An Integrative Approach for Addressing Depression DR SURUCHI

An Integrative Approach for Addressing Depression DR. SURUCHI CHANDRA ACIM OCTOBER 2015

Mechanism of SSRI Action Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis Keri A Lattimore, Steven M Donn, Niko Kaciroti, Alex R Kemper, Charles R Neal Jr. and Delia M Vazquez

Antidepressant Drug Effects and Depression Severity A Patient-Level Meta-analysis Conclusions: The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.

Side effects of SSRI medications Concerns on long lasting effects on brain development and behavior. ‘Switching’ to manic episode Serotonin syndrome Sedation Agitation Increased anxiety Gastrointestinal disturbances Discontinuation syndrome

Flaws in Monoamine Hypothesis SSRIs increase serotonin levels within hours after drug administration. However, it takes at least 2 -4 weeks to see the beneficial effects of SSRI medications. Reducing levels of serotonin in the brain does not cause depression. There is no consistent body of literature to support the hypothesis that serotonin deficiency causes depression. A significant number of people either fail to respond to SSRI or have only partial improvement with SSRI medications.

SSRIs and Neurogenesis This delay in treatment suggests that another process may be involved in SSRI medications. The scientists think SSRIs might promote synaptogenesis and neurogenesis. The selective serotonin reuptake inhibitor antidepressant, sertraline, increases neuronal differentiation and promotes neuronal maturation of human hippocampal progenitor cells.

Revolution in thinking in brain science The idea of the brain as ‘plastic’ and changing replaces an earlier notion of the brain as a fixed machine. Offers hope for a number of psychological neurological conditions in place of a ‘neurological nihilism. ’

Depression as a Subtle Neurodegenerative Event Curr Med Chem. 2011; 18(2): 245 -55. Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development? Ageing research reviews, 2005 The stress system in the human brain in depression and neurodegeneration Oxidative Medicine and Cellular Longevity. Volume 2013 Accelerated Aging in Major Depression: The Role of Nitro-Oxidative Stress

Incidence and Prevelance of Depression The incidence of depression has risen every year since the early 20 th century In the United States, one in six people experience a depressive episode during their lifetime.

Cost of Depression

Neurogenesis, Hippocampus, and Depression Mateus-Pinheiro et al. Clinical Epigenetics 2011 3: 5 doi: 10. 1186/1868 -7083 -3 -5

Pathways leading to hippocampal growth or atrophy.

Tryptophan and IDO Serotonin 5 HTP Tryptophan Proinflammatory IDO Cytokines Kynurenine Quinolinate Kynurenate

Depression as a Whole Body Phenomenon

Emerging View of Depression • Cellular event rather than neurotransmitter depletion • Whole body rather then focused on just the brain • Multiple pathways and systems usually involved

Causes of Physiological Stress Emotional abuse and neglect Excess heat Chemical toxins Loud noises Heavy metals Nutritional deficiencies Infections Pain response High electromagnetic fields Excess cold Physical trauma

Systems/Pathways Implicated in Depression Monoamine neurotransmitters NMDA/Glutamate Neuroendocrine/Stress response e Immune/Inflammatory Mitochondrial dysfunction Gastrointestinal imbalances

The Other Brain The GI system contains about 100 million neurons, more than either the spinal cord or the peripheral nervous system 95% of the bodies serotonin is in the gut SSRI medications can cause nausea, diarrhea, and constipation. But, low doses of SSRIs can be used to treat nausea, diarrhea, and constipation.

Gut Brain Axis A bidirectional communication system between the brain and gastrointestinal systems. Communication occurs along immunologic, neural, and biochemical pathways. Gut microbiota can effect both brain development and behavior. Stress also can alter the composition of gut microbiota. Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009 May; 136(6): 2003 -14. Epub 2009 May 7. Review.

Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009 May; 136(6): 2003 -14. Epub 2009 May 7.

Pathways involved in bidirectional communication between the gut microbiota and the brain. John F. Cryan & Timothy G. Dinan Nature Reviews Neuroscience 13, 701 -712 (October 2012)

Bipolar Disord. 2010 Dec; 12(8): 834 -42. Immune activation by casein dietary antigens in bipolar disorder. Anti-casein Ig. G associations with bipolar I diagnoses, psychotic symptom history, and mania severity scores suggest thatcasein-related immune activation may relate to the psychosis and mania components of this mood disorder. Case-control differences in epitope recognition implicate disease-related alterations in how the casein molecule is digested and/or how resulting casein-derived structures are rendered immunogenic.

