Suicide? Not a Problem

A study in International Clinical Psychopharmacology compared three doses of agomelatine to paroxetine (Paxil or Seroxat) and placebo in the treatment of depression. I will write about the efficacy of agomelatine soon, but this post focuses on the alleged safety of the medications.

In the abstract, the authors wrote, “Agomelatine, whatever the dose, showed good acceptability with a side-effect profile close to that of placebo.” In the discussion, they state “Agomelatine is very well tolerated with an adverse event profile close to placebo.”

Now we are going to compare the rate of suicide and suicide attempts on medication to the rate of suicides and suicide attempts on placebo. Here is the data from the study, which is quoted directly (with added emphases):

During the study, two participants committed suicide, one [of 147 patients] on paroxetine after 11 days of treatment, one [of 137 patients] on agomelatine 25 mg of treatment after 10 days of treatment (both deaths being unrelated to treatment according to the investigator's opinion)... There were seven suicide attempts, one [of 141 patients] on agomelatine 1mg, three [of 147 patients] on agomelatine 5 mg, one on agomelatine 25 mg, two on paroxetine and none [of 139 patients] on placebo (p. 244).

Suicide and suicide attempts are never mentioned again in the article. Imagine that the data went the other direction – that there were suicide attempts and actual suicides on placebo, but not on medication. In such a case, there would almost certainly be further discussion of how the medication seemed to offer a protective effect against suicide. I give the authors credit for at least presenting the relevant data, but it is quite odd that the data on such a serious matter were simply brushed away.

This reminded me a bit of the Paxil/Seroxat study #329, in which suicide attempts were much more common on drug than placebo, but the study investigators deemed that none of these serious events were related to the medication. Same old story: The drugs don’t cause suicidal ideation and actual suicide – only depression can do that. Does Traci Johnson ring a bell for anyone?

Whitewashing of safety data such as in the case of agomelatine (and here and here) should raise suspicions. More on agomelatine (the "ideal antidepressant?") to come.

Could Agomelatine be the Ideal Antidepressant?

The above title is from a journal article (Pandi-Perumal et al., 2006). I’ve not been able to track down the actual article yet, but even asking if something could be “the ideal antidepressant” in a journal article title is patently ridiculous. If a medication caused remission of symptoms in 100% of patients with minimal side effects, it would be ideal. But maybe we've finally cured depression -- perhaps agomelatine really does magically cure depression. Let’s take a look...

The data: I found one study from which I could estimate the treatment estimate based on the abstract (Kennedy and Emsley, 2006). Here’s what the abstract said, in part: “The efficacy and safety of flexible dosing with the antidepressant agomelatine (25-50 mg/day) was evaluated in a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for major depressive disorder-current major depressive episode. Patients receiving agomelatine (25 mg and 50 mg/day) had a significantly lower mean Hamilton Rating Scale for Depression (HAM-D) score at endpoint compared with those who received placebo (14.1 +/- 7.7 vs. 16.5 +/- 7.4, p = 0.026)” Based on these means and standard deviations, I come up with an effect size of .31, which is considered small. A small effect does not make for “the ideal antidepressant.”

Duplicate Publication Watch: Read the abstracts from these two articles (Montgomery, 2006 and Kennedy and Emsley, 2006). I reproduced a segment from the Kennedy/Emsley abstract above and here’s a piece from Montgomery’s writing below:

“In a recent placebo-controlled study, 212 MDD patients were randomly assigned double-blind to receive placebo or agomelatine 25 and 50 mg/day. There was a significant advantage for agomelatine after 6 weeks according to scores on the Hamilton Depression Rating Scale (HAM-D) (P = 0.026) and the Clinical Global Impression Severity (P = 0.017), with an improved response rate (P = 0.03).”

Look familiar?

More hype: Montgomery’s abstract closes with: “Agomelatine may fill the gap in the current therapeutic armamentarium by combining efficacy with a favorable tolerability profile and additional clinical benefits.”

I have not seen the tolerability-related data, but I see not one shred of data to support “additional clinical benefits," unless he's referring to potential improvement in sleep. But if we're thinking of clinical benefits in the manner of better reduction of patient symptoms, there is simply no data to support that assertion. The "gap in the current therapeutic armamentarium" is that current treatments are not much more effective than placebo (as demonstrated by agomelatine), and they have notable side effects. When SSRIs and atypical antipsychotics emerged, they were considered to be much safer and better tolerated treatments than their predecessors and we now know that is not the case. Does this new “ideal” drug have a better safety profile? We had better wait and see before jumping on yet another bandwagon for a treatment that is overly hyped.

