1 Boring Old Man

Ever since the abrupt disappearance of Pharmalot [January 1, 2014 gulp…], I’ve missed it every morning. I knew it was important, but I had no idea how important until it wasn’t there. Other blogs report the pharma stories [like Jack Friday at Pharmagossip], and I’m amazed that they’re so good at finding them. But nobody holds a candle to what Ed Silverman was able to do. Even though I was mainly interested in the ones that had to do with psychiatric drugs, I read most all of them and felt like that I knew about the industry as a whole. It was a rare moment that I ran across something that I didn’t read on Pharmalot first, or at the latest on the next day.

I expect most of us who have felt the loss of Pharmalot to keep up with things have had the same fantasy of finding some way that Ed could be independently supported to continue, but none of us have the required deep-pockets nor the right philanthropic connections. Rupert Murdoch, however, does:

Most of us were surprised, but Ed will still be Ed even with the WSJ. I look forward to seeing what he puts together there. Ed Silverman on the WSJ is better than no  Ed Silverman at all. That’s for sure…

… Later I learned that the FDA is a pretty nice bunch, and if you can’t find what you’re looking for posted online, they’ll send it to you with a simple Freedom of Information Act request made online – charging a nominal fee only if you’re a frequent flyer or your request is hard to gather.

Effect Sizes [Cohen’s d]

Note: The highlighted values are not statistically significant. There are two significance tests in the table. The one way ANOVA tests all values. If it is insignificant, testing the individual groups doesn’t matter. It says that there’s no significance to be found. This was skipped in the FDA Report. If the ANOVA reveals significance, then the pairwise comparisons can be used to locate the significance. If the lower limit of the 95% Confidence Interval is less than zero, it is insignificant.

WHY ALL THIS PREOCCUPATION WITH LURASIDONE? THE FDA?
In the past, I’ve gone back and looked at the clinical trials and the FDA reports, but the real time for looking had really long passed. By the time I looked, the drugs were blockbusters and the patents were close to running out or already expired. So I made a resolution that when some new drug was approved, I was going to start looking early. You can’t really close the barn door after the cows have already escaped was my theory. So I wanted to follow the teachings of preventive medicine – early detection. Vet the studies as soon as you get wind that a new drug has appeared. Once the drug is launched and in heavy use, It’s too late to do much except whine, at least that was my idea. Then came the news that PHARMA was abandoning CNS drug development, which was fine with me. We needed time for things like data transparency, AllTrials, RIAT, EMA data release [the reform movements] to get established. So when me-too drugs like Vybriid® and Latuda® came along, I didn’t think they would go anywhere. But that was naive, and when I saw that next Latuda® approval for Bipolar Depression [or both…], I revived my early detection theory.

So I made my little table up there with the Schizophrenia data and sat back, smug in the knowledge that around the corner was the FOIA FDA report on the Bipolar Depression approval. Even after reading Sandra Steingard’s MIA blog [A New Silver Bullet? The Lurasidone Story] about the Sunovion reps hanging around and seeing all the ads, I still felt like I was ahead of the curve. That was Monday.

A NAP INTERRUPTED:
Tuesday, after a long morning working in the clinic, I was awakened from a recovery nap by a mid-afternoon phone call. It was the FDA calling. The lady on the phone told me she’d seen I’d made other requests, but they were for "older drugs" [I wasn’t liking how this was sounding so far]. She said it was different for recent approvals. I didn’t follow all of what she was saying, but she seemed to be trying to dissuade me from pursuing my request. She said it had to go through several processes one of which was "disclosures" and there might be a charge. Did I still want to stay in the queue? By this time I was awake enough to say, "Sure. How long is the usual wait?" She said "18 to 24 months. You know, we get over 3000 requests every year." long pause. I said "Okay" [having given up with taking out my frustrations with big systems on small bureaucrats long ago]. But when I was fully awake and thought about it, I think I learned something, and have to revise my theory. My now fading enthusiasm for the FDA had been based on experiences where what I was requesting was old hat, and just required copying a disk from somebody else’s previous request. The fantasy that I could get the information on a recent approval in a timely fashion was naive. This drug is going to be well down the line in it’s patent life before I ever see that report, just like before. The previous reports I’ve gotten have had very little redacted, but there’s still apparently government processes that comes before release, some bureaucratic government processes measured in years.

It brings up a problem that’s general to Data Transparency. We’re not looking at the data [if we can even get it] with a magnifying glass. We’re seeing it through a telescope focused somewhere in the past. I thought about an article I read recently in the BMJ [Why did it take 19 months to retrieve clinical trial data from a non-profit organisation?], the travails of the investigators like Peter Doshi and Thomas Jefferson trying to get the Tamiflu studies, the bruhaha over getting trial data from the European Medicines Agency, the years it has taken [and is still taking] to get the data from Paxil Study 329, the disappointing clinicaltrials.gov results database [even when they’re reported much later], etc. While some of the problem can be obstruction by the pharmaceutical industry, there’s another bureaucratic factor that may be a just as big a hurdle. And what’s happening here appears to be its general form – preparing the data, checking for "disclosures."

A REAL TIME PROBLEM:
The essence of the problem involves time. What has happened in the past is that once a drug is approved, the sugar coated articles in the journals are rapidly disseminated by drugs reps to practitioners. For example, the lead-off Lurasidone Schizophrenia article in the American Journal of Psychiatry failed to mention the heavy use of Benzodiazepines in the trial, the larger effect sizes with Olanzapine, or the relatively poor showing at the US sites among other things. So the long lag times in being able to see more of the back story essentially allow the drug to be launched unchallenged by any independent vetting of the studies.

