CHAIR SUMMIT Master Class for Neuroscience Professional Development

#CHAIR2014

7TH ANNUAL CHAIR SUMMIT Master Class for Neuroscience Professional Development

September 11 – 13, 2014 | Westin Tampa Harbour Island

Sponsored by #CHAIR2014

Obesity And Food Addiction: A Global Concern

Mark S. Gold, MD 17th University of Florida Distinguished Alumni Professor and Chairman University of Florida, Retired Gainesville, FL Mark S. Gold, MD Disclosures

● Chairman, Scientific Advisory Boards for Addiction & Psychiatry, Eating Disorders, Overeating, & Obesity for RiverMend Health and Wellspring Obesity Camps for Teens Mark S. Gold, MD Patent Disclosures

Granted Patents & Sold ● Clonidine as an Opiate-Like Drug & Method of eliminating opiate withdrawal symptoms with clonidine in humans. #4,312,878 January 26, 1982 (See Gold, Redmond, Kleber, Lancet 1(8070)929-930, 1978. Patent Gold, Redmond, Kleber, +Aghajanian)—sold to Boerhinger ● Dopamine Depletion Hypothesis of Cocaine and Amphetamine Addiction & Brompocriptine –Dopamine Augmentation method of eliminating cocaine withdrawal. #731,102 and #791,188 ; #20, 1941.2,1986 US 7,611,858 BI April 20, 2007(Gold and Dackis Clin Ther 7(1):6-21, 1984 Dackis and Gold, Lancet 1(8438)1151-1152, 1985- –Sold to Novartis Mark S. Gold, MD Patent Disclosures

Granted Patents & Licensed ● Detection of Cannabinoid Receptor Biomarkers and Uses Thereof Patent # US 7,611,858 BI April 20, 2007 ● Method and Apparatus for Detecting Environmental Smoke Exposure #7/052,468, May 30, 2006. ● Marker Detection Method and Apparatus to Monitor Drug Compliance #60/164,250, Filed November 8, 2000 ● Method and Apparatus for Detecting Illicit Substances #60/292,964 filed May 23, 2001 ● Methods and Apparatus for Therapeutic Drug Monitoring using Exhaled Breath #10/788,501 filed February 26, 2004 ● Novel Methods and Apparatus for Therapeutic Drug Monitoring Using Exhaled Breath # 10/788, 501, Filed February 26, 2004. ● Methods and Systems for Preventing Diversion of Prescription Drugs- #11/578,332, Filed September 20, 2004. ● System and Method for Monitoring Health Using Exhaled Breath - #11/301, 911, Filed December 13, 2005. ● System and Method for Monitoring Health Using Exhaled Breath (Propofol Claims) #11/512, 856, Filed August 29, 2006. ● A Novel System for Monitoring Environmental Contamination from Controlled Substances UF11458 ● Diagnosis and Treatment of Neurological Inflammation WO 2008/008819 ● System and method for monitoring health using exhaled breath # 20070167,853, Filed July 19, 2007. ● Devices and Methods for the Collection and Detection of Substances on Surfaces and Air # 60/971,451. Filed September 11, 2007. Mark S. Gold, MD Patent Disclosures

Granted Patents & Licensed ● System and Method for Real-Time Diagnosis, Treatment, and Therapeutic Drug Monitoring # 20070258894 filed November 7, 2007. ● Medication Adherence Monitoring System # 12/064, 673 filed February 25, 2008 ● Methods and Systems for Preventing Diversion of Prescription Drugs #20080059226 filed March 6, 2008. ● Varenicline, Appetite, and Weight Reduction UF#12961 Filed August 6, 2008 ● Nicotine Agonist in Varenicline in the Treatment of Attention Disorders UF#12964 Filed August 7, 2008 ● Devices and Methods for the Collection and Detection of Substances (Gold et al.) Serial No. 12/208,896; filed September 11, 2008. ● Closed Loop Medication Delivery System Employing Photoplethysmography to Improve Safety UF# 13420 Filed December 10, 2009 ● Baclofen/Naltrexone Combination Therapy for Suppressing Binge Eating of Palatable Food UF#-13854 Filed November 2011 ● Rat Screening Protocol to Predict Novel Treatments for Obesity, UF#14007 April 2012 Mark S. Gold, MD Patent Disclosures

