According to the EMEA press release on Acomplia (31 KB PDF file):
The European Medicines Agency (EMEA) today recommended contraindicating Acomplia (rimonabant) from sanofi-aventis, in patients with ongoing major depression or who are being treated with antidepressants, because of the risk of psychiatric side effects. Doctors in the EU have already been warned about this since June 2006 but the Agency’s Committee for Medicinal Products for Human Use (CHMP) has now recommended upgrading this warning.
Acomplia has been authorised in the EU since June 2006 as an adjunct to diet and exercise for the treatment of obese or overweight adult patients. Psychiatric side effects, in particular depression, were identified as the main safety issue at the time of approval. They were reflected in the medicine’s product information as a warning that doctors should not prescribe Acomplia in patients with uncontrolled serious psychiatric conditions such as major depression.
This is not a big surprise...
In October 2006, the US FDA issued Sanofi-Aventis an approvable letter, which is the bureaucratic equivalent of limbo, or maybe purgatory. It is half-way between approved and not approved. It means that more testing is needed before a final decision is made.
In June of this year, the FDA completed a review (PDF file) of some additional data. A couple of weeks later, Sanofi-Aventis announced (PDF file) that they were dropping their application in the USA. They also noted that they would continue with additional trials, implying that they have not totally given up on the US market. Even so, the FDA is concerned about the adverse effect profile.
Rimonabant has an unusually complex action on a
complex neuronal system.
It acts upon the endocannabinoid system, the same system
affected by cannabis.
Even though it is selective for the CB1 receptors (not having
an effect on CB2 receptors), it affects many different sites in the
brain. Moreover, the effects are not limited to the central
nervous system. It has effects in many peripheral tissues.
Not all of these are known or understood.
Therefore, it has many potential adverse effects.
Because of the complexity and diversity of effects, there is
going to be worry about the possibility of effects that cannot be
predicted, or cannot be uncovered in preclinical trials.An additional point of interest is that the endocannabinoid transmitters are retrograde neurotransmitters, that is, the perform retrograde signaling, from the postsynaptic to the presynaptic cell.
As you can see, the receptors that rimonabant, and tetrahydrocannabinol, act upon, are widely distributed in the brain:
Of course there is a difference between rimonabant and tetrahydrocannabinol (THC). THC is an agonist, thereby stimulating the neurons that possess CB1 receptors; rimonabant is an inverse agonist, thereby actively suppressing neuronal activity.
That slide did not shrink very cleanly, so I will explain. The top white line on the graph shows the effect upon the neuron that an agonist has. The dotted straight line in the middle shows the effect of a drug that blocks the receptor, called an antagonist. An inverse agonist is different. It actively reduces the activity of the neuron. To use an analogy, an agonist moves the car forward. An antagonist stops the car. An inverse agonist puts the car in reverse.
At first that seems like a bad analogy. After all, a neuron is either polarized or depolarized, either on or off; there is no middle setting. In order to understand fully what an inverse agonist is, it is necessary to know what effect the receptor has on the inner workings of the neuron.
Receptors are connected to second messenger systems. (The neurotransmitter being the first messenger). The second messenger is what signals the cell to let it know that the receptor is occupied. It does this by facilitating some kind of chemical reaction.
In some situations, the chemical reaction is normally on, to some extent, when the receptor is not occupied. This is called constitutive activity. CB1 receptors normally have some constitutive activity via a G-protein coupled mechanism. (in fact, the CB1 receptor is coupled to multiple G-proteins.)
An agonist increases the constitutive activity; an antagonist leaves it unchanged; an inverse agonist stops it. Note that some articles do refer to rimonabant as an antagonist; I have to assume this is either because it sometimes does act as an antagonist, or the authors are not being precise.
It turns out that CB1 receptors are involved in a wide variety of functions, having what is called pleiotropic effects. This is described in this article:
Although, the precise mechanisms of action of rimonabant have to be further dissected, it is emerging, from both preclinical and clinical research, that not only is rimonabant an antiobesity drug, but also its pleiotropic functions affect a broad range of diseases, from obesity-related comorbidities to drug dependence and cancer...
Starting from the discovery of the endocannabinoid system, a number of studies have pointed out that altered endocannabinoid signaling and CB1 receptor expression are involved in several pathophysiological situations, ranging from neurological and psychiatric diseases to eating, cardiovascular, and reproductive disorders...