And what is it in the report to the FDA or the anonymized patient data that needs to be gone over to check for "disclosures"? Why not ask the pharmaceutical applicants not to put any secrets in their reports or data in the first place. We heard Neal Parker, a lawyer for AbbeVie [a deal-breaker?…], tell us there was commercially sensitive data, that revealing it would have them lose their competative edge – to which I would say, "Don’t put such things in your report." Good old boy negotiations have no place in drug approval anyway. I can think of no real reason that data submitted to the FDA, or the EMA, or even the raw data prior to analysis should contain secrets that have to be removed. Similarly, the pharmaceutical companies currently setting up expert panels to approve access are claiming that they need time to prepare the data. I don’t think Data Transparency means "prepared data." In fact, it means the opposite. The sugar coated published paper is already "prepared data." Data Transparency means "unprepared data."

THE POINT: If a journal article is a proxy for a data-set generated by a Clinical Trial [which it is][see proxies…], there’s no rational reason that the data should lag behind the publication. If the FDA or EMA Approvals are suggesting that a drug is safe and efficacious, there’s no reason that practitioners and researchers shouldn’t be able to see how that conclusion was reached. And based on past behavior, once the drug is launched, there’s an inertia that carries it forward. If there are questions about the drug, they need to be on the table early on. Particularly in psychiatry, there have been a number of blockbusters with some real problems that would’ve been apparent early on had there been an early review of the raw data.

Psychiatric Times retracts essay on “satanic ritual abuse”

Retraction Watch

by Ivan Oransky

February 13, 2014

Some Retraction Watch readers may recall this episode, recounted in a recent op-ed by Lew Powell:

During the 1980s and early ’90s a wave of nonexistent “satanic ritual abuse” claims shut down scores of day cares such as Little Rascals, McMartin in California and Fells Acres in Massachusetts. In virtually every instance the charges lacked any basis in fact. Today no reputable psychologist or other social scientist will argue otherwise. The defendants were innocent victims of a “moral panic” that bore striking similarities to the Salem witch hunts 300 years earlier.

Psychologist Richard Noll found the charges troubling too, so he wrote a piece last year for Psychiatric Times because:

Despite the discomfort it brings, we owe it to the current generation of clinicians to remember that an elite minority within the American psychiatric profession played a small but ultimately decisive role in the cultural validation, and then reduction, of the Satanism moral panic between 1988 and 1994. Indeed, what can we all learn from American psychiatry’s involvement in the moral panic?

The Psychiatric Times editor said the staff thought the essay was “terrific” and might even be a cover story for their January issue. It was posted on December 6. But you won’t find that article — available here — at Psychiatric Times anymore. As Gary Greenberg relates:

The editor made some suggestions for the print version and asked for Noll to finish them by Dec. 16. But then on Dec. 14, Noll discovered that his article  had vanished from the website. He made gentle inquiries and determined that it wasn’t a glitch, but that PT had intentionally taken down the article. The reasons were vague–something about how they didn’t like the title (which they had chosen), and how they didn’t like the fact that he had named names. But whatever the reason, the article was gone.

Here’s what the editors told Noll when he pushed for an explanation:

Dear Dr. Noll,

I don’t blame you for being miffed at the inexplicable disappearance of your article, and the long delay in getting back to you with an explanation. I’d like to offer a sincere apology for the delay, and to explain what happened. It hasn’t helped that our offices were closed most of last week and that communications between editorial board members and staff have been generally slow because of vacations.

As you know, Professor [redacted] is the final arbiter of History of Psychiatry columns, so our staff enthusiastically went ahead and posted your article. I read it the weekend it was posted, however, and grew immediately concerned that it raised potential liability issues—possibly for you and, by extension, for Psychiatric Times. I therefore thought it prudent to hide the piece from public view until I could get some guidance from our editorial board. The board did support these concerns, and it was suggested that I consider obtaining corporate legal advice. There was also the suggestion that Drs. Kluft and Braun and some others discussed in your essay needed to be given the opportunity to respond to claims made in the piece. However, there was also general consensus that the piece “may be of some historical interest, but not particularly relevant to the problems facing psychiatry today.” Ultimately, it was the board’s recommendation that we not publish the piece.

We respect your expertise and previous contributions to Psychiatric Times. The scenario is a first for us. I’m so sorry it happened this way. We will return your copyright form and hope that you find another venue for the piece…

Powell, we should note, has also been urging the Journal of Child and Youth Care (now called Relational Child & Youth Care Practice) to retract a 1990 issue devoted to In the Shadow of Satan: The Ritual Abuse of Children.

"However, there was also general consensus that the piece ‘may be of some historical interest, but not particularly relevant to the problems facing psychiatry today.’ ”

It seems to me that our real failing is that when we go through the oscillations in science known as paradigm shifts, there are two things that are unique to our mental health specialties. Our highs and lows tend to swing way higher and way lower, often into the realm of absurdity as in this case. And we tend to reject whole paradigms lock stock and barrel as rapidly as we were too quick to embrace them earlier [lock stock and barrel]. I would surmise that the wide swings are in the nature of anything subjective. But I’m not sure I altogether understand the waves of naive acceptance and outright rejection. In other scientific endeavors, the phase of paradigm exhaustion leaves a growing residue of what was useful that leads to a gradual upward movement in the discipline.