Granted Patents & Licensed ● Canadian Patent No. 2,678,969. Medication Adherence Monitoring System - TH Reference: 292401-2231; UF Ref.: 12393; XHALE Ref.: 10457-132CA Nov. 13, 2012 ● Intelligent Drug and/or Fluid Delivery System to Optimizing Medical Treatment of Therapy Using Pharmacodynamic and/or Pharmacokinetic Data UF#13535. January 30, 2013. ● Central Site Photoplethysmography, Medication Administration, And Safety, UF#13843, Xhale Ref: XH-191PCT, Filed February 15, 2013, REF. 290106-103. ● Devices and methods for the Collection and Detection of Substances (CIP). UF#13294 Issued Patent No: 8,388,907 (Gold et.at.) Issued: March 5, 2013. ● Devices and Methods for the Collection and Detection of Substances (Gold et al.) UF#-12604 Serial No. 12/208,896; filed September 11, 2008-US Patent No. 8,414,846 April 9, 2013. ● Devices and Methods for the Collection and Detection of Substances (Gold et al.) UF#14626 Ref# UF.600XC2D1, Serial No. 12/763,924; Filed February 2013.

7 #CHAIR2014

Learning Objective 1

Implement counseling or address weight management strategies for overweight or obese patients. #CHAIR2014

Learning Objective 2

Apply the most up-to-date treatment guidelines, safety and efficacy data, and evidence-based criteria for currently available and emerging therapies for the management of overweight and obese patients, which include diet and lifestyle modifications, pharmacotherapies, and surgery. Weight Obsessed USA

● Most of us are thinking about our weight ● Many are on a diet ● Much of the media is obsessed with the nearly anorexic and those who have had short term weight loss, relapsed, and become obese ● Loss of control over eating, eating more than intended, eating to full or over-full, too many food “lets eat” signals and too little counter-balancing controls Wall Street Journal: Food May be Addicting for Some

A new study suggests that people who struggle to say no to chocolate, french fries or other junk food suffer from something more insidious than lack of willpower, they may actually have an addiction.

Heller K. http://online.wsj.com/article/ SB10001424052748703712504576243192495912186.html? mod=WSJ_hp_MIDDLENexttoWhatsNewsThird. April 5, 2014. How Did I Start Thinking About Obesity as an Addiction? ● I like french fries ● Woodstock ● Tobacco cases ● Drug addiction treatment ! HALT ! Drug craving…eat…chocolate/cake/cookies Our Clinical Research Group Sees Food and Drugs are Related to Each Other & Addictions

● Gold MS, Sternbach HA. Endorphins in obesity and in the regulation of appetite and weight. Integrative Psychiatry. 1984;2(6):203-210. ● Jonas JM, Gold MS. Cocaine abuse and eating disorders. Lancet. 1986;1(8477):390-391. ● Jonas JM, Gold MS, et al. Eating disorders and cocaine abuse: a survey of 259 cocaine abusers. J Clin Psychiatry. 1987;48(2):47-50. ● Gold MS. Etiology and management of obesity. Dir In Psychiatry. 1999;19(20):419-439. ● Gold MS, Frost-Pineda K, Jacobs WS. Overeating, binge eating, and eating disorders as addictions. Psychiatric Annals. 2003;33(2):117-122. ● Gold MS. Eating disorders, overeating, and pathological attachment to food: independent or addictive disorders? Binghamton, NY; Haworth Press. ● Warren MW, Gold MS. The relationship between obesity and drug use. Am J Psychiatry. 2007;164(8):1268. Yale Hosts Historic Conference on Food and Addiction

● New Haven, Conn. — In what is believed to be the first meeting of its kind, Yale University convened nearly 40 experts on nutrition, obesity, and addiction to discuss the controversial topic of food and addiction. ● Nora Volkow, MD, director of the National Institute on Drug Abuse, the keynote speaker, “It is important that we study the reasons that people behave in unhealthy ways even when they are aware of potentially devastating consequences,” Volkow said. “We believe we can learn a lot about obesity by looking at what we know about the science of drug addiction. In this meeting we will be discussing the commonalities in the brain’s reward mechanisms related to compulsive eating as well as drug use for non-medical reasons.” ● Among the topics of discussion: MRI research and other work that shows strong similarities in ways drugs and certain foods affect the brain; the relationship between eating and reward systems in the brain; psychological similarities between food cravings and cravings for drugs, and the implications of this work for government policy, clinical intervention, and the law.

