun in 1965, found that small and medium doses had a simulating effect and in contrast, larger doses were found to have more sedative effects. Rhodiola • Overall, in small and medium doses, R. rosea stimulated norepinephrine (NE), dopamine (DA), serotonin (5-HT), rosea and nicotinic cholinergic effects in the central nervous system (CNS). It also enhanced the effects of these neurotransmitters on the brain by increasing the permeability of the blood brain barrier to precursors of DA and 5-HT. • Rhodiola rosea: A Phytomedicinal Overview Richard P. Brown, Patricia L. Gerbarg, Zakir Ramazanov HerbalGram. 2002; 56:40-52 American Botanical Council • Turmeric/Curcuma • Others not fully discussed today but for which there is extensive support: Anti- • White Willow/Salix Alba • Green Tea/Camella Sinensis Inflammatories • Boswellia/Frankenscence • Rosemary • Resveretrol • Ginger/Zingiber Turmeric/Curcumin • Eschscholzia/California poppy • Matricaria/chamomile • Cratageus/hawthorne • Lavenduala/lavender • Melissa off./Lemon Balm Herbal • Leonarus cardiac/motherwort Nervines • Avena Sativa/oat straw • Passiflora/passionflower • Scutellaria/skullcap • Hypericum/st johns wort • Valeriana/valerian Topical Lavender Cream Alleviates Anxiety, Stress, and Depression in Pregnant Women

• The authors conclude that lavender cream…for 8 weeks significantly improved anxiety, stress, and depression in pregnant women. They recommend further studies to assess the effect of lavender on pregnant women with psychological disorders and women with postpartum Lavender depression. It is important to note that this study applies to the topical use of lavender essential oil.

• Effati-Daryani F, Mohammad-Alizadeh-Charandabi S, Mirghafourvand M, Taghizadeh M, Mohammadi A. Effect of lavender cream with or without foot-bath on anxiety, stress and depression in pregnancy: a randomized placebo- controlled trial. J Caring Sci. 2015;4(1):63-73. Lavender • Nervine and anti-inflammatory • A number of clinical studies have shown various positive outcomes when M. officinalis is used in combination with other herbs. These include the following: promoting sleep (with valerian); • treating restlessness in children (with valerian); Melissa Off./ • stimulating alpha1 electrical brain activity (with lavender, hops, and oat); Lemon balm • treating infantile colic (with German chamomile) and fennel; • reducing oxidative stress (with cinnamon) and laboratory- induced stress (with valerian); • treating dyspepsia; • treating abdominal pain and bloating in patients with irritable bowel syndrome (with spearmint and coriander). • Flax Seeds • Sesame Seeds Phytohormonal • Soy • Phyto-estrogens: The term phytoestrogen is used loosely in the herbal community. There is no current agreed upon definition for this term. Basically the term is used for any plant that: 1) Has one or more constituents with similar chemical or anatomical structure to estrogen. 2) Is changed into a similar compound in vivo. 3) Clinically produces effects that the clinician would expect from Phyto- giving exogenous estrogens. • Phyto-progesterones: Some herbs contain diosgenin, hormonal sarsasapogenin or other related compounds that can be manipulated chemically in laboratories to create progesterone as well as estrone, testoster- 8 and adrenocortical hormones. Some people have thought these herbs have had a progesterone type action in the body. It appears the body can not turn these constituents into progesterone. Herbal Neurotransmitter • St John’s Wort/Hypericum • Saffron Influence • St. John's wort (Hypericum perforatum) has been used to treat depression, as well as digestive disorders, wound healing, fevers, and snakebites, for centuries. In 1984, German physicians had SJW approved by Commission E St John’s Wort/ as a prescription medicine for mild-to moderate Hypericum depression. Almost 10% of women experience depression during pregnancy and women with a history of depression are at risk for worsening of mood during pregnancy. • American Botanical Council Saffron Comparable to Fluoxetine in the Treatment of Postpartum Depression • At study end, 18.8% of the saffron group and 21.9% of the fluoxetine group were remitters; there was no significant difference between the two groups. A total of 40.6% of the saffron group and 50% of the fluoxetine group were responders; there was no significant difference between the groups. All patients had at least a partial response, and there was no significant difference between the two groups in HDRS score reduction from baseline. Patients in the fluoxetine group had a greater frequency of headache, dry mouth, daytime drowsiness, constipation, and sweating, but there was no significant difference between groups in the incidence of these adverse effects

• Kashani L, Eslatmanesh S, Saedi N, et al. Comparison of saffron versus fluoxetine in treatment of mild to moderate postpartum depression: a double-blind, randomized clinical trial. Pharmacopsychiatry. 2017;50(2):64-68. • Effectiveness of in postpartum depression: a systematic review and meta- Acupuncture analysis.

• Li S1,2, Zhong W3, Peng W4, Jiang G1. Acupunct Med. 2018 Jun 15. pii: acupmed-2017-011530. doi: 10.1136/acupmed-2017- 011530. Supplement Choice

• Quality matters and it costs manufactures to insure it. • Know your companies. • Ask questions. • Build relationships. • If your plan doesn’t work, it might be dose or quality dependent. Resources

• Integrative Therapies for Depression: Refining Models for Assessment, Treatment, and Prevention. James Greenblatt, MD and Kelly Brogan, MD • Women’s International Pharmacy • Functional Medicine Practitioners and Naturopathic Physicians • Probiotics: https://ndnr.com/mindbody/the-microbiota-gut-brain-axis-the-biological-clinical-basis-for- using-probiotics-in-mental-health-disorders/ • EWG Clean 15 and Dirty Dozen • Women’s Herbs, Dr. Sharol Tilgner, http://www.herbaltransitions.com/Newsletters