Freud rejected his earlier trauma theory in favor of one based on fantasy, leaving the actually traumatized behind. The revival of trauma theory left those with powerful fantasies behind. In the midst of that rediscovery of traumatic mental illness, the episode Richard wants us to remember emerged. And it’s important to know that the therapists that got caught up in this story weren’t all crazy themselves, nor charlatans. The clarity offered by the victim/persecutor paradigm is a compelling human experience – extending well beyond the borders of the formally paranoid among us. And it came at a time when there were other paradigm shifts around every bend – including the medicalization of psychiatry.

There are other places where our history has unmentioned lacunae – prefrontal lobotomies, insulin coma wards, over-use of convulsive therapy or neuroleptics, etc – breakthroughs gone viral. We’re in the afterglow of some now – the DSM revolution, evidence-based medicine and clinical trials, translational science, clinical neuroscience, psychopharmacology. These are all useful concepts in moderation, but moderation has never been our forte. Are we going to suddenly disappear all of them just as we sought to disappear psychotherapy thirty years ago? or, to return to the point, as we continue to disappear the days when psychiatry battled the devil?

Are we ready now to reopen a discussion on this moral panic? Will both clinicians and historians of psychiatry be willing to be on record? Shall we continue to silence memory, or allow it to speak?

BE WARNED! This post is very boring. It’s what an old man does to escape watching any more Olympic figure skating…

Three years ago, I had my first shot at looking at the FDA Approval documents for a psychiatric drug [seroquel II [version 2.0]: guessing…]. To be honest, I didn’t know anything about how to do such a thing, but I had a lot of help. I learned that the FDA approval process requires two decent clinical trials with statistical efficacy and an acceptable side effect profile for approval. I discovered that PubMed had the abstracts of the published trials, that clinical trials.gov had the trial registrations [and rarely the required posted results], and that in many cases the medical report on the approval were on Drugs@FDA. And I learned that this wasn’t an easy avocation. There were lots of things to consider, too many for a rookie like me, and I often ended up with my eyes crossed scratching my head. Later I learned that the FDA is a pretty nice bunch, and if you can’t find what you’re looking for posted online, they’ll send it to you with a simple Freedom of Information Act request made online – charging a nominal fee only if you’re a frequent flyer or your request is hard to gather.

I looked at the FDA original approval of Lurasidone [Latuda®] for Schizophrenia back in 2011 [see ought to know by now…, echo echo echo echo echo echo echo… , in the shadows…, wait…] but I didn’t pursue it very far. Frankly, I thought it would be something of a dud with its low efficacy and the generic competition. That wasn’t correct apparently, so I’m taking another look. But that’s not what this post is really about. It’s about why the AllTrials campaign is absolutely essential.

About the Table: The top five studies were the ones looked at by the FDA. The bottom two were in the works but not completed. Study D1050049 was a failed study [inert comparator] so they only considered four [D1050006, D1050196, D1050229, D1050229]. The left-hand column has the study [linked to clinicaltrials.gov], the date started, the number of subjects, the dropout rate, the number of sites, and an icon linking to the abstract if published. The second column has the scale used [BPRSd or PANSS] and the correction method for missing values [LOCF or MMRM] with the Primary Variable in bold. The numbers are the raw differences between the drug and placebo. Significant values are bold red:

LS Mean Difference from Placebo
Study #	Efficacy Scale	20mg	40mg	80mg	120mg	160mg	Comparator
D1050006  US    2001   n=149    66% drop out    15 sites	BPRSd (LOCF)		-5.6		-6.7
	BPRSd (MMRM)		-7.3		-9.2
	PANSS (LOCF)		-9.6		-11.0
							Haldol
D1050049  US    2003   n=356    43% drop out    34 sites	BPRSd (LOCF)	-5.0	-5.2	-8.0	-9.8		-7.9
	PANSS (LOCF)	-7.1	-7.2	-13.6	-16.0		-12.3
D1050196 US    2004   n=180    45% drop out    15 sites	BPRSd (LOCF)			-4.7
	PANSS (LOCF)			-8.6
D1050229 MIX    2008   n=496    34% drop out    48 sites	PANSS (MMRM)		-2.1	-6.4	-3.5
	US Sites		+0.6	-2.0	+0.2
	Non-US Sites		-6.5	-10.8	-8.6
	PANSS (LOCF)		-2.7	-6.1	-3.5
							Zyprexa
D1050231 MIX    2009   n=475    38% drop out    52 sites	PANSS (MMRM)		-9.7		-7.5		-12.6
	US Sites		-5.7		-4.8		-11.4
	Non-US Sites		-10.5		-3.8		-9.6
	PANSS (LOCF)		-7.9		-4.8		-11.4
							Seroquel
D1050233 MIX    2008   n=488    28% drop out    65 sites	PANSS (MMRM)			-11.9		-16.2	-17.5
D1001002 Asia    2008   n~440    62 sites	PANSS (?)	unpublished

In addition to the Clinical Trial and PubMed links, I had the FDA Medical Review [the source for the values for the unpublished trials], a special report from the FDA Director, and the full journal articles for the published studies. Lots of stuff.

… the data submitted in this NDA, in this reviewer’s opinion, do not support the efficacy of lurasidone in the treatment of schizophrenia…

1.2 Risk Benefit Assessment: Efficacy has not been established in this NDA submission. The safety profile is more similar to typical antipsychotics with significant akathisia, hyperprolactinemia, parkinsonian-adverse events and dystonias; many of which are dose-related. Lurasidone does not appear to have significant adverse impact on metabolic indices (glucose, lipids, weight, etc.). Lurasidone may be associated with potentially significant hypersensitivity reactions. A comprehensive risk:benefit assessment is premature at this time.