Considering the antitumor properties of the cannabinoid receptor agonists, it could be expected that cannabinoid receptor antagonists, such as rimonabant, if used alone, would enhance proliferation of normal and malignant cells, leading to cancer. Some data excluded this possibility, reporting rather that not only agonists to cannabinoid receptors but also antagonists, used alone, are able to inhibit cancer growth (Bifulco et al., 2004) or induce apoptosis in cancer cells (Derocq et al., 1998; Powles et al., 2005)...
The concerns about the drug expressed at the most recent FDA meeting about rimonabant are summarized in this file, which is a powerpoint presentation. (If you don't have powerpoint, you still can view it using OpenOffice or some other viewer.) Some of the illustrations in this post are from that file.
Concern about malignancy was not documented in that review. Their main concern was that rimonabant, in animals, had a narrow therapeutic index. That is, the concentration required to produce a serious adverse effect was very close to the concentration required to get a therapeutic effect. The particular adverse effect they were concerned about was convulsions. They noted that other CB1 drugs are in development, and they have larger therapeutic indices.
The FDA committee also was concerned about the potential for rimonabant to cause or exacerbate depression, possibly including suicidal thinking. These concerns are quantified and discussed in this document (PDF file). They report that, from clinical trial data, the incidence of anxiety was 5.9% ( vs. 2.1% with placebo); mood alterations with depressive symptoms 4.7% (vs. 2.8%), and Depressive Disorders 3.9% (vs. 1.7%).
With regard to completed suicides, there was one among 5,262 patients treated with rimonabant in one study group of patients, and zero in the 2,474 who got placebo. There were four hospitalizations for depression in the treated patients, one in the placebo group. Overall, in all studies, there were three completed suicides in patients exposed to rimonabant. Two of those were in studies that have not yet been completed, so they were not included in the first analysis. Although no formal statistical analysis was presented, those numbers probably are too small to draw any firm conclusions.
Of greater significance is the finding that occurs when patients with a prior history of a depressive disorder are examined. Among those who received placebo, 8.9% developed a depressive disorder during the trial. Among those who received 20mg rimonabant, 19.1% developed a depressive disorder.
The panel did not find an increased risk for convulsions, based upon clinical trial data. However, patients being treated for epilepsy were excluded from the trials.
That is the consumer to make of all this? The drug is approved for use in Europe, but not in the USA. Agencies on both sides of the Atlantic are looking at the same data, but drawing different conclusions.
This actually is a common circumstance. I can't cite data, but it seems that the EU is quicker to approve drugs, and quicker to pull them from the market. The US is slower to approve drugs, but more reluctant to pull them once they've been approved.
Personally, I think the current EU stance on rimonabant is the correct one. That is based upon the notion that patients will be adequately informed of the potential risks, and that the drug will be prescribed appropriately and its use appropriately monitored.
Comments
Thanks for the excellent backgrounder on rimonabant. It certainly is confusing to consumers when drugs are approved in Europe but not the U.S., and vice versa.
History obviously shows that it pays to be careful with the pharmaceutical weight loss compounds. Earlier offerings have not panned out so well. Nonetheless, it is clear that, through neural mechanisms from dopamine to cannabinoid receptors, diet strongly effects neurotransmission, and the idea of food addictions in addiction-prone people--specifically, carbohydrate-craving obesity as one manifestation of addictive disease--begins to seem quite plausible.
Posted by: Dirkh | July 23, 2007 12:17 AM
Does this medication have a dangerous interaction with anti-depressive medications like cymbalta?
Posted by: katie mccully | March 11, 2008 11:43 PM
Does this medication contain any amphetimines?
Posted by: katie mccully | March 11, 2008 11:45 PM
There are no amphetamines. Unfortunately, I do not have any direct knowledge about drug interactions. Plus, various antidepressants have very different patterns of interaction, so it would not be possible to make a blanket statement about that.
Posted by: Joseph j7uy5 | March 12, 2008 1:10 AM
http://www.amjcaserep.com/abstracted.php?level=5&icid=865124
Posted by: marcello zanna | September 26, 2008 5:24 PM
The Office of Surgeon General always has been overtly political, a captive Ameritania Hotel New York
of the most hysterical public health activists. Its only real powers are tongue-clucking and finger-wagging, usually about the latest moral panic, lecturing the American public to knock off its bad habits, lest somebody get hurt. Richard msn nickleri Carmona's tenure was no different, which is why it's laughable to hear him lecture someone else about science.Posted by: msn | November 4, 2008 5:17 AM
http://www.amjcaserep.com/abstracted.php?level=5&icid=865124
Posted by: marcello zanna | September 20, 2009 4:24 AM