The Rest of the Story

Occasionally, pharmaceuticals developed for one purpose turn out to have applications that differ from the original use.  This may turn out to be the case with riluzole (Rilutek® - Aventis Pharmaceuticals Products Inc.).  [Package insert (PI)]  I've blogged about this before, but this post has some new information, and presents a different perspective.  

Riluzole was approved by the US FDA in December 2004 for treatment of motor neuron disease, known primarily as Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig disease).  The chemical structure of riluzole is shown below:


Recently, a few articles have appeared, suggesting that riluzole might be helpful for some patients with depression and/or obsessive-compulsive disorder.  First, a disclaimer: the research is in a very early stage, and it would be advisable to consider such treatment only within the context of a formal clinical trial (1 2).  

Current pharmaceutical treatment for depression and OCD involve almost exclusively agents that modify the action of serotonin and/or norepinephrine.  In contrast, riluzole modifies the action of a different neurotransmitter: glutamate.

Glutamate is an amino acid.  Its primary function in humans is to serve as a component of protein.  It is often the case, however, that most things in the body serve more than one function.  Glutamate serves also as a chemical messenger, sending signals between nerve cells.  It is the most widely-distributed neurotransmitter in the human brain.  Because it is an excitatory transmitter, excessive amounts can lead to neuronal death.  It is thought that this is part of the pathophysiology of ALS, in that excessive glutamate may lead to premature death of motor neurons.  Therefore, it would make sense to try to find something that inhibits the action of glutamate, and see if that helps patients with ALS.  

Note that riluzole has several actions, only one of which is to inhibit release of glutamate from nerve cells in the brain.  This may or may not have anything to do with how or why it works.  From the package insert:

Mechanism of Action
The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective.

The mode of action of RILUTEK is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release, 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. [...]

Superoxide dismutase is an enzyme containing in cells that protects them from damage, under certain conditions.  

A lot of people with depression or OCD have a satisfactory response to standard treatments.  However, a lot of people don't.  Therefore, when a drug becomes available that does something to the brain, usually it is only a short time before somebody tries to use it to treat those patients who have not shown satisfactory response to standard treatments.  

Currently, it is not known what role glutamate plays in either depression or OCD.  However, since it is so widely distributed in the brain, it would not surprise anyone to learn that it was involved in some way.  See this study in ANAS for discussion. In accordance with the notions described above, people now are trying riluzole to see if it can help treatment-resistant patients with depression and/or OCD.

The American Journal of Psychiatry has published a couple of items on the use of riluzole for depression.  

Riluzole Augmentation for Treatment-Resistant Depression
Am J Psychiatry 161:2132, November 2004

Letter to the Editor

GERARD SANACORA, M.D., Ph.D., STEVEN F. KENDELL, M.D., LISA FENTON, Psy.D., VLADIMIR CORIC, M.D., and JOHN H. KRYSTAL, M.D.
New Haven, Conn.

To the Editor: Glutamate is implicated in the pathophysiology and treatment of mood disorders (1). The following case reports pertain to the use of riluzole, a putative antiglutamatergic agent indicated for the treatment of amyotrophic lateral sclerosis, as add-on therapy for treatment-resistant major depressive disorder. [...]

An Open-Label Trial of Riluzole in Patients With Treatment-Resistant Major Depression
Am J Psychiatry 161:171-174, January 2004

Brief Report

Carlos A. Zarate, Jr., M.D., Jennifer L. Payne, M.D., Jorge Quiroz, M.D., Jonathan Sporn, M.D., Kirk K. Denicoff, M.D., David Luckenbaugh, M.S., Dennis S. Charney, M.D., and Husseini K. Manji, M.D., F.R.C.P.C.

OBJECTIVE: This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in patients with recurrent major depression. METHOD: After a 1-week drug-free period, subjects 18 years or older with a diagnosis of recurrent major depression and a Montgomery-Åsberg Depression Rating Scale score >=20 received riluzole monotherapy (100–200 mg/day) openly for 6 weeks. RESULTS: Nineteen treatment-resistant depressed patients, 53% of whom were classified as having stage 2 treatment resistance or greater, received riluzole at a mean dose of 169 mg/day. Significant improvement occurred during weeks 3 through 6 for all patients and weeks 2 through 6 for completers. CONCLUSIONS: Although preliminary, these results indicate that riluzole may have antidepressant properties in some patients.

