Contrave: A promising new approach in the fight against obesity?

As a family physician whose practice deals exclusively in the treatment of obesity, it strikes me as remarkable how little we understand about the disease, which is Canada’s second-leading cause of preventable death.

In every region of the developed world, obesity doubled in the twenty years between 1988 and 2008, according to World Health Organization, which now count more than a half-billion of Earth’s population as obese. The Public Health Agency of Canada says obesity costs our nation somewhere between $4.6 billion to $7.1 billion annually. And yet, the most effective long-term therapy we’ve come up with to treat the disease is bariatric surgery — a comparatively radical procedure that sees a surgeon restrict the size of the stomach, or cut off a piece of it.

Recently, though, the fight against obesity is showing signs of joining the 21st century. For example, this autumn many in the medical profession expect the Food and Drug Administration in the United States to approve what I believe will be a really promising pharmaceutical therapy for obesity.

The drug’s development stems from an evolving understanding of a certain type of overeating that arises from stress-triggered depression.  The path to obesity may begin for some people with a stressful event the subject perceives as threatening — ranging from early life abuse to the loss of a job or a loved one. The resultant release of stress hormones interferes with the brain’s stimulus-reward circuitry. Essentially, the stress takes away one’s ability to feel pleasure. The resulting condition is referred to as “anhedonia.” one of two primary symptoms of depression.

The next step sees some anhedonia sufferers go off in search of other ways to activate their reward circuitry and feel pleasure. Most of the options remaining to them are unhealthy. Drugs and alcohol will get the job done, as can three substances that are vastly less regulated — sugar, salt and fat.

With few other options available to feel pleasure, the anhedonic person turns to the consumption of calorie-dense foods to fire the pleasure receptors. And over time, conditioning leads to a powerful drive to overeat—with stress and common settings like a couch and a TV triggering an overwhelming impulse to consume.

We live in a stressful world where we have virtually unlimited access to sugar, fat and salt — it’s available any time, nearly anywhere, super-sized and inexpensive. Throw stress at us and studies show that while 30% of us will lose weight, the remaining 70% will eat more and gain weight. Interestingly, 70% of Canadians are obese or overweight.

I have spent more than 12,000 hours treating obesity in the last 10 years and it is becoming increasingly apparent to me that this stress-anhedonia-overeating pathology may be contributing to the struggles of a majority of my patients.

Understanding that a link exists between stress, depression and obesity has begun to allow the pharmaceutical industry to tailor treatments to address the pathway. For example, a California-based company called Orexigen Therapeutics is in the final stages of seeking FDA approval for a drug it’s marketing under the name of Contrave. The pharmaceutical therapy actually is a combination of two drugs — an anti-depressant, buproprion, and naltrexone, an anti-addiction drug currently used to treat people for alcohol dependence. The buproprion alleviates the anhedonia that triggers the overeating, and in clinical trials, Contrave, combined with behavioral modification treatment, helped subjects lose an average of 10% of their body weight. And 10% weight loss is sufficient to treat early-stage diabetes. It’s expected to be approved by the FDA this fall, suggesting the possibility of a similar decision down the road by Health Canada. And other pharmaceutical therapies that combine anti-depressants with other drugs also are in the pipeline.

More exciting than any single drug, though, is the fact that the medical profession is developing new and more sophisticated behavioral and pharmaceutical ways to manage overeating. Will the new understanding stem the rise of obesity-related mortality? Could treatments based on our new understandings of why many overeat help you, or someone you know, address a developing weight problem?

The only certainty is that the medical profession needs more tools, in addition to surgery, to address the growing obesity epidemic — and with new behavioral and pharmaceutical treatments we, in my opinion, are getting them.

David Macklin is director, weight management program, Medcan ClinicThis article originally appeared in the National Post

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  • C2

    Until they make a drug that physically makes an individual too sick to their stomach to eat….not gonna happen.
    People like to eat. There is no drug to fix that. No miracle pill.
    Behavior modification alone will ensure less eating, and I guarantee that is how they lost the weight. These drugs are expensive and never covered by insurance.

    • querywoman

      As I wrote earlier, Victoza has cut my appetite.

