Vortioxetine clinical phase III data show significant improvement in symptoms of major depression
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May 18, 2013

Vortioxetine clinical phase III data show significant improvement in symptoms of major depression

• Takeda and Lundbeck present results from pivotal phase III clinical trials with vortioxetine, an investigational compound for major depression
• First presentation of results from four pivotal clinical studies of doses of up to 20 mg/day
• Clinical studies demonstrate efficacy at doses of 15 mg and 20 mg per day including an improvement of overall functioning
• The safety profile was shown to be consistent with previously completed studies at lower doses

Valby, Denmark, 18 May 2013 – H. Lundbeck A/S [Lundbeck] and partner Takeda Pharmaceutical Company Limited [Takeda] today announced that the companies will be presenting new data on four pivotal studies on vortioxetine, a novel investigational drug under review by the U.S. Food and Drug Administration [FDA] and the European Medicines Agency [EMA] for the treatment of major depression. The phase III data will be presented at the 2013 Annual Meeting of the American Psychiatric Association [APA] in San Francisco, USA.

The objective of these four studies was to evaluate the efficacy and safety profile of vortioxetine in doses ranging from 10-20 mg per day, complementing other studies in the New Drug Application [NDA] submission package that included dose ranges of 5-20 mg per day. Three of the four pivotal studies met the primary efficacy endpoint as measured by the change from baseline of the Montgomery-Åsberg Depression Rating Scale [MADRS] total score at week 8. Statistically significant improvements in overall symptoms of depression were demonstrated, as compared to placebo. A fourth study did not meet the primary endpoint. Results of all four studies provided additional information regarding the safety profile of vortioxetine.

"It is important that we continue to seek new options in depression because, even though there are effective treatments available, many patients remain symptomatic," said Madhukar Trivedi, M.D., professor of psychiatry, UT Southwestern Medical Center. "As a clinician, I’m encouraged by these data. They represent an important addition to the broader clinical profile for vortioxetine and support its potential as a new treatment for patients with MDD."

Dr. Trivedi … serves as scientific advisor for Lundbeck and Takeda.

^{SAN FRANCISCO — The American Psychiatric Association officially kicked off its annual meeting this weekend with the release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. To mark the occasion, incoming APA president Jeffrey A. Lieberman, MD, announced during the opening session that the profession of psychiatry has come of age. "This is the time for us to seize the moment, for mental illnesses to step out of the shadows, for mental health care to be made accessible and fairly reimbursed, and for psychiatry to take its rightful role in the field of medicine," he said… Despite some of the challenges, psychiatric medicine has grown by leaps and bounds, Lieberman said. He gave examples of the emergence of psychopharmacology, neuroimaging, molecular genetics and biology, which have propelled psychiatry to the forefront of modern medicine…}

^{We’re all mad here by DR. ALLEN FRANCES – Human nature doesn’t change that fast, but the labels used to describe it can follow fickle fashions. The vehicle of today’s fashion shift is the publication yesterday of the fifth edition of the “Diagnostic and Statistical Manual of Mental Disorders,” the official compendium of psychiatric diagnoses. DSM 5 has added many new mental disorders that include many symptoms and behaviors previously accepted as simply part of the human condition. The resulting overdiagnosis of mental disorder will have many harmful unintended consequences — the misuse of medication, unnecessary stigma, high costs, misallocated resources, narrowed expectations, a reduced sense of personal responsibility, and the misapprehension that we are all becoming sick individuals living in an increasingly sick society…}

^{Psychiatry faces another crisis of confidence – Psychotherapist Gary Greenberg is more blunt. “Even at its best … psychiatric diagnosis is fiction sold to the public as fact,” Greenberg writes in his new book, The Book of Woe: The DSM and the Unmaking of Psychiatry. “There is a huge disconnect between what psychiatry claims for itself, and what it can actually do,” he says… In other words, 200 years after psychiatry was recognized as a medical discipline, a stark question persists: Is psychiatry credible?…}

^{Time present and time past
Are both perhaps present in time future,
And time future contained in time past.
If all time is eternally present
All time is unredeemable.
What might have been is an abstraction
Remaining a perpetual possibility
Only in a world of speculation.
What might have been and what has been
Point to one end, which is always present…}
^{T. S. Eliot, Burnt Norton}

APA Leaders Defend New Diagnostic Guide
MedPage Today
By John Gever
May 18, 2013

The fifth edition of the "psychiatrist’s bible" was officially released here in all its 947-page glory, with its developers offering a spirited rebuttal to their critics. Known as DSM-5, the new version of the American Psychiatric Association’s [APA] Diagnostic and Statistical Manual of Mental Disorders was launched at a press briefing to kick off the organization’s annual meeting. Most of the changes from the previous edition had already been made public, at least in general outline.

At the briefing, DSM-5 Task Force chairman David Kupfer, MD, of the University of Pittsburgh, defended several of the most heavily criticized revisions from DSM-IV, as the last edition was called. Other top APA leaders, including current president Dilip Jeste, MD, of the University of California San Diego, and president-elect Jeffrey Lieberman, MD, of Columbia University in New York City, addressed another, more recent controversy over DSM-5, which was sparked by a blog post from National Institute of Mental Health [NIMH] Director Thomas Insel, MD. In his blog, Insel criticized the DSM classification system’s scientific validity, and his remarks were then reported in consumer media as suggesting DSM-5 is "out of touch with science," as a New York Times headline put it.

