The FDA recently approved lisdexamfetamine (LDF) for the treatment of the newly minted DSM-5 diagnosis of Binge Eating Disorder. This caused me some consternation and this blog will be as much about my reaction to this news as to the news itself.
The use of stimulants to curb appetite is nothing new. This was a common practice in the 60’s and 70’s and then it was shunned in respectable medical circles because we “knew” amphetamines were dangerous drugs. We also knew that their effects on dampening appetite tended to wear off over time. This is commonly cited as a reason not to be concerned about their use in youth.
I was introduced to these drugs as being addictive substances that were used to create animal models of psychosis. Yet, there has been an expansion of the use of stimulants in the past decade with very little discussion of the possible risks entailed. Their approval for the treatment of “binge eating disorder” follows the expansion of ADHD from childhood into adulthood. I doubt it is a coincidence that this happened at the time when most of the antidepressants went off patent.
In fact, the only thing that I can discern as novel about the new – still patented – stimulants on the market is that they are harder to abuse. That is what lexdexamfetamine is – a tamper proof form of amphetamine. But what is critical here is that there are clear market advantages for the manufacturer – the numbers of people who are potential consumers is greatly increased and the amount of time each person might be encouraged to take these drugs has now gone from about a decade to lifelong. What concerns me is that I do not believe – FDA approval aside- that there has been an adequate reckoning with their risks.
In January, JAMA Psychiatry published an online article, “Efficacy and Safety of Lisdexamfetamine for Treatment of Adults With Moderate to Severe Binge-Eating Disorder.” This is one of the studies that led to the FDA’s approval. In this double-blind 11-week study, about 150 individuals were randomized to receive placebo or one of three doses of LDF. They found that the two higher doses resulted in a statistically significant decrease in binge eating episodes. They report a remarkable low incidence of side effects.
So what is the problem? After all, this is not a situation where people are going to be forced into taking a drug they do not want or think they need. I happen to know how demoralizing it can be to be overweight. And we all know there are long-term health risks associated with obesity.
This is the problem. First of all, the results — although statistically significant — were not all that impressive. All groups improved; the group on the higher doses improved a bit more. Binge eating episode dropped from ~ 5 to 1/week in the placebo group and from about 5.5 to 0.5/week in the highest-dosed LDF group. On average, in the higher group, they lost about 4 kg (~9 lbs) over the course of the 11-week study. The placebo group did not lose weight.
The authors report they are doing a longer-term followup study to see if over time there is further weight loss. I think it could go either way; many people who take these drugs tend to accommodate over time to the appetite suppressant effects (although in this study appetite suppression was fairly low).
We should not lose sight of the fact that this was a drug company sponsored study and they acknowledge the assistance from professional writers. This was a multi-center study with no site having more than about 10 subjects enrolled. These kinds of studies do not have a good track record in our field.
This is the conflict of interest disclosures from this article:
“Dr McElroy is a consultant to or member of the scientific advisory boards of Alkermes, Bracket, Corcept, F. Hoffmann-LaRoche, Ltd, MedAvante, Naurex, Shire, Sunovian, and Teva; has received grant support from the Agency for Healthcare Research and Quality, Alkermes, AstraZeneca, Cephalon (now Teva), Eli Lilly and Company, Forest, Marriott Foundation, National Institute of Mental Health, Naurex, Orexigen, Pfizer, Shire, Takeda, and Transcept; is listed as an inventor on US patent 6,323,236 B2 (Use of Sulfamate Derivatives for Treating Impulse Control Disorders); and, along with the patent’s assignee, University of Cincinnati, has received payments from Johnson & Johnson, which has exclusive rights under the patent. Dr Hudson has received consulting fees from Alkermes, Genentech, HealthCore, Pfizer, Roche, and Shire and has received grant support from Eli Lilly and Company, Otsuka, and Shire. DrMitchell is a consultant to Shire and served as an investigator on a Shire-funded protocol. DrWilfley has received research support from Shire and United Health. Drs Ferreira-Cornwell, Gao, Whitaker, and Gasior hold stock and/or stock options in Shire Development, LLC. No other disclosures were reported.”
So we have an 11-week study that leads to FDA approval and the only impact this has – for after all this drug is already available – is that the drug company can now market it for this indication. In real life, this will not be used for 11 weeks; it will be used for much longer, maybe indefinitely. The study excluded people who have a history of substance abuse although they report one death in someone who abused methamphetamine. The authors acknowledge that there is a high rate of substance use among people who also meet the criteria for binge eating disorder. Undoubtedly, this drug will find its way to people who have problems with addiction. Stimulants are popular drugs for diversion – that is the entire raison d’etre for LDF. In a study published around the same time, researchers surveyed college students on their “non-medical” use of stimulants for weight loss. This means using the drugs when they are not prescribed. The incidence was about 4% in this population but it correlated with other risky behaviors including self-induced vomiting, laxative and diuretic abuse. Common sense and clinical experience tells me that it will be nearly impossible to know who is combining the use of these drugs with other risky behaviors. We already have a diversion problem with stimulants; widening their approved indications will only exacerbate that problem.
And these drugs can cause psychosis. I know this will likely be minimized in the studies. But as noted above, amphetamines have long been used to create animal “models” for psychosis. I am stupefied when colleagues play down this risk; I see at least one student a year who developed psychosis after using stimulants; sometimes after convincing a doctor (often at their college health service) that they have ADHD.
The authors of this study see this as a promising new development for our field. They see as an unmet need the fact that “no pharmacologic treatments for binge eating disorder are approved by the FDA. Additional clinical trials are needed to identify effective pharmacotherapies.” The lead author of this study is Susan L. McElroy, a well-known psychopharmacologist. I have written before about an encounter she and I had many years ago that foreshadowed — more than I could have ever imagined — the future paths of our careers. She was one of the psychiatrists who helped to shepherd in an early blockbuster drug, divalproex sodium, and along with it the expansion of the Bipolar franchise (rapid cycling, irritable mania, Bipolar type II).
I will take it at face value that from her perspective, she has been working to improve the welfare of others and she views her work for drug companies as a noble effort to bring much-needed treatments to people who are ill. She is now working at what looks to be a well-endowed hospital and research center, and I suspect her benefactors believe as strongly in her mission as some of us believe it is misguided.
Jeffrey Lieberman recently published a bit of a rant against those who he characterizes as anti-psychiatry. As I was reading and thinking about this study and my core distaste for it, I wondered whether I am anti-psychiatry. Maybe this is what psychiatry is – a race to find new drugs and new markets. It is hard for me to garner enthusiasm for this. I truly do not understand how psychiatrists of my generation could still be so enthusiastic about approaches that do not seem to have panned out. I do not understand why they seem loathe to question our basic paradigms or why they consider those who do question them to be suspect. I have a strong opinion that our first order of business should be that we put the brakes on. We do not know enough about what we are doing – particularly with regard to the long-term use and discontinuation of these drugs – to allow me to support forging ahead in the way we have done over the past 60 years.