I was also able to look at one of the studies that wasn’t quite ready for prime time [D1050233]. Even though those numbers may look good, there were some big question marks. There were 65 sites, 36 Non-US, but there was no breakdown between US/Non-US responses in the article. Even more troubling to me, there were four groups [Placebo, 80mg, 160mg. and Seroquel], 65 sites, and a total of  72% of 488 subjects who completed the study. That means that the average size for each group at any given site was (488 x 0.72) ÷ (65 x 4) = 1.4 subjects/group/site. I never heard of such a thing! There’s a way to test for that statistically [General Linear Model with effects for country, site, and treatment]. In English what I’m saying is that it’s almost as possible that the variance is due to site differences as to treatment effect.  They did an "ANCOVA at Week 6 LOCF endpoint with treatment and pooled center as fixed factors and Baseline value as a covariate" which doesn’t say country or site to me. But, and this is the point, I don’t have the numbers so I can’t run that down. There’s also enough other strategic language in that article to make me plenty suspicious of the whole presentation. Study D1001002 had no results on clinicaltrial.gov and no publication so I assume it was a bust.

With all this information that I’ve been able to ferret out, I’m pretty sure that this is one of those situations where the data has been skewed and I doubt that Lurasidone is much of a contender as a drug for Schizophrenia. But I can’t really tell because we can’t have the data to definitively vet these studies. And now we have this month’s indication creep articles [or both…, creepy…] to think about, with even less to go on. It’s just really frustrating to read these three totally industry generated and industry authored articles in the American Journal of Psychiatry knowing how distorted the reporting has been with all of the Atypical Antipsychotics and not be able to independently corroborate their conclusions, no matter how many rocks we look under.

 

I really never took a business course or thought about marketing before I started writing this blog. I don’t even bargain with car salesmen. But I’ve learned a few things in the last couple of years. I didn’t understand indication creep until a couple of years ago. I was sitting in a too-hot courtroom trying not to nod off and the witness [Tone Jones] said "You can’t be a billion dollar drug in a 1% market" [the prevalence for Schizophrenia is 1%]. I came alert with an AHA! experience. That’s why once they get FDA Approval, they start going for other indications. Here’s how that indication race looked a few years ago with the Atypical Antipsychotics [the year Latuda® came on the scene]:

Without other diagnosis·specific indications, they can’t legally advertise. This is all pretty crazy, because nobody thinks these drugs are diagnosis·specific – at least nobody I know. But that’s the way the game has been played. Get the drug approved for a diagnosis, then spend the years of its patent life trying to get other indications for new ad launches. Towards the end of the patent, be sure to have a study or two in kids so you can get a pediatric extension.  If it’s a blockbuster, try to get a long acting version approved [Paxil CR®, Seroquel R®] or maybe a purified isomer [Lexapro®, Focalin®] or even a metabolite [Pristiq®].

But back to indication creep. According to the NIMH site, the prevalence of Bipolar Disorder is between two and three percent and the majority of episodes are depressive, so they add a market at least as big as the one they had. And we all know that Bipolar Disorder is way over·diagnosed. Let me say that one more time, Bipolar Disorder is way over·diagnosed. So their market grows even more because [did I mention] Bipolar Disorder is way over·diagnosed. And they covered their bases by the pair of studies – both monotherapy and adjunctive therapy, making it a clean sweep. But Johanna’s comment to the last post points out a more subtle marketing ploy that is probably even more lucrative:

Funny you should mention the glossy-magazine-advertisement bit. I was just reading People Magazine yesterday, and came across a two-page spread advertising Latuda for bipolar depression (featuring a picture of a nice-looking 20-something woman with a vaguely hopeful expression on her face).

Worse yet, the “safety information” had been carefully worded to repeatedly refer to Latuda as an “antidepressant.” People will be offered this drug for no better reason than “my antidepressant doesn’t seem to be working” — and will have no earthly idea what they are fooling around with.

And depressed people began showing up in the clinic on  Seroquel XR® being used as an antidepressant [with none of the criteria to meet these diagnoses except a depressed mood AKA unhappiness]. Now as Johanna discovered, that same strategy appears to be being picked up by Latuda®. The People Magazines in my doctor’s office are frayed and from an earlier historical epoch, so I hadn’t realized that Latuda® was being advertising there – but I’m  not surprised. I don’t exactly know what to call this variant of indication creep – maybe grammatical sprawl.

The formal linking of these drugs to a DSM diagnosis based on clinical trials sounds good on paper, but in truth, it is not easy to defend – yet it’s the law of the land. But if only people actually meeting the DSM criteria were put on the drugs, we wouldn’t have anything like our current problem. I doubt that many people get a diagnosis of Schizophrenia made casually. But diagnostic precision goes way downhill after that. I mentioned that Bipolar Disorder is way over·diagnosed, but it doesn’t hold a candle to Major Depressive Disorder which is often diagnosed by a report that "I’ve been depressed" with little else. So any way that a pharmaceutical company can get the word depression into an ad is a major marketing success. I expect they were cheering at Sunovion when this months American Journal of Psychiatry came out.