Yale Office of Public Affairs & Communications. Yale Hosts Historic Conference on Food and Addiction. http:// opac.yale.edu/news/article.aspx?id=1581#. July 9, 2007. Accessed Sept. 20, 2011. Yale Hosts Historic Conference on Food and Addiction

● Although terms such as “chocoholic” and “carbohydrate addict” are prevalent in popular culture, there is little scientific consensus about food as an addiction, said Yale Psychology Professor Kelly Brownell, co-chair of the meeting. ● “Everything changes if food is found to have addictive properties, especially the legal and legislative landscape around marketing foods to children,” said Brownell, director of the Rudd Center for Food Policy and Obesity at Yale. “People often use the language of addiction to explain their relationship with food cravings, withdrawal, irresistible impulses—it is all there.” ● Co-chair Mark Gold of the University of Florida, said that in the past, addiction was defined by tolerance and withdrawal. “After our work and that of others on cocaine, it was clear that addiction was more like a pathological, often fatal attraction,” Gold said. “The definition of addiction was changed and gambling and sex addiction were considered addictions. Overeating and obesity are candidates for Addictive Disease and such a hypothesis is both testable in humans and can produce novel approaches and treatments for a major public health problem.” ● Gold said that food, especially highly palatable food, can produce the same effects as drugs of abuse. “It is common for people to eat more than they intend despite dire consequences,” he said. “Failed diets and attempts to control overeating, preoccupation with food and eating, shame, anger, and guilt look like traditional addictions.”

Yale Office of Public Affairs & Communications. Yale Hosts Historic Conference on Food and Addiction. http://opac.yale.edu/news/article.aspx?id=1581#. July 9, 2007. Accessed Sept. 20, 2011. Handbook of Food Addiction

Mark S. Gold, MD Kelly D. Brownell, PhD University of Florida Dean, School of Public Health, Duke University

Brownell KD, Gold MS, eds. Handbook of Food Addiction. Oxford University Press; 2011. Food and Addiction

A Comprehensive Handbook ! Kelly D. Brownell, Mark S. Gold ● Assembles leading scientists and policy makers from fields such as nutrition, addiction, psychology, epidemiology, and public health to explore and analyze the scientific evidence for the addictive properties of food. Increasing Scientific Interest

Number of publications containing the words “food addiction”

20"

15"

10"

0" 2000" 2001" 2002" 2003" 2004" 2005" 2006" 2007" 2008" 2009" 2010" Year

Gearhardt, Davis, Kuschner, & Brownell, under review ● Food addiction research may reinvigorate the search for effective obesity drugs, said Mark Gold, who chairs the psychiatry department at the University of Florida in Gainesville. Gold said the treatments he is working on seek to alter food preferences without suppressing overall appetite. We are trying to develop treatments that interfere with pathological food preferences, he said. Let’s say you are addicted to ice cream, you might come up with a treatment that blocked your interest in ice cream, but doesn’t affect your interest in meat.

Langreth R, et al. Bloomberg News. Website http://www.bloomberg.com/news/2011-11- 02/fatty-foods-addictive-as-cocaine-in-growing-body-of-science.html. 2011. What is An “Addiction”? Look at Criteria Used to Study Substance Dependence

Anticipation Tolerance BINGEING

CRAVING WITHDRAWAL Negative affect Physical signs Enhanced Increased locomotion Cross-sensitization Consumption

Avena NM, et al. J Nutr. 2009;139(3):623-628. PMID: 19176748. Drug Withdrawal and Hyperphagia: Lessons from Tobacco and Other Drugs

Edge PJ, Gold MS. Curr Pharm Des. 2011;17(12):1173-1179. PMID: 2149209. The Target is Always “The Brain”

The nucleus accumbens lighting up Dopamine Receptor Levels are Low in Obese Subjects

DVR 3.0

o Comparison Subject Obese Subject BMI = 23 BMI = 50

Wang GJ, et al. Lancet. 2001;357(9253):354-357. PMID: 11210998. Dopamine D2 images of Drug Addiction

Cocaine Control Abuser Heroin Control Abuser

Methamphetamine Control Abuser Alcohol Control Abuser Drug abusers have low brain dopamine activity (shown here using [11C]raclopride PET studies) indicating an understimulated reward system. National Institute on Drug Abuse. Addiction Science: From Molecules to Managed Care. Available at: http://www.drugabuse.gov/pubs/teaching/teaching6/Teaching4.html. 2008 Wang GJ, et al. Obesity. 2011;19(8):1601-1608. PMID: 21350434. Decreased Dopamine D2 Receptors in Obese Human, Monkey and Rodent

Human1 1 Bonnet macaques Rat2 High

BMI = 23 BMI = 23 Weight = 400 g

Low

BMI = 50 BMI = 42 PET [11C]raclopride ARG [3H]spiperone ARG = autoradiography; PET = positron emission tomography 1Wang GJ et al. J Nucl Med. 2008;49(Suppl 1):208P. 2Thanos PK et al. Synapse. 2008;62(1):50-61. PMID: 17960763. Drugs of Abuse vs. Food