By the way, I tried to find more clinical trial data on this drug from the Novartis website, but their clinical trial register was not functional at the time.

Seroquel for Everything and Academic Spokespeople

Part 1. Seroquel for Depression and Anxiety. AstraZeneca is slowly rolling out the PR for Seroquel as a treatment for depression and generalized anxiety disorder. At something called the 7th International Forum on Mood and Anxiety Disorders, AstraZeneca (via academic frontman Stuart Montgomery) has trotted out data from their latest clinical trials which purportedly show that Seroquel beat placebo for depression and GAD. Here's a quote from the detached, independent, non-conflicted academic author, Stuart Montgomery...

Dr. Stuart Montgomery, Imperial College School of Medicine, University of London and author of the [depression] monotherapy study, said: These study results are remarkable -- all of the doses of SEROQUEL XR examined provided improvements in MDD and GAD symptoms. Results from further studies that are still ongoing will add to our understanding of SEROQUEL XR in these conditions.

What is remarkable is not that 'Quell had a slight advantage over placebo but that an "independent" academic psychiatrist is willing to pimp Seroquel so blatantly. It would appear that Dr. Montgomery is aware of who is putting butter on his bread. Finding a modest to perhaps moderate advantage for a drug over a placebo in treating depression and/or anxiety is far from remarkable, given that there are dozens of drugs and psychotherapies that have demonstrated similar or better efficacy. Then again, it is remarkable that Seroquel is related to increased risk of diabetes (1, 2, 3, 4), which is likely not the case for competing depression treatments. Of course, since the movement has now started to treat depression with antipsychotics (1, 2), perhaps we will see many people with depression moving toward an increased risk of diabetes. It might be worth noting that on the MADRS, which was the measure of depression reported in the press release, one question is regarding eating -- the more you eat, the better your score. So an antipsychotic linked to weight gain is set to do well in that those who eat a lot will score better on this item, which is then taken as a sign that they are less depressed.

I've been tracking the Seroquel for everything bandwagon for some time now (1, 2, 3, 4) and I can't wait to see where this is headed next.

Part 2. The Academic Salesperson. As Krusty the Klown might say, "I heartily endorse this event and/or product"...

Here are some other Stuart Montgomery quotes from press releases:

Agomelatine

"Agomelatine is an interesting and potentially very valuable antidepressant that is effective in both moderate and severe depression", says Professor Stuart Montgomery from the Imperial College School of Medicine in London. "The new agent has a unique mode of action, improves sleep without affecting daytime alertness and its efficacy is not compromised by sexual side effects, tolerability problems or discontinuation symptoms.

Escitalopram (Lexapro)

"These results are important because they show we have a treatment at our disposal which is effective without sacrificing the good side-effect profile obviously preferred by patients," commented study author Professor Stuart A. Montgomery, Imperial College School of Medicine, London, United Kingdom. "The ideal combination for any first line treatment is good efficacy and good tolerability - this study shows that escitalopram has all the potency of the non selective SNRIs combined with the good tolerability of the conventional SSRIs," he concluded.

Lexapro (again)

“This consistent advantage really came out as a surprise,” marvelled Prof Montgomery. “These are shocking data that no one was expecting”. He added: “At that stage we already knew that there was something special about the drug”.

Finally, Prof Montgomery mentioned results coming from further studies that he referred to as “staggering” – these were decisive in establishing Lexapro’s long term effectiveness in treating both GAD and SAD.

One more piece on Dr. Montgomery may be of interest to readers (via The Guardian ):

A leading figure in the world of psychiatry gave a pharmaceutical company advice on how to get its new drug approved while he was sitting on the committee which was deciding the licence application.

An internal memorandum from Pfizer, the world's largest drug company, says Stuart Montgomery would be happy to become a paid adviser and declare an interest to the Committee on the Safety of Medicines (CSM) once the drug, an antidepressant to rival Prozac, had been through the licensing process.

Read the whole article and see what you think.

When Dr. Montgomery or other key opinion leaders with similar conflicts of interest speak, we are supposed to view them as independent expert researchers whose enthusiastic product endorsements are based purely based on science. The manner in which every drug company trot out eager academic spokespeople is a sign that academic medicine has become rotten to the core.