Now comes the indication march proper [already in place well before the initial F.D.A. Approval]:

Sunovion® Latuda Phase III Clinical Trials
NCT ID	Title	Recruit	StartDate
NCT00868699	6-week Study, Bipolar I Depression (Monotherapy)	YES	04/2009
NCT00868959	24-week Extension Study, Bipolar I Depression	YES	04/2009
NCT00868452	6-week Study, Bipolar I Depression (Add-on)	YES	04/2009
NCT01284517	6-week Study, Bipolar I Depression	YES	11/2010
NCT01358357	Bipolar Maintenance Adjunctive to Lithium or Divalproex	YES	06/2011
NCT01421134	MDD With Mixed Features – Flexible Dose	YES	09/2011
NCT01423253	MDD With Mixed Features – Extension	Not Yet	09/2011
NCT01423240	MDD With Mixed Features	Not Yet	10/2011

They’re following in the footsteps of some of the greats, well warned about the shoals of false advertising and other sleaze by the antics of their predecessors. Their problem – the generics are here. Even just plain Seroquel went off-patent this week – so, at $14+/pill for Latuda, it’s going to be an uphill climb. What they have going for them is that it seems to be weight neutral [so far]. What’s on the downside? It’s a decidedly weak sister [efficacy-wise]; it has an annoying EPS profile; and maybe, just maybe, people are finally tired of over-medicating and being over-medicated. But at Sunovion, hope springs eternal…

Lurasidone Monotherapy in the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study

by Antony Loebel, M.D. Josephine Cucchiaro, Ph.D. Robert Silva, Ph.D. Hans Kroger, M.P.H., M.S. Jay Hsu, Ph.D. Kaushik Sarma, M.D. Gary Sachs, M.D.

American Journal of Psychiatry. 2014 171:160–168.

Objective: The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder.

Method: Patients were randomly assigned to receive double-blind treatment with lurasidone [20–60 mg/day [N=166] or 80–120 mg/day [N=169]] or placebo [N=170] for 6 weeks. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale [MADRS] and depression severity score on the Clinical Global Impressions scale for use in bipolar illness [CGI-BP], respectively.

Results: Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20–60 mg/day group [-15.4; effect size=0.51] and the 80–120 mg/day group [-15.4; effect size=0.51] compared with placebo [-10.7]. Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both the 20–60 mg/day group [-1.8; effect size=0.61] and the 80–120 mg/day group [-1.7; effect size=0.50] compared with placebo [-1.1]. Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in the 20–60 mg/day [6.6%], 80–120 mg/day [5.9%], and placebo [6.5%] groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone.

Conclusion: Monotherapy with lurasidone in t120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters.

Lurasidone as Adjunctive Therapy With Lithium or Valproate for the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study

by Antony Loebel, M.D. Josephine Cucchiaro, Ph.D. Robert Silva, Ph.D. Hans Kroger, M.P.H., M.S. Kaushik Sarma, M.D. Jane Xu, Ph.D. Joseph R. Calabrese, M.D.

American Journal of Psychiatry. 2014 171:169–177.

Objective: Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression.

Method: Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone [N=183] or placebo [N=165], added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale [MADRS] and depression severity score on the Clinical Global Impressions scale for use in bipolar illness [CGI-BP], respectively.

Results: Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group [-17.1 versus -13.5; effect size=0.34]. Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo [-1.96 versus -1.51; effect size=0.36] as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone.

Conclusions: In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.

^{top study on the left, bottom study on the  right}

The two new articles are related to Lurasidone’s approval for Bipolar Depression. They report great efficacy and safety, but considering the disconnect between the published and the private versions last time around, I submitted an FOIA request for the approval documents [not linked on the Drugs@FDA web site]. Surprisingly, the Results Database on clinicaltrials.gov is completed. but has little information not found in the papers. I’m particularly interested to see how it fared in the US.

Editorial

Lurasidone and Bipolar Disorder

by Belmaker RH

American Journal of Psychiatry. 2014 171:131–133.

[full text online]

Lurasidone is a new atypical antipsychotic developed by Sunovion Pharmaceuticals, Inc., that was approved for use in schizophrenia in the United States in 2010. It was approved for use in bipolar depression in July 2013, and the two back-to-back articles in this month’s Journal constitute pivotal studies for medication approval for bipolar depression by the FDA. Lurasidone is a strong dopamine D2 receptor blocker, as are almost all currently known antipsychotics used in schizophrenia, so its development and approval came as no surprise. Consistent with the major thrust of development in the schizophrenia treatment area today, lurasidone’s preclinical development was associated with the search for a dopamine D2 blocker with little or no extrapyramidal symptoms and little or no prolactin rise. Sometimes an absence of cholinergic muscarinic blockade and a felicitous balance of agonism and antagonism at some of the large number of serotonin receptor subtypes can achieve this desirable side effect profile. It has been achieved already in some other compounds, but the big prize today in pharmaceutical development of atypical antipsychotics is avoidance of the metabolic side effects such as weight gain, hyperlipidemia, and impaired glucose metabolism. The molecular basis of this cardiovascular profile is not fully known, so it has not been possible to use designer medicinal chemistry to create the ideal compound from basic principles. Some trial and error is necessary both in animals and eventually in clinical trials. Lurasidone may fit this basic bill…

Is this a new era in psychiatry and psychopharmacology? The history of psychopharmacology certainly saw some periods of discovery of entirely new principles, such as the first antipsychotic [chlorpromazine], the first antidepressant [imipramine], the first benzodiazepine, and lithium, the first mood stabilizer . On the other hand clinicians have become a bit jaded during a long era of “me too” compounds where new antipsychotics and new antidepressants seem to appear daily—hailed by leaders of the field and feted with dinners and weekends for clinicians willing to attend, later to lose their patents and be discarded on the scrap heap of history.

