way past time…

Posted on Thursday 23 May 2013

Experimental Antidepressant Moves Closer to US Approval
by Deborah Brauser
May 20, 2013

The experimental antidepressant Vortioxetine is safe and effective for treating major depressive disorder [MDD], findings from several new phase 3 randomized controlled trials [RCTs] suggest. Three studies of a total of 1545 US patients with MDD showed that those who received 20 mg of Vortioxetine had significantly decreased symptom scores on the Montgomery–Asberg Depression Rating Scale [MADRS] after 8 weeks of treatment compared with those who received matching placebo. However, there was no difference in symptom scores between the 10-mg and the 15-mg dose compared with placebo.

Interestingly, a fourth study conducted in Europe and South Africa with 608 patients showed that both the 15-mg and 20-mg doses of Vortioxetine were associated with significantly lower MADRS scores than placebo. "We wanted to address the correct dose, and across the studies, the 20-mg had the most consistent findings over placebo," principal investigator Madhukar Trivedi, MD, professor of psychiatry at University of Texas Southwestern Medical Center in Dallas, told Medscape Medical News. Dr. Trivedi noted that "it’s very hard to figure out why" the 15-mg dose did well in the European study but not in the US studies, "but this often happens in antidepressant trials."

"Overall, the way I think about this as both a clinician and a researcher is that there are currently a lot of antidepressants with varying degrees of efficacy. And yet we know a very large number of the patient population doesn’t achieve remission with the currently available treatments. If Vortioxetine gets approved, I think it will be a welcome addition," he said.

Data from 7 trials, including these 4 that were presented here at the American Psychiatric Association’s [APA’s] 2013 Annual Meeting, have been jointly submitted to the US Food and Drug Administration [FDA] by Takeda Pharmaceutical Company and H. Lundbeck A/S as part of a New Drug Application. "Vortioxetine is an investigational multimodal antidepressant thought to work through a combination of 2 pharmacological modes of action: serotonin [5-HT] receptor activity modulation and 5-HT reuptake inhibition," write the investigators…

A few days ago, I had a post based on an article/press·release about a new antidepressant called Vortioxetine that has been submitted to the FDA for approval and was being presented in posters at the American Psychiatric Association Convention this week in San Francisco [beyond unacceptable…]. Then I ran across this Medscape article about it from the APA Convention itself. In my earlier post, I questioned Dr. Trivedi’s endoresment because I could find no evidence in PubMed or ClinicalTrials that he had been part of any study. But in this second article, he’s listed as the Principle Investigator. I rechecked my work, but he wasn’t there [more below]. So I spent more time than I’d like to admit making this table of the history of the Vortioxetine studies:

Vortioxetine Studies
ClinTrials# PubMed# Sponser
Site[s] Dose[s] Active

1 09/07 NCT00839423 21767441 11492A   GLOBAL 0,5,10 venlafaxine
     10/08 NCT00761306   11492C   GLOBAL 510  
2 11/08 NCT00672958 22963932 303   US 0,5  
3 12/08 NCT00672620 23252878 304   US 0,2.5,5 duloxetine
4 04/09 NCT00635219 22209361 11984A   GLOBAL 0,2.5,5,10 duloxetine
5 08/09 NCT00735709 22901346 305   GLOBAL 0,1,5,10  
6 03/10 NCT00811252 22572889 12541A   GLOBAL 0,5 duloxetine
     04/10 NCT00694304 22978748 11984B   GLOBAL 2.510  
     08/10 NCT00707980   301   GLOBAL 2.510  
7 09/11 NCT01140906   13267A NR3-055 EU,SA 0,15,20 duloxetine
8 01/12 NCT01163266   316 NR9-06 US 0,10,20  
9 03/12 NCT01153009   315 NR9-01 US 0,15,20 duloxetine
10 03/12 NCT01179516   317 NR9-02 US 0,10,15  
11 04/12 NCT01255787   CCT-002   GLOBAL 0,5,10,20  
     10/12 NCT01323478   13267B   EU 1520  
12 12/12 NCT01355081   CCT-003   JAPAN 0,5,10  

Notes: The studies are ordered by Completion Date. The un-numbered studies are 1 year extensions of other studies in the list. In the Dose[s] or Active Comparator columns, significant values are BOLD and those where the significance is unknown are in RED. The studies labeled GLOBAL are from multiple sites all over the planet.

Narrative: All of these studies were industry funded. It looks like they got off to a good start in 2007 with a successful study at the 5mg and 10mg doses, but then hit a wall for the next several years, unable to reproduce their initial success in the US along with a failed study. When they finally achieved significance again [5 & 6], they had a poster at the 2011 APA meeting with Dr. Michael Thase presenting [Investigative Depression Drug Does Better in Europe than United States]. That Medscape report reads very much like the one above two years later [same reporter]. To their credit, the negative and failed studies were published. Dr. Thase was an author on two [2 & 5] though they were published 5 and 3 years after completion, after the APA meeting. Buoyed  by their success, they launched a new round of studies at a higher dose [20mg] which were reported by Dr. Madhukar Trivedi last week [above]. They mention submitting 7 studies to the FDA, the 4 in the poster presentation and 3 others [?].

clinicaltrials.gov: All of these studies were industry funded. Studies 1-11 have been completed for over a year, and yet none of these studies have results posted on clinicaltrials.gov as prescribed. Worse, no study has the Principle Investigator listed on clinicaltrials.gov. Instead, they say something like "Study Director: Email contact via H. Lundbeck A/S LundbeckClinicalTrials@lundbeck.com" or "Study Director: Senior Medical Director, Takeda Global Research & Development Center, Inc". The same for the PI at the individual clinical sites. I’ve been vetting these studies for several years now and there used to be an actual person listed. Then, about a year ago, they started putting in these depersonified placeholders [I’ve tried emailing several and never gotten a response and I wrote clinicaltrials.gov and never heard back].