Mitochondria PLo. S One. 2015 May 6; 10(5 Mitochondria DNA change and oxidative damage in clinically stable patients with major depressive disorder. Our study suggests that oxidative stress and mitochondria may play a role in the pathophysiology of MDD. More large-scale studies are warranted to assess the interplay between oxidative stress, mitochondria dysfunction and MDD.

Mitochondria and Toxins Mitochondria are like canaries in a coalmine: susceptible to early-stage effects that predict cell and organ toxicity later. Mitochondrial DNA is uniquely susceptible to the damaging effects of ROS. Mitochondrial DNA generally has less capacity to repair itself, relying on just one enzyme for both replication and repair of DNA Schmidt CW, 2010 Mito-Conundrum: Unraveling Environmental Effects on Mitochondria. Environ Health Perspect 118(7). COPYRIGHT SURUCHI CHANDRA, 2012

Tests for Mitochondrial Dysfunction Ammonia Alanine/Lysine ratio (Plasma Amino Acids) Lactate Pyruvate Acylcarnitine levels Free and total carnitine levels Creatine kinase Urine organic acid screening COPYRIGHT SURUCHI CHANDRA, 2012

Mitochondrial Cocktail Co-factor for pyruvate carboxylase ◦ Biotin Precursors for electron acceptors(NAD and NADP) ◦ Niacin (B 3) or nicotinamide Antioxidant support for reactive oxygen species ◦ Coenzyme Q 10, lipoic acid, vitamin C and vitamin E Complex I ◦ Carnitine, thiamine (B 1), pantothenic acid (B 5), and riboflavin (B 2) Complex IV ◦ Copper (only if low) Glutathione reductase support ◦ Selenium “Treatment of Mitochondrial Disease With Vitamin Co-Factors” by Richard I. Kelley, MD COPYRIGHT SURUCHI CHANDRA, 2012

Holistic Model for Treatment of Mitochondrial Dysfunction Avoid toxins that may interfere with function Avoid medicines that interfere with mitochondrial function Use herbs that protect and support mitochondria Individualized mitochondrial cocktail High ORAC/antioxidant foods Reduce excess consumption of omega 6 oils Treat any chronic bacterial issues and infections COPYRIGHT SURUCHI CHANDRA, 2012

Adaptogens Are plant derivatives, not simple compounds such minerals or vitamins. Many have been used in traditional medical systems for centuries to deal with anxiety, fatigue, or trauma. Are believed to normalize bodily responses to stress and to help maintain homeostasis by acting in a non-specific manner May modulate the immune, antioxidant, hormonal, and nervous systems.

Plant Adaptogens Summa (Pfaffia paniculata) Golden Artic Root (Rhoiola rosea) Astragalus (Astragalus membranaceus) Tulsi or Holy Basil (Ocimum sanctum) Schisandra (Schisandra chinensis) Aswhaganda (Withania somnifera) Licorice (Glycyrrhiza glabra and G. uralensis )

Plant Adaptogens Asian ginseng (Panax ginseng) American ginseng (Panax quinquefolius) Siberian ginseng (Eleutherococcus senticosus) Georgian Snow Rose (Rhododendron Caucasicum) Maca (Lepidium meyenii)

Rhodiola rosea In depressive rats, Rhodiola rosea improved serotonin levels in the hippocampus and induced neural stem cell proliferation. (Chen, 2009)

Rhodiola rosea activates the synthesis or resynthesis of ATP in the mitochondria in rats. (Abidov, 2003) Rhodiola enhances superoxide levels and protects against the toxic effects of paraquat (herbicide) in Drosophila (Schriner, 2009) Rhodiola rosea extract protects human cortical neurons against glutamate and hydrogen peroxide-induced cell death through reduction in the accumulation of intracellular calcium. (Palumbo, 2012) COPYRIGHT SURUCHI CHANDRA, 2012

Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study Phytomedicine. 2000 Dec; 7(6): 463 -9. WSG also exhibited an antidepressant effect, comparable with that induced by imipramine, in the forced swim-induced 'behavioural despair' and 'learned helplessness' tests. The investigations support the use of WS as a mood stabilizer in clinical conditions of anxiety and depression in Ayurveda.

