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Integrative Healthcare Symposium 2016
The 2016 Integrative Healthcare Symposium Annual Conference gathered more than 1,400 health care practitioners in New York City from February 25 to 27. The multidisciplinary event featured sessions addressing the disruption of the gut microbiome by commonly prescribed pharmaceuticals and the integrative approach to treating depression.
The Gut Balance Revolution
Dr. Mullin’s message for pharmacists, delivered in an interview after his presentation, was straightforward advocacy for a bottom-up therapeutic strategy rather than a top-down “strike first with your heaviest weapons” approach to getting acute disease states under control. His rationale is that agents and diets that perturb the gut microbiome can incur a heavy price, leading to diabetes, obesity, nonalcoholic fatty liver disease, dementia, and cardiovascular disease.
Noting the general principle that increased species diversity increases an ecosystem’s efficiency and productivity while making it less functionally susceptible to external stressors, he pointed out that gut microbiome diversity helps with barrier integrity and with training the immune system, and overall has a great impact on health and well-being. Factors contributing to dysbiosis of the gut microbiota include host genetics, lifestyle (e.g., diet, stress), reduced early colonization (e.g., hospital birth, altered microbe exposure), and medical practices (e.g., vaccination, antibiotics, excessive hygiene). Two phyla (mainly anaerobic) of bacteria have been linked to obesity, the firmicutes positively and the bacteroidetes negatively—presumably through effects on metabolism—with animal studies demonstrating induced obesity with transplanted firmicutes.3
With respect to his two specific pharmacological targets—the overuse of proton pump inhibitors (PPIs) and antibiotics—Dr. Mullin cited a meta-analysis of studies of small intestine bacterial overgrowth (SIBO).4 In it, eight of 11 studies showed increases in SIBO risk with PPI use, with an overall odds ratio of 2.282 (range, 0.577–39.087; P = 0.008). PPIs, he said, delay small intestine transit. “Our community acknowledges that PPIs are overprescribed. The point is that they should not be first-line therapy. They should be last resort or short term and not chronic, just like steroids. We overkill diseases with heavy medications to get them under control and then people can’t withdraw or substitute because they have become physiologically dependent,” Dr. Mullin said.
A recent study documented adverse gut microbiome changes in PPI users versus nonusers consistent with changes that predispose individuals to Clostridium difficile and other enteric infections.5
For more than 50 years, the meat industry has effectively used subtherapeutic doses of antibiotics in animals to induce increased growth and weight gain. Reduced gut microbiome diversity in humans is a likely effect of ingested antibiotics on top of prescribed antibiotics, with extended consequences. Recovery of gut biodiversity after a week’s course of clindamycin, a regimen commonly prescribed for dental procedures, Dr. Mullin said, may take up to two years.6 Furthermore, it has been proposed that subtherapeutic levels of antibiotics lead to increased adiposity through increased production and uptake of short-chain fatty acids. One study showed that repeated exposure to broad-spectrum antibiotics at ages zero to 23 months is associated with early childhood obesity.7 That risk is potentially modified through more narrow antibiotic selection. Altered gut microbiota promote obesity and insulin resistance through reduced fatty-acid oxidation in muscles, increased triglyceride incorporation and inflammation in adipose tissue, and increases in short-chain fatty acids and inflammation in the liver. Another study showed Helicobacter pylori eradication to be associated with body-mass index increases.8
Dr. Mullin cited studies showing the antiobesity effects of probiotic supplementation, including reduced body weight, lowered visceral and subcutaneous fat area, and improved serum glucose and homocysteine levels.9
While many questions remain around optimal probiotic use (e.g., dosages, schedule, mixtures, human or synthetic, oral or injectable, fecal bacteriotherapy) and prebiotic use, Dr. Mullin said, the majority of studies showing benefits for C. difficile and antibiotic-associated diarrhea have been conducted with Saccharomyces boulardii.
Diet, he said, must also be emphasized, with avoidance of high-fat and sugary foods during antibiotic administration. The substitution of artificial sweeteners, however, promotes gut dysbiosis and may induce glucose intolerance.10
How can patients be tapered off PPIs? The answers are not formulaic. “You can’t just say you can replace them with zinc or Tagamet. Answers will be individualized, and the process may be long and complicated,” Dr. Mullin said. “But you can start with Tums and, of course, lifestyle. The big obstacle is that people do not want to lose weight or cut down on their cigarettes or caffeine or alcohol. They want to live the magic bullet lie.”
Healing Depression and Integrative Depression Care
Conventional care for depression typically focuses on administering drugs that change neurotransmitters. “That works sometimes, but with depression it doesn’t work most of the time, because what’s going on in the brain is really just the tip of the iceberg, an end product of the state and stress of the body’s physiology,” Dr. Bongiorno said. In Chinese medicine, he added, the brain is hardly considered an organ.
Still, listening to the patient—the foremost tool for diagnostics—can provide insight into which neurotransmitters are out of balance. Low levels of serotonin may manifest in obsessive worry, anxiety, negative attitudes, and carbohydrate cravings. Dopamine/norepinephrine deficits can show up as low motivation and lack of forward impulse. Gamma-aminobutyric acid imbalance can manifest as an inability to turn the mind off and an inability to relax. Low melatonin may appear as insomnia, and acetylcholine can show up in memory problems with impaired creative and/or math function.