Cymbalta and Effexor: Hype Over Science

Remember the hype around the serotonin-norepinephrine reuptake inhibitors (SNRIs)? Effexor and Cymbalta impact both serotonin and norepinephrine, so they should be more effective than SSRI’s in treating depression? Mind you, that’s not a high bar to clear - it’s not like SSRI’s are much better than placebo. So get the hell outta the way, Prozac and Paxil, because Cymbalta and Effexor will unleash their incredible efficacy onto the world of psychiatry. Doubt me? Read this 2009 article regarding the wonders of Pristiq (son of Effexor) and learn about how “The emergence of the selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) antidepressants has improved the treatment of MDD.” Or this press release from Wyeth. Or Dr. Danny Carlat’s experience selling Effexor to his peers. I don’t think anyone who has followed drug marketing would deny that both Wyeth and Lilly tried to pimp Effexor and Cymbalta as working better because of their SNRI properties.

But is that actually true? A team of German researchers examined the data and concluded that neither Effexor nor Cymbalta really work better than SSRIs. They actually found a small advantage for Effexor over SSRIs for treatment response (but not depression remission), but they also found that the manufacturer was hiding studies from them (and the rest of the world). I haven’t said this for a while, but enter Charles Nemeroff. To understand the research by the Germans, we first need to recall that a 2008 study (lead author: Nemeroff) found

...the pooled effect size across all comparisons of venlafaxine versus SSRIs reflected an average difference in remission rates of 5.9%, which reflected a NNT of 17 (1/.059), that is, one would expect to treat approximately 17 patients with venlafaxine to see one more success than if all had been treated with another SSRI. Although this difference was reliable and would be important if applied to populations of depressed patients, it is also true that it is modest and might not be noticed by busy clinicians in everyday practice. Nonetheless, an NNT of 17 may be of public health relevance given the large number of patients treated for depression and the significant burden of illness associated with this disorder. [my emphasis]

As I wrote then, the benefit to public health claim is ridiculous. To understand the reasons why this is so laughable, please check out my prior post on the topic. This meta-analysis included a bunch of data from Wyeth that was previously unpublished...

Which leads to the freshly published meta-analysis on how Effexor compares to SSRIs. The German researchers requested unpublished data from Wyeth and only got some of it - you’d think that just maybe Wyeth sent them the “good news” data and maybe held back on some of the “bad news” data. So when an ever-so-small benefit emerged for Effexor (5% high treatment response rate), well, call me crazy, but I ignored it. We’re not playing with a full dataset because the manufacturer wants to keep some of it hidden, so shame on Wyeth and let’s look at Effexor with a little bit of suspicion. So Effexor vs. SSRIs - no difference. Except that more people drop out of clinical trials on Effexor due to side effects compared to SSRIs (about 3% more). So even if you believe that Wyeth’s hidden data really doesn’t impact these findings, we’re left with a very small advantage for Effexor that is probably negated by its slightly higher dropout rates.

Cymbalta. It had a 3% higher dropout rate due to adverse events and the same efficacy as SSRIs. So nothing to write home about, except that it costs a boatload more than generic SSRIs and is harder to tolerate. But Cymbalta has been marketed to the gills and is clearing $3 billion a year in sales. Hey, this is the company marketed Zyprexa for dementia (oops), and for, well, lots of other stuff (1, 2). So it’s not surprising at all that they can take a mediocre antidepressant like Cymbalta and turn it into a big moneymaker - the wonders of a good marketing department. But Depression Hurts and Cymbalta is a painkiller. Well, that’s fine and dandy until you actually look at the data which show Cymbalta doesn’t do much for pain in depression.

It’s time to get over the hype surrounding SNRIs. The next “advance” in antidepressants, well, who knows what it will be - but let’s hope it’s something a little more substantial than SNRIs. But I’m not hopeful. And no, I don’t want to hear anything more about agomelatine.

I know it’s been a long time between posts. So pardon me if my writing is more awful than usual. And it doesn’t mean I will be posting regularly. Thanks to the multiple readers who sent me a copy of this article.

Citation to new meta-analysis of Effexor and Cymbalta:
Schueler, Y., Koesters, M., Wieseler, B., Grouven, U., Kromp, M., Kerekes, M., Kreis, J., Kaiser, T., Becker, T., & Weinmann, S. (2010). A systematic review of duloxetine and venlafaxine in major depression, including unpublished data Acta Psychiatrica Scandinavica DOI: 10.1111/j.1600-0447.2010.01599.x