Lurasidone may be somewhere between those two situations. Sometimes incremental progress in psychopharmacology can gradually add up after much preclinical work, many clinical trials, and tinkering with several different compounds to an advance that is real. The discovery of a D2 blocker with a concomitant receptor profile that avoids extrapyramidal symptoms, avoids hyperprolactinemia, avoids cardiovascular side effects, and is also effective in bipolar disorder — this could be a serious advance of the field. Together with the large number of overlapping genetic linkages between schizophrenia and bipolar disorder, one might en- vision an impact on the battle over unitary psychosis theory that could even affect DSM-6.

What would a historian say? A historian might note that in the first edition of Diagnosis and Drug Treatment of Psychiatric Disorders by Klein and Davis, the first textbook of psychopharmacology, the usefulness of typical old-fashioned neuroleptics such as chlorpromazine in many forms of depression was emphasized and use of other typical neuroleptics for prophylaxis of bipolar disorder was widespread around the world, especially for patients who were non-adherent with lithium or in areas where blood testing was unavailable. It could be said that we have rediscovered the wheel. But it could be a better wheel than chlorpromazine or fluphenazine were in their times.

If you look as close as we can get to the Latuda® data in Schizophrenia, the data from outside the US is what got it approved [see ought to know by now…, in the shadows…]. So I hope the FDA FOIA will clear that up for these two large  international studies in Bipolar Depression. But independent of the back story on the science, my emotional reaction was that I was reading some glossy magazine off the drugstore rack with advertisements for two new products – a screening test for depression and a new drug. It felt like it ought to have coupons like those pull-out sections of the Sunday paper. I worried that I was going off half cocked, and went back and read what I’d found out about Latuda® before, and lamented what I couldn’t find out about these two articles. But I couldn’t shake the feeling that the American Journal of Psychiatry was allowing itself to be a launching pad for new commercial products instead of the flagship journal for American scientific psychiatry. I didn’t know whether to be sad, or mad, or both…

hat tip to Ed Levin… 

Revitalizing Psychiatric Therapeutics

by Steven E. Hyman

Neuropsychopharmacology Reviews. 2014 39:220–229.

The term ‘revolution’ in science and medicine is often used hyperbolically, but the period from 1949 to 1957 can fairly be described as revolutionary for psychopharmacology. A remarkable burst of discovery began with John Cade’s recognition of the therapeutic potential of lithium in 1949. Henri Laborit first administered chlorpromazine for preoperative sedation in 1952, but quickly recognized its possible utility for the treatment of psychotic patients. Iproniazid, the first monoamine oxidase inhibitor antidepressant, failed in its intended use as a treatment for tuberculosis in the early 1950s, but in clinical trials, significant elevation of patients’ moods was noted. Imipramine, the prototype monoamine reuptake inhibitor antidepressant, was synthesized as a candidate antipsychotic drug based on modifying the tricyclic molecular structure of chlorpromazine. Imipramine failed to treat psychosis but was recognized to have antidepressant effects. By 1957, both the MAOI iproniazid and the tricyclic drug imipramine were recognized as antidepressants…

Unfortunately for individuals with psychiatric disorders, the astonishing developments of the 1950s have been followed by a similarly improbable half-century of stagnation. This period has been characterized by failure to improve the efficacy of pharmacologic treatments for established clinical indications or to extend effective treatments to additional significant symptom clusters. The most significant success during the past five decades has been in the domain of toxicity. Thus, for example, antidepressants approved since the late 1980s [eg, the selective serotonin reuptake inhibitors] are far safer and more tolerable than the older tricyclic drugs and MAOIs. A second generation of antipsychotic drugs exhibits decreased liability to cause serious motor side effects, including tardive dyskinesia, compared with first-generation drugs — but carries its own serious side effects including significant risk of weight gain and associated metabolic derangements.

It’s hard for me to imagine it now, but I saw that twenty years as an era of biological psychiatry at the time – oblivious to how industry driven it really was. The rash of new drugs came from the pharmaceutical industry. The departments of psychiatry were assisted by grants from the pharmaceutical industry. Many of the journal articles came from the pharmaceutical industry. The DSM categories were targeted by the pharmaceutical industry, both on and off-label. The Clinical Research Organizations were an offshoot of the pharmaceutical industry. Many of the leaders in psychiatry were affiliated with and partially supported by pharmaceutical industry [known as KOLs].

It is important to view the stasis of the past five decades with clear eyes, rather than defensively. The disorders of higher brain function that neuropsychopharmacology is concerned with have greater associated challenges than those that face many other fields of medicine. Nonetheless, the difficulties inherent in confronting polygenicity, disease heterogeneity, and limitations of current animal models appear more similar than different across medical disciplines. The pace of technology development seems only to be accelerating, and should thus give us hope. Despite the challenges, there is a substantial opportunity to win back industry and to revitalize psychiatric therapeutics by embracing clear thinking and by putting technologies to work.

While I chose this piece by Dr. Hyman, I could’ve picked any number of Dr. Insel’s NIMH blogs over the last several years, or the conference mentioned above [APF Convenes Unique Pipeline Summit], or Dr. Lieberman’s recent piece [Time to Re-Engage With Pharma?], or many other similar commentaries to illustrate the two dominant themes these days: "we need more and better drugs" and "we need to lure PHARMA back." Even as the pharmaceutical industry exits the scene, Hyman’s appeal remains focused on getting them back – again highlighting how industry-dependent modern psychiatry became.