Standardized extracts of Bacopa monniera protect against MPP+ and paraquat-induced toxicity by modulating mitochondrial activities, proteasomal functions, and redox pathways. (Singh M, 2012) Pretreatment with Bacopa monnieri extract offsets 3 nitropropionic acid induced mitochondrial oxidative stress and dysfunction in the striatum of prepubertal mouse brain. (Shinomol GK, 2012) Protective effect of Bacopa monniera on methyl mercury induced oxidative stress in cerebellum of rats. (Sumathi T, 2012) COPYRIGHT SURUCHI CHANDRA, 2012

Minerals and Depression

Should We All Take a Bit of Lithium? Opinion SEPT. 13, 2014 “Evidence is slowly accumulating that relatively tiny doses of lithium can have beneficial effects. They appear to decrease suicide rates significantly and may even promote brain health and improve mood. ” “Some scientists have, in fact, proposed that lithium be recognized as an essential trace element nutrient. Who knows what the impact on our society would be if micro-dose lithium were again part of our standard nutritional fare? “

J Affect Disord. 2015 Oct 3; 189: 282 -286. Trace lithium is inversely associated with male suicide after adjustment of climatic factors. Biol Trace Elem Res. 2015 Apr; 164(2): 165 -8. Jan 6. A negative association between lithium in drinking water and the incidences of homicides, in Greece

Front Neurosci. 2015 Jan 14; 8: 457 Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins Zhong Nan Da Xue Bao Yi Xue Ban. 2011 Jun; 36(6): 461 -76. doi: 10. 3969/j. issn. 1672 -7347. 2011. 06. 001. Neuroprotective action of lithium in disorders of the central nervous system.

Lithium forms and Dosing Lithium carbonate Lithium orotate Ionic lithium liquid Organic vegetable bound lithium

J Neural Transm. 2008 Dec; 115(12): 1621 -8. doi: 10. 1007/s 00702 -008 -0115 -7. Epub 2008 Sep 3. Antidepressant-like activity of zinc: further behavioral and molecular evidence. Chronic treatment with zinc induced a 17 -39% increase in the BDNF m. RNA and protein level in the hippocampus. These data indicate a rapidly acting antidepressant-like activity of zinc in CMS and the involvement of zinc in the regulation of BDNF.

Magnesium and Depression Antidepressant-like activity of magnesium in the olfactory bulbectomy model is associated with the AMPA/BDNFpathway Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.

Magnesium threonate/brain Physician. 2013 Sep-Oct; 16(5): E 563 -75. Magnesium L-threonate prevents and restores memory deficits associated with neuropathic pain by inhibition of TNF -α. Mol Brain. 2014 Sep 13; 7: 65. doi: 10. 1186/s 13041 -014 -0065 -y. Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer's disease mouse model.

Why Do We Need Mineral Supplementations? §Many patients do not have ideal diets §Decreasing mineral content of in soil §Some minerals are wasted in under periods of stress §Minerals imbalances may occur in setting of chronic infections, such as Lyme disease

Rising CO 2 poses significant threat to human nutrition At the elevated levels of atmospheric CO 2 anticipated by around 2050, crops that provide a large share of the global population with most of their dietary zinc and iron will have significantly reduced concentrations of those nutrients, according to a new study led by Harvard School of Public Health (HSPH).

Loss of Minerals Under Stress Anxiety and stress among science students. Study of calcium and magnesium alterations Magnes Res. 2006 Jun; 19(2): 102 -6 It is known that anxiety is related to partial magnesium reduction associated with a urinary magnesium excretion increase, as observed in the present data.

Zinc/Copper Imbalances and Chronic Infections Zinc levels are lower and copper levels are increased in pulmonary tuberculosis and other chronic infections. Zinc and copper levels normalize after antitubercular therapy. Zinc and copper given together was found to be more effective in treating Trypanosoma infection than either zinc or copper alone.

Diet, Stress, and the Brain SUPPORT STRESS Increase reliance Cause stress to the system Support detoxification Introduce toxins Provide essential nutrients and building blocks Lead to nutrient depletion and deficiency Provide anti-inflammatory and immune support Contribute to inflammation and immune deficiency

Phytochemicals, the Brain, and Stress

Phytochemical constituents as future antidepressants: a comprehensive review. Plant metabolites from different categories including polyphenols (flavonoids, phenolic acids, lignanes, coumarins), alkaloids, terpenes and terpenoids, saponins and sapogenins, amines, and carbohydrates were found to possess antidepressant activity.

Phytochemical constituents as future antidepressants: a comprehensive review. Naringenin has represented its antidepressant effect by elevation of serotonin (5 -HT), norepinephrine, brain-derived neurotrophic factor (BDNF), and glucocorticoid receptors. Piperine demonstrated inhibition of monoamine oxidase enzymes, elevation of brain 5 -HT and BDNF levels, and modulation of the hypothalamus-pituitary-adrenal axis.