● DA- Drugs increase extracellular ● DA- With food, DA release wanes DA each time they are with repeated access administered ● ACh- Satiety. ACh increases ● ACh- Aversion. ACh is increased during a meal (DA is high) during withdrawal (DA is low) ● Opioids- Antagonists do not ● Opioids- Antagonists precipitate precipitate withdrawal withdrawal signs

National Institute on Drug Abuse. Drugs, Brains, and Behavior - The Science of Addiction. Revised 2010. http://www.nida.nih.gov/scienceofaddiction/. Accessed June 18, 2014. Moss M. New York Times Magazine. http://www.nytimes.com/2013/02/24/magazine/the- extraordinary-science-of-junk-food.html?pagewanted=all&_r=0. 2013. What is the Result?

Is Soda the New Tobacco?

Bittman M. New York Times: Week in Review. Website http://www.nytimes.com/ 2010/02/14/weekinreview/14bittman.html. 2010. Sugar Addiction Obesity is a Huge Problem

● 2/3 of Americans are overweight. ● 1/3 of Americans are obese. ● Type two diabetes is on the rise. ● Pediatric obesity is increasing. Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010

1990 2000

2010

BRFSS = Behavioral Risk Factor Surveillance System

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30% *BMI ≥30, or about 30 lbs. overweight for 5’4” perso Source: Center for Disease Control. CDC’s Behavioral Risk Factor Surveillance System. http://www.cdc.gov/obesity/data/adult.html. 2014 Obesity in America in 2012

Source: Center for Disease Control. CDC’s Behavioral Risk Factor Surveillance System. http://www.cdc.gov/obesity/data/adult.html. 2014 The Beltline of America Too Much Fast Food Too Many Sweets Too Many Desserts A Boatload of Trouble! A Truckload of Trouble! (Double Trouble) A Syringe Full of Trouble! A Chest Full of Trouble! A Brain Full of Trouble! Joints Full of Trouble Trouble for the Sleep Apnea Doctors Higher Rates of Cancer Due to Obesity From Malibu to 50!

1970 2014 What's Really In a Chicken Nugget?

50% or less muscle tissue, a hodgepodge of pure fat, blood vessels, pieces of bone, nerves and cartilage ● It is really a chicken by-product high in calories, salt, sugar and fat that is a very unhealthy choice. ● There are also plenty of chemical additives and preservatives to be wary of such as dimethylpolysiloxane, an anti-foaming agent found in Silly Putty and propylene glycol found in antifreeze. deShazo R, et al. Am J Med. 2013;126:1018-1019. Even the Vets are Seeing It Too Much Food and Not Enough Exercise

● The majority of adult dogs and cats in U.S. homes are overweight or obese, and the problem has gotten worse over the past year, according to the Association for Pet Obesity Prevention.

Photos: Association for Pet Obesity Prevention Process Addictions: Risk Factors

Risk Factors Process Addictions Food Sex Gambling Prenatal environment X X X Child-rearing and culture X X X Genetic X X X Diet = high energy intake X Couch potatoes X Lack of exercise X Abnormal eating behavior X Psychiatric comorbidities in self/family X X X Information for chart from: Gold MS, Merlo LJ, Bruijnzeel AW, Roytberg A, Herkov MJ. Addiction to Drugs, Food, Gambling, Sex, and Technology: Shared Causal Mechanisms? In: Cottler LB, editor. Mental Health in Public Health: The Next 100 Years. New York: Oxford Press; 2011. p118-48. #CHAIR2014 Other Than Start A Drug Epidemic… What Can be Done? Obesity Is Caused by Long- Term Positive Energy Balance

Fat Stores

92 Current “Treatment” Strategies for Obesity

● Blame the patient ● Diet ● Tapes, books, classes ● Exercise ● Detoxification and abstinence ● Take drugs of abuse or related prescribed medications ● Surgery ● All the above…and again EAT SLOWLY Altered Hypothalamic Response in Obese Humans

fMRI signal changes (%)

-4

-8 Obese - 2.0 10 mm Lean Z -12 Glucose Ingestion +2.0 - 8 - 4 0 4 8 12 16 20 24 28 32 36 40 Time (min)

Matsuda M et al. Diabetes. 1999;48(9):1801-1806. PMID: 10480611. The top images show the brain regions that had significantly higher metabolic activity in obese subjects compared with controls (as measured by PET scans and superimposed on an anatomical MRI image of the brain). The lower images show the same regions with higher metabolic activity superimposed on a homunculus -- a diagram of the somatosensory cortex showing which regions are responsible for sensory input from various parts of the body. The hot spots lie in the areas receiving sensory input from the lips, tongue, and96 mouth.