The lamentations in his opening paragraphs have been true for five decades. Nothing new. They include the quarter century following the introduction of the DSM-III. The exciting and promising new drugs that flowed from the pipeline during that time are now relabeled me-too drugs, variations on the 1950s discoveries. But in their days, they were heralded as breakthroughs rivaling sliced bread. While they may be better tolerated than the originals, even the claim of decreased toxicity is something of a reach. The exuberant medicalization of psychiatry by the 1980’s revolution, the 1990’s decade of the brain, and the dawn of clinical neuroscience that followed span this period Hyman now characterizes as stagnation. Even his title, Re·vitalizing Psychiatric Therapeutics, suggests a previous period of vitality, yet he has just told us that it was, in fact, scientifically stagnant. What was vital about the longed for past was the pharmaceutical industry’s pipeline that produced the string of new drugs whose success rested on hope and hype, rather than enduring improvements in efficacy or safety. But they sure pulled in the revenue that supported all concerned – that kind of vital.

Rather than a continuing monomaniacal focus on reviving this past that relied so heavily on industry and illusion, it seems  to me that we would be better placed to harken back to what has been relinquished or laid aside in this era of johnny-one-note psychopharmacology. While cure has always been the ultimate goal of the medical profession, what we do throughout medicine when it’s unattainable is deliver care. And there was a time when psychiatrists prided themselves on having a unique expertise in that area – particularly in those cases where the tangles of biography and life are taking an ongoing toll, cases where medications can never be more than short term adjuncts. And even in cases where medications are effective, there are residual symptoms [see Hyman’s third paragraph above] currently best managed with psychosocial interventions.

Dr. Kupfer reports receiving consulting fees from the American Psychiatric Association for serving as the chair of the DSM-5 Task Force.

"I do have to report my Caesar’s disclosure. I’ve had no contact with industry, the pharmaceutical industry, now for seven years. They wouldn’t even recognize me. The only disclosure I have is as a consultant to the APA for the past seven years…"

I’ve highlighted two things – Kupfer’s disclosures and the date the page was released. From the content of his talk I’m guessing the video must’ve been recorded last summer, not long after the DSM-5 was released in May 2013.

Failure to Report Financial Disclosure Information

ONLINE FIRST

by Robert D. Gibbons, PhD; David J. Weiss, PhD; Paul A. Pilkonis, PhD; Ellen Frank, PhD; and David J. Kupfer, MD

JAMA Psychiatry. Published online November 20, 2013.

To the Editor We apologize to the editors and readers of JAMA Psychiatry for our failure to fully disclose our financial interests in an article that reported a diagnostic tool, the Computerized Adaptive Test for Depression [CAT-DI]. Following acceptance of the paper, we disclosed that “The CAT-DI will ultimately be made available for routine administration, and its development as a commercial product is under consideration.” The company that owns the rights to CAT-DI and several related tests is Psychiatric Assessments, Inc [PAI], which uses the trade name of Adaptive Testing Technologies [ATT] on a website describing these tests.

Lead author Robert D. Gibbons, PhD, is the president and founder of PAI, which was incorporated in Delaware in late 2011, then registered to do business in Illinois in January 2012. Dr Gibbons awarded “founder’s shares in PAI” to us, yet all 5 of us failed to report our financial interests in connection with our article and again in a Reply to Letters to the Editor regarding the article. Neither PAI nor ATT has released the CAT-DI test [or any other test] for commercial or professional use, but our ownership interests were relevant to the research article and Reply we submitted and should have been disclosed to the editors. Our submitted disclosure lacked transparency, and we regret our omission.

And here’s the operative segment of the timeline leading up to the article referred to in that apology:

Dr. Kupfer should have disclosed to APA his interest in PAI in 2012…

It seems like Dr. Kupfer et al are pursuing a strategy of only acknowledging this particular Conflict of Interest when forced, as in the situation with JAMA Psychiatry, and avoiding talking about it otherwise – mirrored so far by the APA President and Board of Trustees. I guess we could call it a hope-it-blows-over plan. So it falls on people like the watchdog who sent me the link to this example to spend time keeping tabs on Dr. Kupfer’s Disclosures. The Task Force tried that hope-it-blows-over strategy with the critiques of Drs. Spitzer and Frances during the DSM-5 Revision period itself, and it didn’t work out as well as they might’ve hoped. Maybe it will work this time.

Tripartite Conflicts of Interest and High Stakes Patent Extensions in the DSM-5

by Cosgrove L. · Krimsky S. · Wheeler E.E. · Kaitz J. · Greenspan S.B. · DiPentima N.L.a

Psychotherapy and Psychosomatics. 2014 83:106-113.

[full text on-line]

Background: The revision process for and recent publication of the DSM-5 initiated debates about the widening of diagnostic boundaries. The pharmaceutical industry had a major financial stake in the outcome of these debates. This study examines the three-part relationship among DSM panel members, principal investigators [PIs] of clinical trials for new DSM-5 diagnoses, and drug companies.

Methods: Financial conflicts of interest [FCOI] of DSM panel members responsible for some new diagnoses in the DSM-5 and PIs of clinical trials for related drug treatments were identified. Trials were found by searching ClinicalTrials.gov. Patent and revenue information about these drugs was found using the US Food and Drug Administration’s Orange Book and manufacturer Annual Reports.