No single approach is likely to be effective, but a totality of measures addressing issues of sleep, stress, diet, inflammation, and exercise, adding hydrotherapy, detoxification, and supplements, can be very powerful, Dr. Bongiorno said.
Deciding whether to take a conventional or integrative approach rests on the answers to several important questions. If the patient is at risk for self-harm or harming others, conventional therapies should be given first with natural remedies as adjuncts. The same is true if the patient cannot take care of herself, himself, or family. Natural therapies can be selected if the patient falls outside the first two categories and is willing. Pregnancy and breastfeeding call for case-by-case evaluation. When a patient is already on pharmacological treatment for depression, natural treatments can be initiated and, as they take effect, the former can be tapered.
Dr. Bongiorno suggested very complete laboratory tests, including the standard assays plus others for folic acid, methylenetetrahydrofolate reductase, carnitine, serum mercury, celiac disease, urine kryptopyrroles, environmental metals, SIBO, and leaky gut. Saliva testing, he said, is more accurate for assessing cortisol levels than is serum testing.
The lab tests will give insight into choosing among the endless variety of supplements to meet repletion needs. Pointing out that supplements are at the bottom of the list of strategies, he said that they probably are not going to be effective “if you are not working on sleep and all the others.”
Sleep disturbances are common precursors to depression onset or recurrence. Research has shown that 70% of sleep apnea patients have depression,11 and 30% of patients with insomnia are depressed.12 Helpful supplements include melatonin (including prolonged release), tryptophan, valerian, casein decapeptide, magnesium glycinate/threonate, and phosphatidylserine.
Treatment resistance with conventional antidepressants may be overcome when deficiencies revealed in lab tests are addressed with supplemental folic acid, testosterone, estrogen, thyroid hormone, zinc, vitamin B12, and creatine. Dr. Bongiorno cited a study showing full responses to antidepressant medications when B12 levels were higher (439.1 pmol/L) versus nonresponders (347.2 pmol/L) and partial responders (396.0 pmol/L)13 and another showing enhanced responses to escitalopram by week 2 among women with major depression who received creatine (5 g) versus placebo.14 Augmentation of antidepressant response has been shown for omega-3 fatty acids, as well.
The basic “three you need” supplements for depression, Dr. Bongiorno said, are a multiple vitamin, fish oil (2 g per day), and probiotics (lactobacillus/bifidus) for 30 days. Other supplements with research supporting their efficacy in depression include chromium, rhodiola, berberine (which inhibits monoamine oxidase-A), and curcumin. Response rates with the combination of curcumin and fluoxetine were higher (77.8%) than with either agent alone (fluoxetine, 64.7%; curcumin, 62.5%) in major depressive disorder.15 An Australian meta-analysis of six studies of saffron (Crocus sativus) (15 to 30 mg once daily) revealed large treatment effects.16
Dr. Bongiorno’s favorite supports for neurotransmitters include tyrosine, macuna, SAMe, 5-HTP, and Apocynum venetum (Rafuma leaf extract).
Dr. Bongiorno noted that research from 2005 revealed that 15% of 315 depression patients preferred medication alone, 24% preferred psychotherapy alone, and 60% preferred both.17 “Those who received a preferred treatment experienced more rapid improvements.” He concluded with Hippocrates’ fifth-century recommendations: a vegetable diet, physical movement, water therapy, and St. John’s wort.
- Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008;3(4):213–223.
- Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol 2013;11(5):483–490.
- Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut 2015 Dec 9. pii: gutjnl-2015-310376. doi: 10.1136/gutjnl-2015-310376.
- Jernberg C, Löfmark S, Edlund C, Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology 2010;156(Pt 11):3216–3223.
- Bailey LC, Forrest CB, Zhang P, et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014;168(11):1063–1069.
- Francois F, Roper J, Joseph N, et al. The effect of H. pylori eradication on meal-associated changes in plasma ghrelin and leptin. BMC Gastroenterol 2011;11:37.
- Festi D, Schiumerini R, Eusebi LH, et al. Gut microbiota and metabolic syndrome. World J Gastroenterol 2014;20(43):16079–16094.
- Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014;514(7521):181–186.
- Edwards C, Mukherjee S, Simpson L, et al. Depressive symptoms before and after treatment of obstructive sleep apnea in men and women. J Clin Sleep Med 2015;11(9):1029–1038.
- Radecki SE, Brunton SA. Management of insomnia in office-based practice. National prevalence and therapeutic patterns. Arch Fam Med 1993;2(11):1129–1134.
- Hintikka J, Tolmunen T, Tanskanen A, Viinamäki H. High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry 2003;3:17.
- Lyoo IK, Yoon S, Kim TS, et al. A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry 2012;169(9):937–945.
- Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res 2014;28(4):579–585.
- Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol 2014;29(6):517–527.
- Lin P, Campbell DG, Chaney EF, et al. The influence of patient preference on depression treatment in primary care. Ann Behav Med 2005;30(2):164–173.