BRAIN CHANGES SLOWLY— Long Time Frame Necessary

● Conspires to keep the weight on ● Mood Effects ● Long Term Abstinence – Like Effects ● Brain Changes Perpetuate Overeating and Obesity Nutrition Plate Unveiled, Replacing Food Pyramid Moderate Exercise Yields Big Benefits

● Moderately strenuous exercise, about 30 min/day, can lead to enormous benefits in terms of your mood, health, weight and the ability to live an independent and fulfilling life. The exercise doesn't need to be athletic or difficult. Studies have shown that simply walking at a brisk pace for 30 min or more on most days can lead to significant health improvements. Add simple strengthening exercises 2-3x/wk to up benefits. ● Lower blood pressure: A reduction of 5-10 mm Hg is possible. In some cases, that's enough to prevent or reduce the need for blood pressure medications. ● Improve cholesterol: Exercise often increases the concentration of high-density lipoprotein (HDL or "good" cholesterol in the blood), especially when accompanied by weight loss. Exercise also helps reduce triglyceride levels. ● Prevent or manage type 2 diabetes: Exercise helps insulin work better, lowering blood sugar. ● Manage weight: Coupling exercise with a healthy diet is the best way to shed fat and maintain a healthier body composition. ● Prevent osteoporosis: Exercise may increase bone density and protect against bone mass decline, especially if weight-bearing activities are involved. ● Prevent cancer: Exercise has been shown to strengthen the immune system, improve circulation, reduce body fat and speed digestion. Each has a role in preventing cancer, particularly cancers of the colon, prostate, uterine lining and breast. ● Maintain mental well being: Exercise may help reduce stress, improve mild-to-moderate depression and anxiety, improve sleep and boost moods. ● Increase energy and stamina: A lack of energy often results from inactivity, not age Science Daily Featured Research. Moderate Exercise Yields Big Benefits. Science Daily Website. http:// www.sciencedaily.com/releases/2008/01/080104123421.htm. 2008 Obesity treatment “is high priority” among drug research, said Dr. Mark Gold, chair of psychiatry at the University of Florida, who focuses on addiction and eating habits. They’ve failed most of the time before. Our brains crave calories to store for hard times, said Gold. Unfortunately for us, that worked very well when we had little food and we needed incentive to hunt. Right now, with abundant food, it’s very easy to get food and fast food, he said. The global obesity epidemic is due to food being widely available. The food has evolved, but our brains haven’t really changed from the time that we had to hunt and grow our own food. Many of our brains’ pathways are linked to appetite, he said. It’s hard to create a drug to suppress appetite when there could be many unknown factors involved. Park M. Why isn't there a safe weight-loss pill? CNN Health Website http://www.cnn.com/2011/HEALTH/04/15/diet.drugs.fail/. 2011. 2013 AHA/ACC/TOS Guideline for the Management of Obesity in Adults: NHLBI NHLBI ACC/AHA ACC/ Recommendation Grade ES COR AHA LOE Identifying Patients Who Need to Lose Weight (BMI and Waist Circumference) 1a. Measure height and weight and calculate E CQ2 I C (expert BMI at annual visits or more frequently. opinion) 1b. Use the current cutpoints for overweight A CQ2 I B (BMI ≥30) to identify adults who may be at (strong) elevated risk ofmortality from all causes. 1c. Advise overweight and obese adults that A CQ2 I B the greater the BMI, the greater the risk of (strong) CVD, type 2 diabetes, and all-cause mortality. 1d. Measure waist circumference at annual E CQ2 IIa B visits or more frequently in overweight and obese adults. Advise adults that the greater the waist circumference, the greater the risk of CVD, type 2 diabetes, and all-cause mortality. The cutpoints currently in common use (from either NIH/NHLBI or WHO/IDF) may continue to be used to identify patients who may be at increased risk until further evidence becomes available

For additional information and full guidelines visit http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437739.71477.ee Drugs Approved by FDA for Treating Obesity

DEA Year Generic Name Schedule Approved Use Approved Orlistat None Long-term 1999 Lorcaserin IV Long-term 2012 Topiramate/phentermine IV Long-term 2012 Sibutramine* IV Long-term 1997 Diethylpropion IV Short-term 1973 Phentermine IV Short-term 1973 Phendimetrazine III Short-term 1961 Benzphetamine III Short-term 1960