The "letter to the editor" is a semi-formal report of two cases in which depressed patients got better when riluzole was added on to their existing antidepressant regimen.  The "Brief Report" is a description of the outcome for 19 patients who received riluzole as the sole treatment.  The results are encouraging.  However, it is very important that the results be interpreted with caution.  That is why Zarate et. al. conclude with the statement: "Although preliminary, these results indicate that riluzole may have antidepressant properties in some patients."  

Regarding the potential use of riluzole for OCD, there is one preliminary study:

Riluzole Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder: An Open-Label Trial
j.biopsych.2005.04.043

Vladimir Coric, Sarper Taskiran, Christopher Pittenger, Suzanne Wasylink, Daniel H. Mathalon, Gerald Valentine, John Saksa, Yu-te Wu, Ralitza Gueorguieva, Gerard Sanacora, Robert T. Malison and John H. Krystal

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut

Case report

Background

Most patients with obsessive–compulsive disorder (OCD) show only partial reduction of symptoms with standard therapy. Recent imaging data suggests glutamatergic dysfunction in the corticostriatal pathway in OCD. We investigated the efficacy of augmentation therapy with riluzole, a glutamate-modulating agent, in treatment-resistant OCD.

Methods

Thirteen patients aged between 18 and 65 years with a primary diagnosis of OCD that had proven resistant to standard treatment were treated with the addition of riluzole to their existing pharmacotherapy. Yale–Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Inventory (HAM-D), and Hamilton Anxiety Inventory (HAM-A) scores were obtained weekly.

Results

Thirteen treatment-resistant OCD patients received riluzole 50 mg twice a day. Y-BOCS scores improved significantly over time. Of 13 patients, 7 (54%) demonstrated a >35% reduction in Y-BOCS scores, and 5 (39%) were categorized as treatment responders. HAM-D and HAM-A scores for the group also significantly improved over time. Riluzole was well tolerated with no serious adverse effects noted.

Conclusions

Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties. The addition of this agent may be of practical clinical benefit in patients with OCD.

In this study, results were more modest, but still significant.  Note that in all cases, riluzole was added to pre-existing treatment.  It was used in the dose that is standard for ALS, 100mg per day.  The study was not designed specifically to assess the effect of riluzole on depression, or on anxiety symptoms not related to OCD, but they did find a significant effect in those symptom clusters as well.

It happens all the time that such preliminary results are reported, patients flock to their doctors wanting the new treatment, and the results may turn out to be poor.  Even worse, patients may end up worse off than they were before.  In the case of riluzole, there are many reasons for caution.

Recall that the FDA has been criticized recently, due to allegations that they have been too lax in assessing the safety of new drugs.  Although Rilutek® has been approved by the FDA, it was approved for use in a condition that is rare, rapidly progressive, and invariably fatal.  The threshold for approval in such cases is different than the threshold for other drugs.  Although it is common for physicians to use drugs off-label, there are good reasons to be especially careful when doing so.  The FDA thinks that Rilutek® is safe, in relative terms; that is, it is safe in relation to the disease for which it was approved.  For an invariably-fatal disease, that threshold is fairly easy to meet.  Note that in the Kaplan-Meier survival curve, the improvement seen in ALS patients is significant, but hardly impressive.  Since all the patients died eventually, we have no way of knowing if there would have been an late-onset adverse events.

Note also that the approved dose of Rilutek® is 100mg per day.  The patients in the monotherapy study got more than that; some got 200mg per day.  

The Rilutek® package information contains warnings about variability in metabolism of riluzole in Japanese patients, men vs. women, smokers, the elderly, and patients with liver disease.  

RILUTEK, even in patients without a prior history of liver disease, causes serum aminotransferase elevations. Experience in almost 800 ALS patients indicates that about 50% of riluzole-treated patients will experience at least one ALT/SGPT level above the upper limit of normal, about 8% will have elevations > 3 X ULN, and about 2% of patients will have elevations > 5 X ULN. A single non-ALS patient with epilepsy treated with concomitant carbamazepine and phenobarbital experienced marked, rapid elevations of liver enzymes with jaundice (ALT 26 X ULN, AST 17 X ULN, and bilirubin 11 X ULN) four months after starting RILUTEK; these returned to normal 7 weeks after treatment discontinuation. 

In case that's all Greek to you...