    • Sara Stein MD

      Some of the biggest insurers are now covering the newest weight loss medications, and likely all of them will in time, but maybe not as name brand. I have seen some of these medications turn off the interest in food for anything other than survival like a light switch, but the issue becomes long term when the medications are either less effective on that person, or the body overrides the mechanism. The meds don’t work on everyone, and may not work forever, they are simply one more tool in a very complex disease.

  • PoliticallyIncorrectMD

    Just curious… In the third world countries where the rates of obesity are much lower, are people less depressed or there is simply less opportunity to overindulge in food?

    • querywoman

      Slightly different bend: American insurance companies know that fat people have a lower risk of suicide.

      • Sara Stein MD

        Careful not to oversimplify. The incidence of suicidal ideation and attempts increases with increased BMI in all populations. In Class 3 obesity, the gender differences in rates disappear when compared to Class 1. Obese adolescents have much greater suicidal thought and attempt rates- very hard to separate out from bullying when calculating completions. There are higher rates of suicidal thoughts and attempts in morbidly obese adults with fewer completed suicides, with the exception of post bariatric surgery. The suicide rate post bariatric surgery is much higher than normal, mechanism unclear, possibly related to micronutrient deficiencies and changes in psychosocial parameters.
        http://www.ncbi.nlm.nih.gov/pubmed/23576272
        http://www.psychweekly.com/aspx/article/articledetail.aspx?articleid=1573

        • querywoman

          I’m not a doctor, and I’m not trying to oversimplify anything. The medical profession oversimplifies being at, a few pounds over some made-up figures, as being the root of all evil.
          I dislike the term, obesity!
          Fat is a description of what it is.
          The very fat probably are more likely to commit suicide, due to not being able to move around, the stigma, etc.
          I’m not surprised that suicide goes up after bariatric surgery. It has many risks!

          Manual Uribe, a very fat man in Mexico, who lost several hundred pounds, recently died before reaching age 50.

        • RenegadeRN

          Thank you for the information! I had forgotten the higher suicide rate post bariatric surgery.

          I appreciate your knowledge of the subject.

    • SarahJ89

      I lived in Ireland in the early 70′s. The diet was very heavy in carbohydrates. I remember having “supper” every night with my Irish friends. It was a meal eaten at 10:00 pm comprising tea, bread and jam with lashings of butter and maybe some cake. A cup of Horlick’s or hot milk and some biscuits before bed was traditional.

      Meat was scarce. A ham sandwich would comprise two slices of bread (their bread was amazing–even their store “Wonder Bread equivalent”), heavily buttered, with a few nearly translucent slices of ham. When I was growing up anyone who was hungry at the end of a meal was told to have bread and jam, which was always available. We definitely had opportunity to overindulge.

      The Irish considered a fat baby to be a pretty baby and their babies were round and rosy. The toddlers had legs like tree stumps. I believe the Famine lent its hand to this preference.

      But I never saw a fat adult. The reason was because we had to walk a lot. Very few people had a car or phone. If I wanted to ask a question of a friend I have to walk to the bus stop, then walk to their house from the bus stop to ask a question. Since we were all in the same boat the pace of life accommodated this activity. I think the lack of rush-rush-rush I experience in the US was a factor. Less stress of that kind = less stress eating. I lived in Dublin, the Big City, and it was still pretty relaxed.

      American tourists complained endlessly about all the walking. Most Americans who moved there gained weight at first from the diet, then lost it as they walked so much. We just had to move a lot more.

      My work now in the US is entirely sedentary. It drives me crazy, actually. I’m trying to set up a treadmill desk before I go bonkers. I’m working on losing weight I gained from untreated hypothyroidism and it’s clear to me that movement is going to be a key to my success.

      • Patient Kit

        I agree about the walking. I live in a city (NYC) where most people routinely do a lot of walking, most of which we don’t even count as part of our daily exercise. Most of us don’t own cars. Sure we use the subway, buses and taxis when we have to go further. But most of us think nothing of walking 20 blocks (roughly a mile) and we walk up and down a lot of stairs to get in and out of the subway. There are more and more bicycles in NYC too.

        Personally, I can’t walk to work because I live in Brooklyn and work in Manhattan. But I routinely walk to the grocery store, the post office, the bank, the drug store, the gym, etc. Contrast that to when I visit a friend in suburbia where they get in their car inside their garage, drive to the store to get milk (!) and circle a parking lot looking for the closest possible parking spot to the store’s front door. This always amazes me. I think all the walking makes a huge difference, especially if our jobs involve sitting in front of a computer.