* Withdrawn from U.S. market See supplemental bibliography for full references. 9/10/2014 (Reuters) - A new diet pill Contrave got approval to be sold in the United States on Wednesday, only the third obesity treatment in more than a decade to win approval from the Food and Drug Administration. Made by Orexigen Therapeutics Inc, Contrave is a combination of the antidepressant bupropion and Orexigen's formulation of naltrexone, designed to prevent drug dependence. (

1.usa.gov/1wguwo4)

Naltrexone & Bupropion Naltrexone 8mg / bupropion mg 90 bid Can increase to 2 tabs bid. It could work for food addicon when you look at components.

5HT2c Knockout Mice Lack the 5HT2c Receptor and Overeat Lorcaserin

● 5HT2c receptor agonist ● Works in hypothalamus to decrease appetite ● Lorcaserin was FDA approved on 6/27/2012 ● For obese patients with BMI at or above 3 ● For overweight patients with BMI 27 to 30 who have at least one condition related to excess weight, such as type two diabetes, high lipids, or high blood pressure.

PI for lorcaserin tablets. Drugs@FDA Website. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/022529lbl.pdf. 2012. BELVIQ (lorcaserin)

● Take one 10 mg tablet twice a day with or without food for weight loss. BELVIQ

● 5HT2c receptor agonist ● Works in hypothalamus to decrease appetite ● BELVIQ was FDA approved on 6/27/2012 ● For obese patients with BMI at or above 30 ● For overweight patients with BMI 27 to 30 who have at least one condition related to excess weight, such as type two diabetes, high lipids, or high blood pressure. Expected Weight Loss with Currently Approved and Investigational Drugs

Agent Drug Placebo Net Weight Loss Orlistat* 7.3 kg 3.5 kg 3.0 kg Lorcaserin* 8.2 kg 3.4 kg 4.8 kg Topiramate/phentermine* 14.7 kg 2.5 kg 12.2 kg Bupropion/naltrexone 8.2 kg 1.9 kg 6.2 kg Pramlintide/metreleptin 12.7 kg No placebo 12.7 kg (vs. no PBO) Tesofensine 11.2 kg 2.0 kg 9.2 kg Liraglutide 7.2 kg 2.8 kg 4.4 kg Bupropion/zonisamide 7.2 kg 2.9 kg 4.3 kg Phentermine 6.8 kg 2.8 kg 4.0 kg Topiramate 4.5 kg 1.7 kg 2.8 kg Velneperit 7.1 kg 4.3 kg 2.8 kg Cetilistat 4.3 kg 2.8 kg 1.5 kg * Approved by FDA as adjuncts to a reduced calorie diet and increased physical activity Powell AG, et al. Clin Pharmacol Ther. 2011;90(1):40-51. PMID: 21654742. Phentermine/Dexfenfluramine

● “Phen-fen” was taken off the market due to heart valve (5HT2b receptor) and pulmonary artery hypertension(5HT1b receptor) problems related to dexfenfluramine. Phentermine is still available as a pill for weight loss. ● Cardiovascular problems were not seen on echocardiograms during the lorcaserin studies in humans Lorcaserin Pharmacology

● Prescribed one 10 mg tablet twice a day with or without food for weight loss ● Half life is 11 hours ● T max is 2.3 hours ● One 10 mg tablet twice a day with or without food ● Steady state within 3 days ● Concentrates in the brain ● Mild to moderate cytochrome P450 2d6 inhibitor PI for lorcaserin tablets. Drugs@FDA Website. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/022529lbl.pdf. 2012. Blossom Study

● 62.1 % of patients who completed one year on lorcaserin 10 mg BID lost 5% of body weight compared with 34.7% on placebo ● 34.3% of patients who completed one year on lorcaserin 10 mg BID lost 10% of body weight compared with 15.5% on placebo

Fidler MC, et al. J Clin Endocrinol Metab. 2011;96(10):3067-3077. PMID: 21795446. Belly Fat (intra-abdominal fat): Waist Circumference Often Correlates with Risk of Diabetes and Heart Disease Bloom Diabetes Mellitis Study

● 44.6% of patients who took lorcaserin 10 mg BID for a year lost 5% of body weight compared to 17.9% on placebo ● 20.8% of patients who took lorcaserin 10 mg BID for a year lost 10% of body weight compared to 5.8% on placebo ● Hemoglobin A1c in patients who took lorcaserin 10 mg BID for a year fell 0.9 points, compared to a drop in hemoglobin a1c of 0.4 in placebo ● Fasting blood glucose fell 27.4 points, compared to 11.9 point drop on placebo ● Waist circumference decreased on lorcaserin O’Neil PM, et al. Obesity. 2012;20(7):1426-1436. PMID: 22421927. Bloom Diabetes Mellitis Study