Cruciferous Vegetables and the Brain

Nrf 2 participates in depressive disorders through an anti -inflammatory mechanism. Psychoneuroendocrinology. 2013 Oct; 38(10): 2010 -22. doi: 10. 1016/j. psyneuen. 2013. 020. Epub 2013 Apr 23. Furthermore, treatment of Nrf 2 knockout mice with the antiinflammatory drug rofecoxib reversed their depressive-like behavior, while induction of Nrf 2 by sulforaphane, in an inflammatory model of depressionelicited by LPS, afforded antidepressant-like effects. In conclusion, our results indicate that chronic inflammation due to a deletion of Nrf 2 can lead to a depressive-like phenotype while induction of Nrf 2 could become a new and interesting target to develop novel antidepressive drugs

Beige Food Diet

J Am Coll Nutr. 2015; 34 Suppl 1: 48 -55. doi: 10. 1080/07315724. 2015. 1080527. Mitigation of Inflammation-Induced Mood Dysregulation by Long-Chain Omega-3 Fatty Acids Major mood disorders are associated with both LCn-3 fatty acids deficiency and elevated immuneinflammatory signaling. • Prospective evidence suggests that low LCn-3 fatty acid biostatus increases risk for developing inflammation-induced mood dysregulation. • Taken collectively, this evidence suggests that increasing LCn-3 fatty acid intake and biostatus represents a promising strategy to mitigate the detrimental effects of elevated immune-inflammatory signaling on mood.

Balancing Omega 6/Omega 3 fats: Reduce consumption of processed and foods and polyunsaturated vegetable oils (corn, sunflower, safflower, soy, and cottonseed. ) COPYRIGHT SURUCHI CHANDRA, 2012

Brain Research Bulletin Volume 31, Issue 6, 1993, Pages 697 -700 Phosphatidylserine increases hippocampal synaptic efficacy J Neuroimmunol. 2004 Jun; 151(1 -2): 12 -23. Evidence of a protective effect of phosphatidylserine-containing liposomes on lipopolysaccharideinduced impairment of long-term potentiation in the rat hippocampus

Cholesterol and Mood: What’s the Link? The relationship between serum cholesterol and mood is complex and research findings to date are inconsistent. Research findings going back to the early 90 s show that serum cholesterol - especially the HDL fraction - is significantly lower in many patients with major depressive disorder than in nondepressed individuals, and that clinical improvement following antidepressant therapy is often associated with a significant increase in serum total cholesterol. A review of 6 randomized trials dating from the 1980 s through the early 1990 s found that while lowering abnormally high serum cholesterol levels (below 150 mg/d. L) decreased the number of deaths from coronary heart disease, cholesterol lowering was actually associated with increased mortality due to suicide or violence.

Food, toxins, and depression Vet Q. 2014; 34(3): 120 -31. doi: 10. 1080/01652176. 2014. 980934. In vitro dopaminergic neurotoxicity of pesticides: a link with neurodegeneration? Environ Sci Pollut Res Int. 2015 Jul 1 Urinary heavy metals, phthalates and polyaromatic hydrocarbons independent of health events are associated with adult depression: USA NHANES, 2011 -2012.

Physical Exercise Habits Correlate with Gray Matter Volume of the Hippocampus in Healthy Adult Humans Scientific Reports 3, Article number: 3457 (2013)

Underlying Causes Ideally Want to Address and Remove: Hormonal imbalances Microbiome disturbances Nutritional imbalances Infections Toxicity (metals, chemical toxins, and EMFs) Emotional stress Genetic SNPs

Late stage neuropsychiatric symptoms of Lyme disease • • Depression Mood Swings Psychosis Violent behaviors/irritability • OCD • Anxiety/Panic Attacks • Sleep disorders • • Seizures ADHD-like symptoms Autism-like behavior Chronic Fatigue Syndrome • Fibromyalgia

Misconceptions About Lyme Disease ◦ All patients recall a tick bite or bulls eye rash. ◦ Lyme disease is only a concern in Northeastern states. ◦ ELISA is a sensitive screening test ◦ Only one infectious pathogen is transmitted by the tick bite. ◦ A short course of antibiotics resolves all cases of Lyme disease.

In Vitro Effectiveness of Samento and Banderol Herbal Extracts on the Different Morphological Forms of Borrelia Burgdorferi mento (1: 300 dilution) Control Banderol (1: 300 dilu

It’s Not All in Your Head: Treat the Whole Body Assess and address: ◦ ◦ ◦ ◦ Mitochondrial dysfunction Possible infections and dysbiosis Hormonal imbalances Gastrointestinal disturbances Oxidative stress Detoxification and limit exposure to environmental toxins Fatty acid and cholesterol imbalances ◦ Omega 6/omega 3 ratio ◦ Low cholesterol