Results: Thirteen trials met inclusion criteria [testing drugs for some new DSM disorders]. Sixty-one percent of the DSM Task Force members and 27% of Work Group members reported FCOI to the trial drug manufacturers. In 5 of the 13 trials [38%], PIs reported ties other than research funding to the drug manufacturer. In 3 of the trials [23%], a PI had financial ties to the drug manufacturer and was also a DSM panel member who had decision-making authority over the revision process.

Conclusions: These findings suggest that increased transparency [e.g., registration on ClinicalTrials.gov] and mandatory disclosure policies [e.g., the American Psychiatric Association’s disclosure policy for DSM-5 panel members] alone may not be robust enough strategies to prevent the appearance of bias in both the DSM revision process as well as clinical decisions about appropriate interventions for DSM disorders.

A Pill for Every Ill

Newsweek

By John Ericson

February 6, 2014

[full text online]

… When the APA released the fifth edition of its manual in May 2013, it was instantly criticized by several researchers and clinicians, who claimed that some of the revisions and modifications reflected the agenda of an editorial panel that did not have the public’s best interest in mind. For example, many therapists and parents denounced the decision to define Asperger’s syndrome as a part of the autism spectrum rather than a stand-alone diagnosis. Some said it would skew statistics. Others said it would mess with identities…

… That, however, wasn’t the biggest concern. Other experts, including Sheldon Krimsky, professor of Urban & Environmental Policy & Planning at Tufts University, have pointed out that changes to the DSM can also be big business, with lots of downstream profit for everyone involved. If, for example, the DSM-5 finds a new "indication" for a particular drug, the developer can renew its patent and keep generic competitors off the market for another three years. For most industries, this would have a pretty modest impact on revenue. But in the business of curing ills, in which price tags can be very high and demand is often buoyed by nature, those three years can make a huge difference.

Thirteen clinical trials met inclusion criteria. These clinical trials were designed to investigate 10 patented drugs and one investigational new drug. Nine of these trials were testing ‘blockbuster’ drugs with patents that had expired or would expire in the next 2 years. Table 1 [see full text] provides a summary of trial drugs, their patent status, and their 2012 revenue [obtained from the drug manufacturers’ 2012 annual reports]. The trial drug manufacturer was one of the sponsors or collaborators for 8 of the 13 trials [62%].

… Take, for example, the drug Cymbalta – one of a group of drugs referred to by the industry as "blockbusters" – drugs that rake in at least $1 billion in annual revenue. Cymbalta, which is prescribed for major depressive disorder and generalized anxiety disorder, earned its blockbuster title almost five times over in 2012, bringing in nearly $5 billion to developer Eli Lilly. Lilly’s patent on Cymbalta expired in December 2013, and the developer should soon begin to lose revenue to generics… But thanks to the changes made by the APA to the DSM, the money will likely keep rolling in.

… In past editions of the DSM, a so-called bereavement exclusion from major depressive disorder recommended that actively grieving individuals not be diagnosed with depression. In the DSM-5, this recommendation has been erased, giving rise to "bereavement-related depression" – a subset of major depressive disorder that is treatable by all the standard methods [and drugs] that ease depression. But if you didn’t need to treat the loss of a loved one with medication in 2000, is it really necessary in 2014?

… Companies like Lilly certainly want it to be – and they may just get their way. Public records regarding clinical investigations show that Lilly’s expired patent on Cymbalta will in all likelihood be renewed, as it is currently the focus of a new trial for the pharmacological treatment of bereavement-related depression. In other words, it’s going to end up being the drug of choice for treating what was merely called "grief" at the time of Lilly’s original patent filing.

… The APA’s disclosures regarding the DSM-5 include several instances that appear to support the contention that the public’s best interest has fallen in the shadow of financial gains. Take, for example, the Cymbalta trial: Of the 43 APA panel members involved in the implementation of this new diagnosis, 20 had disclosed financial conflicts of interest with drug manufacturer Lilly. These disclosures, which range from stock holdings and consultancies to honoraria and research funding, suggest that more diagnoses ultimately means more money for everyone involved…

hat tip to Altostrata…

Was there a direct connection between the influence exerted by the pharmaceutical companies and their affiliated psychiatrists in high places that opened up this possibility of patent extensions? Given the track record of the industry/academic psychiatry alliance for decades, only a fool would say "No." And whether that could be proved in court doesn’t even matter. That’s the kind of thing David Kupfer, Derral Regier, James Scully, and the APA Presidents/Trustees are there to protect us from having to even think about. Instead of handing out defensive homilies and damage control press releases, we could’ve used a lot more evidence that they were doing their jobs. And this is also why even the appearance of Conflict of Interest has been the traditional standard in medical ethics until the recent era.

Frances believes that while pharmaceutical companies may indeed pounce at every opportunity to drive revenue and retain exclusivity, the panel members themselves have also been blinded by their desire to help "the missed patient" – the individual in pain who, for one reason or another, disappears through cracks in the system. "The experts on the DSM-5 were given a tremendous amount of freedom, and what this resulted in was a kind of dream list of new diagnoses that turned the everyday problems of life into mental disorders," he tells Newsweek. "They are naive about how something that may work in their hands will be misused in the average practice." adding "The biggest risk is not financial conflict of interest, but intellectual conflict of interest," he says. "The pressure of experts is always to expand their area."

Finally, as a policy objective, it is critical that the APA recognize that transparency alone is an insufficient response for mitigating implicit bias in diagnostic and treatment decision-making. Specifically, and in keeping with the Institute of Medicine’s most recent standards, we recommend that DSM panel members be free of FCOI. In the future, DSM panel members should also be prohibited from serving as PIs of trials for any disorder being considered for inclusion in the DSM.