        • EmilyAnon

          I live in L.A. where we drive 1 mile to the gym for a 2 mile workout on the treadmill. Walk on the streets here? You’d stand out like a sore thumb. Well not that bad, but almost ;-)

        • SarahJ89

          I live in a rural area, in a rabbit warren of short dead end dirt roads. During the school year the school bus stop is crammed with SUVs. The parents *drive* their kids to the bus stop! None of these roads are longer than half a mile (I’ve clocked them to help me figure out how long my walks are). I just don’t get it, really.

  • Becky

    My sister studied abroad last year in Denmark, and most of the food available to buy was healthy. And 30% of people rode their bikes to work. If the U.S.A. was like that, the obesity rate would be lower. But it’s not, so we will always have a higher obesity rate.

    • querywoman

      Most of our food is junky and overprocessed. I think all the weird oils in food are probably worse than the corn syrup and other sugars. Hydrogenating oils is scary! You can see in an dictionary that corn syrup is made through a chemical process. Refined cane sugar is simply a highly stripped product, not as significantly modified as the oils and the corn syrup are.

  • querywoman

    I disagree that obesity is a disease.
    However, while I am still fat, I have lost 75 pounds on Victoza and from getting mostly off insulin. I had started losing weight before I went on Victoza from managing to keep good control and reducing my insulin.
    When my doctor put me on insulin, I lost 26 pounds in two months, felt good, but suddenly got pneumonia for the first time, and spent eight days in the hospital.
    It was a positive weight loss, and all my doctors agree that it lowered my immunity.
    I lost 10 or 15 months in the few months after that while recovering.
    My endocrinologist, who is a highly skilled man, has practiced in three countries and in 2 US states.
    I promptly went to him after the serious pneunomia to report the illness. I delayed my follow up to the pulmonologist a little because I needed to see him.
    I realized that even my endocrinologist knew very little about weight loss. It’s totally new, seeing positive weight loss. I saw the pulmonologist several times after the serious illness. I told him I didn’t even know how much the endo knew about my weight loss, that the medical profession had never been able to help people lose weight. The pulmonologist assured me that the endo didn’t know much about weight loss. Of course, the pulmo knew even less.
    My weight has been stable about 18 months.
    My endo says he has only seen this kind of weight loss in one or two other patients.
    Of course, the weight loss is not the only thing that pleases him. My blood sugar doesn’t fluctuate as much, and I feel more stable.
    I was hospitalized two days about six months ago for pneumonia. My endo grimaced when I got out and reported it. We have to count that spell as bad luck. I know I had the flu. No matter what you doctors do, patients still can catchy nasty flu and/or pneumonia and die.
    All my endo can do is run blood work, discuss it with me, and make very careful changes with my meds to avoid stressing and weakening my system. I am also hypothyroid.
    I am his best response to Victoza, and I think I am his number one best managed patient. But, the two cases of pneumonia are reason for caution.
    The only relevance of my own story to other patients is that new treatments are coming.
    My doctor considers it positive that I still eat the same things, in a lesser amount. Victoza seems to have controlled a lot of my carb cravings. I’m still the same person as I always have been, and there is no deprivation.

  • RenegadeRN

    I am very curious about Contrave, but only for the naltrexone/ dopamine link. I could care less about the bupropion part of it, deem it unnecessary actually. Respectfully, I disagree that fat people are mostly depressed.

    Food manufacturers have become extremely skilled at manipulating sugar, salt and fat ratios in processed foods to ensure a dopamine reward, much like the drug addict experiences. So every bite of your favorite junk fires those reward centers in your brain- BINGO! They’ve got ya!….just as they planned.

    Quite a number of people experience this dopamine reaction from opioid chemicals produced from certain processed foods- and naltrexone, theoretically, should make them less appealing. Again, be interested to see the real world effects on this particular drug.

    All the others have been a dismal failure, and hard to believe they even made it to market.

    • RenegadeRN

      Wouldn’t let me edit, for some odd reason…I want to edit the word “fat” and replace with obese.

      Re-reading my post , I think maybe it sounds insensitive, and my intention was not to offend. Sometimes I post before the caffeine kicks in! ;-)

  • SarahJ89

    Be very careful with this. Hypothyroidism causes both disthymia (misspelled) and weight gain. Jumping too quickly into obesity medication may not be a good idea.