I can think of no legitimate reason for not listing a Principal Investigator. I can only assume that there wasn’t one – that these clinical trials are farmed out and handled by staff. What I suspect is that neither Dr. Thase nor Dr. Trivedi were involved in any of these studies directly, but were brought on board to legitimize the presentations later by looking over the results. I can’t prove that because the information that’s supposed to be available on clinicaltrials.gov isn’t there [and I imagine that’s the reason why it’s not there]. Likely, these are studies run by industry staff and only later apportioned to willing academics [KOLs]. That just shouldn’t be. It’s not even close to the point of having clinicaltrials.gov, or for that matter, having an actual scientist as Principle Investigator.

Nancy Wilson who found that press release has followed up and contacted UT Southwestern [see comment]:
Today I was informed that UT Southwestern will be investigating the complaint I submitted to the Ethics and Compliance Hotline on 05/20/13.  As well, I heard from the UT Board of Regents. The Chancellor’s office will be reviewing the Viibryd article and the Vortioxetine article. The Board representative said they take these things seriously. I like that.
Lets hope that this time, instead of accepting simple reassurances and denials or the evasive postings on clinicaltrials.gov, the investigators ask for solid proof that Dr. Trivedi was a functioning Principle Investigator who was actually involved in these studies while they were conducted instead of simply a hired KOL acting as a front man for the posters. If I’m wrong, I’ll apologize [but track record suggests I won’t be needing to do that]. We’ve really had quite enough of this kind of form without substance science in psychiatric clinical trials. That’s the impetus behind the Cochrane Collaborations and the AllTrials campaign. If you haven’t yet signed the petition, check it out here. It’s way past time for change!
    May 23, 2013 | 8:46 PM

    I still like Robin Williams’ drug for treating mental health. I know Mickey, you want a respectable and responsible site including comments, but, I hope after you read the post, you’ll let it stay as I am just quoting a famous comic who’s line left me in convulsive laughter in the aisle of the auditorium when he said it:

    “I have the perfect drug for all these problems: Fuck-it-all!”

    I mean, when you think about it, what has psychopharmacology just decomposed to these days, come up with a fancy name for a me too compound, and there you have it: people just want to swallow a tablet or capsule and then utter that line!

    Happy Memorial Day, probably fitting for the conclusion of the APA conference.

    See Ya!

    May 23, 2013 | 9:39 PM

    Dr. Nardo,

    Thanks for your research on this, for trying to get to the bottom of what’s going on with this new antidepressant (principal investigator, etc).

    Sometimes, I wonder why the FDA, NIMH and other federal agencies are not doing the same – with each of the drugs, all of the clincal trials, approvals, etc.

    There’s a lot of corruption out there, particularly with psychoactive drugs.




    Nancy Wilson
    May 23, 2013 | 10:23 PM

    Thank you, Mickey. I sent this to the investigator and the Chancellor’s office.


    May 23, 2013 | 11:31 PM

    Mickey, this Dr Thase is the same Dr Thase that shows up here spinning the size of the antidepressant effect https://www.youtube.com/watch?v=Zihdr36WVi4 ? If so, is anybody surprised? The only drama in Martin Keller’s story is that he got caught. Nobody should be surprised though that these things happen.

    May 24, 2013 | 1:12 AM

    I found the concept of a “Co-PI and Co-Investigator”:
    The source is, ahum, the University of Minnesota.

    Sandra Steingard
    May 24, 2013 | 10:17 AM

    I am a regular reader and I want to say once again how much I appreciate the effort and work you put into this. It is so important. I hope many others are reading as well.
    Many thanks.

    Richard Noll
    May 24, 2013 | 12:48 PM
    May 24, 2013 | 5:48 PM

    Thanks Richard. Just as I was about to embed it, they pulled it. Alas…

    May 25, 2013 | 6:58 PM

    “The experimental antidepressant [insert drug here] is safe and effective for treating major depressive disorder [MDD]….”

    We’ve heard this, literally, at least 20 times over the years.

    May 25, 2013 | 8:57 PM

    Yeah, we’ve heard it before alright…

    And for anyone paying attention (especially, the past five years), we’ve heard these drugs barely out-perform placebo for major depressive disorder only (and *only* after half the undesirable clinical data is tossed out).

    What few people know is that when an antidepressant is pitted against an *active* placebo (one with a side effect), the antidepressant is *not* any clinically better than the placebo.

    Timothy Scott, Ph.D. – Placebo vs Antidepressant, (3:00 into video) –


    What a scam!


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