Another Addiction Drug for Obesity?

I have often blogged on the close link between certain forms of obesity and addiction. Not only do many patients battling with obesity openly admit to a “food addiction”, several drugs targeting obesity such as rimonabant (a CB-1 receptor antagonist) or contrave (a combination of buproprion and naltrexone) specifically target the neurocircuitary of the brain’s addiction system. A new addition to this approach may be Gaba-vinyl-GABA (GVG) or vigabatrin, an epilepsy drug currently undergoing Phase II trials for patients with cocaine and methamphetamine dependence. In a study published by Amy deMarco and colleagues from Brookhaven National Laboratory, Upton, NY, in the journal Synapse last week, vigabatrin resulted in a dose-dependent 12-20% reduction in body weight in Sprague Dawley and adolescent and adult Zucker fatty rats. Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the catabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. The mechanism of action of vigabatrin is attributed to irreversible enzyme inhibition of GABA-T, and consequent increased levels of the inhibitory neurotransmitter, GABA. Vigabatrin is sold as Sabril in Canada by Ovation Pharmaceuticals Inc for the adjunctive management of epilepsy which is not satisfactorily controlled by conventional therapy. Its major neurological side effects include somnolence, impairment of peripheral vision and risk for seizures. Increases in liver enzymes have also been reported. No doubt, it will be interesting to see how the clinical trials of this compound for obesity pan out. Apparently, Brookhaven Labs have licensed out the compound to Catalyst Pharmaceutical Partners, (Coral Gables, Florida), who plan to test it for binge-eating disorder (BED). I am not sure why exactly the researchers (and Catalyst Pharmaceuticals) believe that BED is the best population to test this in, as this disorder (as blogged before) readily responds to CBT and does not actually present with typical features of addiction. In fact one of the key features of BED, the sense of dispair and failure that follows a binge episode is the exact opposite of a “high” experienced by drug users. In any case, to me, patients with BED seem the least likely obese population to respond to an addiction drug – but who knows, we’ll find out soon enough (always happy to eat my words). AMS Edmonton, Alberta

Addiction Drug for Obesity?

This week, Orexigen, a biopharmaceutical company in La Jolla, CA, announced that it won a patent covering its obesity drug Contrave. Contrave actually consists of a sustained-release version of two older drugs: bupropion, which is currently used as an antidepressant and smoking cessation aid, and naltrexone, which is used for opioid addiction and alcoholism. Contrave is currently undergoing Phase III trials for obesity and the company hopes to file for FDA approval in late 2009. Why is Contrave, a combination of two drugs that have been around for a while, novel? Firstly, there is no doubt that depression is a common problem in treatment-seeking obese individuals, many of whom are “self-medicating” with food – i.e. eating highly palatable foods that increase serotonin levels in the brain to improve their mood (albeit temporarily). There is indeed evidence that buproprion may help some people lose weight. Secondly, many patients with obesity will be the first to admit that for them eating is akin to an addiction – a statement that is not surprising given that opioid-mediated reward mechanisms may play an important role in the hedonic aspects of ingestive behaviour and that this behaviour may well involve exactly the same neurocircuitary that plays a role in other addictions. So the idea of combining two drugs that address depression and addiction, respectively, is certainly one with merit and may well prove to be highly effective in obese patients in whom depression and hedonic eating are significantly contributing to hyperphagia. I have not seen data from these trials and have no relationship with Orexigen. I do however, like the concept of this drug and can’t wait to try it on some of my patients, who I can well imagine would benefit. Obviously, we need to await the results of the Phase III program and certainly need to very carefully look at the side effect profile of the two drugs used in combination. But I do think that this could indeed be a useful drug for some patients battling obesity – although it is unlikely to be the “magic bullet” for everyone. Remember, obesity is a highly complex and heterogeneous disorder and there is absolutely no reason why any one treatment should work for all. AMSEdmonton, Alberta

Can Diabetologists Take On Obesity Care?

For the past 30 years or so, I have given countless talks to diabetologists urging them to pay more attention to obesity management – all to little avail.  Interestingly enough, now, that we have new effective medications for obesity, which come with loads of pharma funding for research, education and conferences and as we near the end of significant new pharmacological developments in diabetes care, we are witnessing a sudden surge in interest amongst diabetologists and their professional organisations in taking on obesity as part of their “portfolio”. This is good!  Not only is there considerable overlap between patients with type 2 diabetes (T2DM) and those with obesity (indeed, it is hard to find a T2DM patient without obesity), effective treatment of obesity can lead to substantial improvements in glycemic control (and even complete remission of T2DM), and the incretin-based medications for obesity are also of use for managing T2DM.  Moreover, given the sheer number of diabetologists out there, together with the rather extensive and well-established infrastructures for diabetes care, expanding their mandate to also managing obesity appears a logical and long-overdue step. However, there are some important caveats.  For one, the majority of people with obesity do not have diabetes and will probably never get it. For these individuals, going to  a diabetes centre would seem strange, given that glycemic control is the least of their worries.  Anyone who has any experience with obesity medicine knows that people presenting at obesity and bariatric centres are rarely there because they are concerned about their HbA1c levels. Their problems are chronic pain, sleep apnea, infertility, polycystic ovary syndrome, fatty liver disease, urinary stress incontinence, osteoarthritis, GERD, migraines, and a host of other issues that have nothing to do with glycemic control.  Furthermore, a substantial proportion of patients presenting at bariatric centres have depression, anxiety, ADHD, BED, history of trauma, chronic grief, addictions, internalised weight bias, and plain old emotional eating, all of which need to be properly diagnosed and managed as part of obesity care.  Finally, no one can claim to have expertise in obesity medicine, who is also not comfortable with the pre- and post-surgical management of patients undergoing bariatric surgery (so far, despite strong evidence, diabetologists have rarely referred a patient for bariatric surgery never mind getting involved in their post-surgical care). While there is no reason why diabetologists should not be able to learn about and attend to… Read More »