● Hemoglobin A1c in patients who took lorcaserin 10 mg BID for a year fell 0.9 points compared to a drop in hemoglobin A1c of 0.4 in placebo ● Fasting blood glucose fell 27.4 points compared to 11.9 point drop on placebo ● Waist circumference decreased on lorcaserin

O’Neil PM, et al. Obesity. 2012;20(7):1426-1436. PMID: 22421927. Efficacy

● Completers who took lorcaserin 10 mg BID for a year lost 8% of their body weight ! For a 220 pound person, weight loss for a completer would be 18 pounds in a year ● Responders who lost at least 5% in the first 12 weeks lost 11% to 12% of their body weight in a year ! For a 220 pound person, weight loss for a responder would be 24 to 26 pounds in a year

O’Neil PM, et al. Obesity. 2012;20(7):1426-1436. PMID: 22421927. Main Clinical Side Effect is Headache

● Main clinical side effect of lorcaserin was headache ● Headache was in 16.8% of lorcaserin patients compared with 10.1% of control patients ● Headache was usually mild, occurred early in therapy, and decreased even though lorcaserin was continued

PI for lorcaserin tablets. Drugs@FDA Website. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/022529lbl.pdf. 2012. Other Effects of Lorcaserin

● No elevation of blood pressure. ● No elevation of pulse rate. ● No depression. ● No heart valve problems on echocardiogram studies. ● Lorcaserin can elevate prolactin levels. ● Pregnancy category X since weight loss is contraindicated during pregnancy.

PI for lorcaserin tablets. Drugs@FDA Website. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/022529lbl.pdf. 2012. Serotonin Syndrome

● Since lorcaserin stimulates a serotonin receptor in the brain, there is a potential for serotonin syndrome if patients take lorcaserin along with other medications that raise the serotonin level ● Symptoms of serotonin syndrome include high blood pressure, confusion, agitation, hyperthermia, muscle rigidity, vomiting, diarrhea…. sometimes very severe PI for lorcaserin tablets. Drugs@FDA Website. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/022529lbl.pdf. 2012. Monitor Your Patients

● See your patient for 12 week follow-up after starting lorcaserin to be sure that the patient has lost at least 5 % of body weight ● Lorcaserin is indicated along with diet and exercise for weight loss ● As patients lose weight, the dose of diabetes medicines and blood pressure medicines may need to be reduced or eliminated ● Patients on antidepressants who may want to discontinue ! Some patients may be candidates to discontinue their antidepressant ! Other patients are not good candidates to discontinue their antidepressant Naltrexone and Bupropion Combination

● Combination of naltrexone and bupropion for weight loss ● Cardiovascular studies are underway to see if this combination can be approved by the FDA

Greenway FL. A Study of Two Doses of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects. ClinicalTrials.gov Identifier: NCT00532779. 2007 Bupropion + Naltrexone* Phase IIb Mean Weight Loss Over 48 Weeks

48 Week Data with Bupropion (BUP) and Naltrexone (NAL) Completers Population

0 -1 BUP-PBO + NAL-PBO -2 NAL IR 48mg + PBO -3

-4 BUP SR 400 mg +

-5 PBO

-6

-7 BUP SR 400 mg + -8 NAL IR 16 mg MeanChange (%) -9 BUP SR 400 mg + -10 NAL IR 32 mg -11 BUP SR 400 mg + -12 NAL IR 48 mg N = 419 -13

BL 4 8 12 16 20 24 28 32 36 40 44 48 *Not FDA approved for treatment of obesity Greenway FL, et al. J Clin Endocrinol Metab. 2009;94(12):4898-4906. PMID: 19846734. Phentermine and Topiramate Combination

● FDA approved in 2012 for weight loss and consists of 4 different dose combinations of phentermine and topiramate ● Only available from certain mail in pharmacies and under a FDA required REMs program ● Topiramate has been associated with cleft palate deformities in some newborns if the mother was on topiramate during the pregnancy

PI for phentermine hydrochloride; topiramate extended release capsules. Drugs@FDA http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2013/022580s004lbl.pdf. 2012 Effects of Baclofen and Naltrexone, Alone and in Combination, on the Consumption of Palatable Food in Male Rats (Off-label use)