    Disclaimer: I spent over 20 years being treated for “treatment refractory depression” that was cured within two weeks with ten dollars worth of levothyroxin. I’m still working on the weight gain from all those years.

    • Becky

      How were you diagnosed with hypothyroidism?

      • SarahJ89

        I asked for yet another blood test. The results were the same as always. But the parameters for “normal” had changed so instead of being considered “low normal” I was now eligible for treatment of my many hypothyroid symptoms.

        It was like rising from the dead. Many years earlier a very kind doctor had told me “Your lab results say you are low normal, but you have every symptom of a low thyroid. I’d like to treat you for this to see if it helps.” Alas, he died suddenly of a massive heart attack before he could treat me.

        I forgot about this until after I finally receive treatment. But over the years the symptoms worsened greatly.

        The scary thing is that a lot of labs and many doctors are using the old scales of “normal” to interpret TSH. It was sheer luck that I finally found someone who’d adopted the new scale. I had become so depressed I nearly killed myself. It would have been an entirely preventable death had anyone looked at my symptoms instead of focusing narrowly upon a test result.

        • Becky

          Wow. I’m sorry it took so long to get treatment. Where can I find the new scale?

          • SarahJ89

            There is a wealth of information on the About.com website. Go to the home page, type “hypothyroidism” into the search box and Bob’s your uncle. There’s an active thyroid page on that site. I take some of it with many grains of salt but her take on the controversy over the “correct” reading of TSH results is accurate, IMO.

            The old scale was .5 to 5.0. My results were always “low normal.” When they changed the scale to .3 to 3.0 I was suddenly in need of treatment. Some people would accuse the endos of doing this to expand their income but I really don’t think we hypothyroid folks are big money makers. And our meds are cheap–not that doctors generally make anything from the meds they prescribe anyway.

            I do just terrific if my TSH is on or about 1.0. Higher or lower? Not good at all. If I had to go back to being considered “low normal” I would probably kill myself. I realize that sounds melodramatic, but I made a very serious attempt a year or so before I was diagnosed. 25 years of dysthimia (still misspelled!) kinda drags you down. I simply could never face that again.

            My situation was complicated by PTSD. But I had a laundry list of hypothyroid symptoms that should have been hard to miss. They were always dismissed because my test was “low normal.” Ugh.

          • Becky

            Thank you for the advice! Every psychiatrist I have seen has asked about my thyroid.

          • SarahJ89

            Have they done a TSH test? I should hope so, since they’re MDs. Read up on it at the About.com site because you don’t want to be told you’re “normal” or “low normal” when the lab and/or doctor are using the older values.

          • Becky

            Yes my TSH has been tested. There are some integrative/holistic psychiatrists that test more extensively to include T3, T4, etc. since some people with a normal TSH can still have hypothyroidism. I looked into how much those tests cost, and it is illegal in Maryland for patients to order their own blood tests. I have to have my doctor order it.

          • SarahJ89

            I was (eventually) lucky. I’m just a plain vanilla TSH-impaired person who responds to levothyroxine. I added Vitamin D because I was still having trouble with winter, lotsa trouble. Alaskans on an unrelated list I was on wrote to me privately to recommend Vit. D. I was so impressed I did it and it put things over the top.

  • Sara Stein MD

    I too treat obesity, and also addiction and psychiatry – I’ve tried the naltrexone/bupropion combination (in similar doses) with patients being very comfortable prescribing them separately – it’s like all meds, it works for a few, doesn’t work for a few, and some don’t tolerate it. However, it precipitated the fastest suicidal depression in one man I’ve ever seen – one dose of 12.5 mg naltrexone and 100 mg bupropion and he was in the black hole for 3 days with his family and friends watching him so he didnt hurt himself. No history. He’s fine but it scared both of us!

    I now have a healthy respect for that combination and do a test dose of low dose naltrexone 4-5 mg first. If they can’t get the compounded low dose, then I have them quarter the naltrexone tablet. It may be that food addiction is a poor indication but using food as an antidepressant/antianxiety medication defines a population that will do well with this medication. The more tools we have for obesity, the more chances we have of helping people be successful.

    Note to anyone who wants to add an eat less move more comment because that’s the cure for obesity – move on to someone else. You’re working off obsolete data.

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