Can Gastrointestinal Effects Alter Mental Health After Bariatric Surgery?

Although the overall impact of bariatric surgery on mental health is overwhelmingly positive, there remains a subset of individuals in whom mental health issues like self-harm or addictions may appear after surgery.  Now a paper by Robyn Brown and colleagues, published in Nature Reviews Endocrinology, presents an intriguing hypothesis, that alterations in the gut-axis may play a role in these problems.  As readers are well aware, bariatric surgery (with some variations depending on the type of procedure) results in profound changes in gut function including alterations in incretin release, intestinal flora, bile acid disposition, and vagal signaling. As discussed in the paper, all of these factors may potentially affect mental health. However, the evidence is sparse and often contradictory. As the authors point out, despite a strong potential for some of these alterations induced by surgery to alter mental health, few mechanistic studies appear in the animal or clinical literature that could potentially lead to better mechanistic insights and hopefully effective preventive and treatment measures.   Be the role of the gut in adverse mental health outcomes after bariatric surgery as it may, it’s perhaps important to recall that there are plenty of other probable contributing factors to adverse mental health in bariatric patients.  These include high rates of pre-existing depression, unmet expectations regarding the life-changing effects of weight loss, post-surgical alterations in the absorption of antidepressant and anxiolytic medications, and changes in alcohol metabolism, which might increase disinhibition and impulsivity, leading to self-harm.  In addition weight regain and recurrence of weight-related comorbidities, body dissatisfaction (perhaps heightened by excess skin after weight loss), as well as the reduced capacity to eat or enjoy highly-palatable foods as an emotional coping strategy may play a role in individual patients. Thus, although fear of mental health issues post surgery should probably not deter anyone from undergoing surgery if they really need it, clinicians should be aware of the possibility of adverse mental health outcomes and counsel and monitor patients accordingly.  DrSharma,Berlin, D

Some Limitations In Applying The Etiological Framework To Obesity Assessment

To conclude this series of citations from my article in Obesity Reviews on an aeteological framework for assessing obesity, that guides us through a systematic assessment of factors influencing energy metabolism, ingestive behaviour, and physical activity, it is important to consider some limitations of this (and any other) etiological approach to obesity management: While we have taken efforts to provide a comprehensive and wide‐ranging list of considerations in the assessment of obesity, we fully recognize that a full work‐up of all permutations of the proposed factors may well be beyond the scope of a busy practitioner. In this regard, the old saying applies: ‘when you hear hoofs, think of horses not zebras’. Thus, consideration should be first given to the most common and obvious reasons laid out in this paper, many of which should be immediately apparent to the experienced clinician (e.g. homeostatic hyperphagia resulting from meal skipping, hedonic hyperphagia related to depression, immobility due to osteoarthritis, weight gain due to atypical antipsychotics, etc.). Also, the use of comprehensive self‐directed questionnaires such as the Weight and Lifestyle Inventory, a multiple‐page self‐report questionnaire that the patient completes before treatment visits, designed to identify the root causes of obesity and perform an environmental analysis, may be helpful in this regard. Future efforts must also aim to provide simple clinical algorithms that will guide the busy clinician through the maze of factors that can potentially precipitate and/or exacerbate positive energy balance. Nevertheless, as in a patient with oedema, despite complete recognition of the underlying factors, the clinician often has no option but to manage the patient with the judicious use of fluid restriction and diuretics. Similarly, in patients presenting with obesity, the underlying contributing factors (e.g. genetics, addiction, depression, back pain, etc.) may not be easily amenable to causal treatment. In these cases, ‘symptomatic’ treatment of obesity with caloric restriction and exercise regimens may well in many cases prove to be the only option. Nevertheless, we maintain that careful identification and management of the possible socio‐cultural, psychological and biomedical barriers will likely increase the feasibility, compliance and adherence to these measures. Recognition of the causes and barriers will also help set out realistic expectations regarding the degree of weight loss that is likely to be achievable and sustainable, an important aspect of weight management. Despite the increased time required for the comprehensive work‐up of an obese patient, we believe that this framework will… Read More »