Excess consumption of palatable food has been shown to affect reward-related brain regions, and pharmaceutical treatments for drug addiction may also be effective in treating overeating of such foods. The GABA-B agonist baclofen and opioid antagonist naltrexone have both been used to treat addiction, and have been shown to suppress intake of certain foods. The combination of these drugs has shown to be more effective in reducing alcohol consumption than either drug alone. The present study assessed the effects of naltrexone and baclofen, alone and in combination, on intake of foods comprised of various macronutrients. Male Sprague-Dawley rats were given 12-hr daily access to chow and a fat emulsion, sugar-fat emulsion, or a sugar solution for 21 days. Rats were then administered (intraperitoneal) baclofen- naltrexone combinations (0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen), and naltrexone (0.1, 1.0 mg/kg) and baclofen (1.0, 1.8 mg/kg) alone. The high dose of the baclofen-naltrexone combination reduced palatable food intake in both the fat and sugar-fat groups compared with vehicle, without affecting chow consumption in these groups. Naltrexone showed little significant effects on intake of either palatable food or chow. Baclofen also reduced palatable food intake in the fat and fat-sugar groups, but differences were only noted between the low and high dose. The combination of baclofen and naltrexone may be a useful tool in selectively targeting the consumption of high-fat and sugar- and fat- rich foods. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Avena NMBocarsly ME, Murray S, Gold MS. Exp Clin Psychopharmacol. 2014 Jul 28. [Epub ahead of print] PMID: 2506901. Bariatric Surgery Type 1

Pros ● Roux-en-Y gastric ● Statistically significant bypass is a procedure in weight loss results and which a small pouch is improvement in obesity made at the top of the related health issues stomach, and the upper intestine is connected to ● Considered “gold the new pouch. It limits standard” the amount of food that Cons can be eaten, limits ● Moderately affects the absorption of some foods, absorption of essential and also causes changes vitamins and nutrients like in hormones that regulate B12, folic acid, and iron food intake.

Karenkov M. ed. Bariatric Surgery: Technical Variations and Complications. New York. Springer. 2012. Bariatric Surgery Type 2

Pros ● Lap-Band® surgery ● No cutting, stapling or induces weight loss by stomach rerouting placing a band around the required and band can be top portion of the adjusted until correct stomach, thereby capacity is achieved reducing the capacity of the stomach. Food eaten Cons passes through the ● Requires the most effort remaining portion of the to achieve success, with stomach and into the slowest reported weight small intestine where it is loss absorbed

Karenkov M. ed. Bariatric Surgery: Technical Variations and Complications. New York. Springer. 2012 Bariatric Surgery Type 3

Pros ● Laparoscopic sleeve ● Most effective option for gastrectomy is a patients at highest risk for procedure where the surgery or as bridge to stomach is stapled and other procedures divided into a narrow tube which reduces the amount Cons of food that can be eaten, ● Relatively new procedure, and also causes changes with long-term in hormones that regulate effectiveness yet to be food intake. The small proven intestine is not changed.

Karenkov M. ed. Bariatric Surgery: Technical Variations and Complications. New York. Springer. 2012 Bariatric Surgery and Surgical Skills

● The technical skill of practicing bariatric surgeons varied widely, and greater skill was associated with fewer postoperative complications and lower rates of reoperation, readmission, and visits to the emergency department ● Although these findings are preliminary, they suggest that peer rating of operative skill may be an effective strategy for assessing a surgeon's proficiency

Birkmeyer JD, et al. NEJM. 2013;369(15):1434-1442. PMID: 24106936. Obesity Treatment: The Next Generation

● Need for effective prevention & intervention strategies ● Guideline-based approaches stage treatment by BMI and comorbidities ● Majority of pharmaceuticals developed to combat obesity, do so by suppressing appetite in general ● Better to specifically reduce intake of foods rich in fats or sugars (calories+) with little nutritional value ● GABA-B agonist, baclofen (used to treat alcoholism) has been shown to aid in reduction of binge eating behavior in both preclinical and clinical studies ● Food addiction model is the route to targeting neural reward system mechanisms

Avena NM, Murray S, Gold MS. Frontiers in Psychology. 2013;4(721):1-3. No PMID. Jensen MD, et al. J Am Coll Cardiol. 2014;63(25 Pt B):2985-3023. PMID: 24239920. Clinical Connections

● Counsel your patients about weight management strategies ● Encourage healthier food choices, eating slowly, portion control, exercise, lifestyle changes ● Apply the most up-to-date guidelines and evidence-based criteria for treatment options ● New medications are available to treat obesity along with lifestyle changes #CHAIR2014

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