ΡΗΛUΤΕΚ, ακόμη και στους ασθενείς χωρίς μια προγενέστερη ιστορία της ασθένειας ήπαρ, aminotransferase ορών αιτιών ανυψώσεις. Η εμπειρία σε σχεδόν 800 ασθενείς νόσου του Alsheimer δείχνει ότι περίπου 50% των ρηλuζολε-αντιμετωπισμένων ασθενών θα δοκιμάσει τουλάχιστον ένα επίπεδο ALT/$l*SGPT επάνω από το ανώτερο όριο κανονικού, περίπου 8% θα έχει τις ανυψώσεις 3 Χ UΛΝ, και περίπου 2% των ασθενών θα έχει τις ανυψώσεις 5 Χ UΛΝ. _ ένας ενιαίος μη-νόσος του Alsheimer ασθενής με επιληψία μεταχειρίζομαι με συνακόλουθος θαρψαμαζεπηνε και πχενοψαρψηταλ δοκιμάζω χαρακτηρίζω, γρήγορος ανύψωση συκώτι ένζυμο με ίκτερος (ALT 26 Χ UΛΝ, ΑΣΤ 17 Χ UΛΝ, και ψηληρuψην 11 Χ UΛΝ) τέσσερις μήνας μετά από αρχίζω ΡΗΛUΤΕΚ αυτοί επέστρεψαν σε κανονικές 7 εβδομάδες μετά από την αναστολή επεξεργασίας. 

...what this means is that there is a risk of liver damage with riluzole.  (I have no idea why Babelfish thinks "riluzole-treated patients" are "patients of illness of Alsheimer.")  It is pointed out that about half of the ALS patients have at least some elevation of liver enzymes when they are treated with Rilutek®.  They recommend regular monitoring of the levels of these enzymes, in case some patients develop overt liver damage.  

They also note that there were a few patients on Rilutek® who developed low white blood cell counts.

Riluzole is broken down in the liver by several different pathways, and there are many active and inactive metabolites.  It is highly bound to plasma protein.  Those are indications that it has a high potential for drug interactions.  Aventis did not do clinical studies to check for interactions.  It is likely that they would have to do more safety and interaction studies if they asked the FDA for approval to market Rilutek® for treatment of something common, such as depression or OCD.  

There has been some concern in the media about the impact of direct-to-consumer advertising of pharmaceutical products.  Blog posts, such as this one, raise a more complicated issue.  Most people reading this have either no idea, or only a vague idea, of who I am.  The fact that I use a lot of jargon and cite reputable journals may give the impression that I actually know what I am talking about.  In this post, I've tried to convey an appropriate level of caution.  I am not trying to sell anything.  (Note the absence of blog ads.)  I don't own stock in Aventis, except maybe there is some in my 401k; I deliberately don't invest directly in pharmaceutical companies.   But you don't know any of that, and you have no way of checking.  You could send an email to joseph.j7uy5-at-gmail/dot/com, but even that would not provide you with any information that is more reliable that what you are reading now.  

There are many sites on the Internet that include a lot of jargon and cite reputable journals, yet contain all kinds of misleading, commercially-motivated, and/or downright dangerous statements.  I suggest thinking of it this way: If you might consider making a potentially life-changing medical decision based upon some anonymous blog post, ask yourself this: would you consider investing a large amount of money in an unknown company, based upon an anonymous blog post that reads like this: ΡΗΛUΤΕΚ, ακόμη και στους ασθενείς χωρίς μια προγενέστερη ιστορία της ασθένειας ήπαρ, aminotransferase ορών αιτιών ανυψώσεις?  If not, good for you; if so, I suggest that you disconnect from the Internet immediately, and don't connect ever again.

No, the point here is not to urge anyone to go out and ask for a prescription.  Rather, I am hopeful that some health care professionals will read this and learn something that might be useful at some later date.  Nonmedical readers should take away a couple of points.  One, there is ongoing research into difficult-to-treat psychiatric conditions, so there always is hope that those who do not respond to conventional treatments may, someday, have more options available.  Two, there are some skills that one must acquire in order to assess medical claims.  Reading this post might help sharpen those skills.  And finally, always be skeptical of anything you read on the Internet, no matter how authoritative it may seem.  

Спасибо за чтение Корпус Коллозум. Возвратитесь скоро. До свидания.  Vielen dank dafür, Das Korpus Callosum zu lesen. Kommen Sie bald zurück. Auf Wiedersehen!.  Gracias por leer la Recopilación Callosum. Vuelto pronto. ¡Adiós!.  Merci de lire le Corpus Callosum. Revenu bientôt. Au revoir!  These translations courtesy of Paralink.com.  (I hope I didn't just insult somebody.)