Kupfer identified several specific changes from DSM-IV in the new edition that had drawn the most heat from others in the mental health community and patient advocacy groups…

• Autism Spectrum: …
• Bereavement Exclusion in Major Depression: …
  APA fact sheet distributed at the briefing pointed to several features that "usually" distinguish depressive illness from normal grief in patients experiencing recent losses. They include continuous unrelieved negative mood and feelings of worthlessness and self-loathing. In normal grief, extreme sadness is typically intermittent and self-esteem is unaffected, the fact sheet said.

• Disruptive Mood Dysregulation Disorder (DMDD]: …
  The diagnosis "is intended, in part, to address issues about potential overdiagnosis and overtreatment of bipolar disorder," Kupfer said.

• Mild Neurocognitive Disorder:
  In a critique of DSM-5 published on the eve of its launch, the head of DSM-IV’s development in the 1980s, Allen Frances, MD, of Duke University in Durham, N.C., singled out the new edition’s inclusion of mild neurocognitive disorder as another example of medicalizing normal function… "There has been concern that we may have added a disorder that may not be important enough to merit clinical attention," Kupfer said… "Clinicians have lacked a reliable diagnosis to assess such [impairments] and to understand what might be the most appropriate treatment or services," Kupfer said. Including mild neurocognitive disorders in DSM-5 "serves two essential needs," he said. One is that it provides "an opportunity for early detection," while another is that it "encourages the development of an effective treatment plan before deficits become more pronounced and progress to dementia."

• Insel’s Comments: …
  Apparently without meaning to, Insel set off a firestorm with an April 29 "director’s blog" post on the NIMH website, in which he lamented that the DSM – not just the new edition but its predecessors as well – is not grounded solidly in biology. Rather, he said, "the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.

At the press briefing here, APA officials reiterated that there is, in fact, no disagreement with Insel. "We support what he’s trying to do," said John Scully, MD, the APA’s chief executive officer. "We want him to get biomarkers for us." Added Lieberman, "He [Insel] was trying to exhort the biomedical research community to try to break new ground that will lead to more dynamic and fundamental changes in psychiatric diagnosis." Yet, Kupfer suggested, the flaws in DSM-IV for daily clinical practice needed to be addressed in the short term, and an extension of the symptom-based approach remained the only alternative. "While we don’t yet have the biomarkers that we are hoping are on the edge of discovery, patients can’t keep waiting, and we can’t keep waiting," he said.

• Other Criticisms …

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^{I don’t buy it. We are bombarded by articles making all kind of things out of Dr. Insel’s blog post, Transforming Diagnosis, an announcement that the NIMH will move away from the DSM-5 – coming just a couple of weeks before the DSM-5 even goes on sale. Like everyone else, I’ve joined in on the speculation and commentary on the reasons for this surprising move [old news…, a flair…, groundhog day…, replaces with…, damage control…, our jobs…, said it again…]. When I talk too much about the same thing, it’s because there’s something I’m trying to figure out but I haven’t gotten there yet. So for the last several days, I’ve been going over the history and rereading the articles trying to get the story clear in my mind rather than reacting to the media frenzy. I’ve done that now and here’s the conclusion. I don’t buy it. If you don’t either, and already know why, don’t bother to read further. It’s way too long. I just wanted to write it down so I didn’t have to keep mulling it over in my mind.}

^{For most of the DSM-III disorders, however, the etiology is unknown. A variety of theories have been advanced, buttressed by evidence – not always convincing – to explain how these disorders came about. The approach taken in DSM-III is atheoretical with regard to etiology or pathophysiological process except for those disorders for which this is well established and therefore included in the definition of the disorder. Undoubtedly, with time, some of the disorders of unknown etiology will be found to have specific biological etiologies, others to have specific psychological causes, and still others to result mainly from a particular interplay of psychological, social, and biological factors. The major justification for the generally atheoretical approach taken in DSM-III with regard to etiology is that the inclusion of etiological theories would be an obstacle to use of the manual by clinicians of varying theoretical orientations, since it would not be possible to present all reasonable etiologic theories for each disorder.}

^{Robert Spitzer, in the DSM-III, p 6.}

^{1. Psychiatry is a branch of medicine.}
^{2. Psychiatry should utilize modern scientific methodologies and base its practice on scientific knowledge.}
^{3. Psychiatry treats people who are sick and who require treatment.}
^{4. There is a boundary between the normal and the sick.}
^{5. There are discrete mental illnesses.  They are not myths, and there are many of them.}
^{6. The focus of psychiatric physicians should be on the biological aspects of illness.}
^{7. There should be an explicit and intentional concern with diagnosis and classification.}
^{8. Diagnostic criteria should be codified, and a legitimate and valued area of research should be to validate them.}
^{9. Statistical techniques should be used to improve reliability and validity.}

[1. & 2.] were directed against psychoanalysis and said that psychiatry was a medical enterprise, not involved in matters psychological. The next three [3.-5.] were a counter to the criticisms from Dr. Szasz and others who said that there was no such thing as mental illness and that psychiatry was not a medical specialty. Number 6. said that physicians were only to be involved with the biological aspects of mental illness. It didn’t say that all mental illness was biological, just that biology was the legitimate domain of psychiatric physicians. And the last three [7.-9.] were a call to use scientific methods in classification.

Research Domain Criteria (RDoC): Toward a New Classification Framework for Research on Mental Disorders
^{by Thomas Insel, Bruce Cuthbert, Marjorie Garvey, Robert Heinssen, Daniel S. Pine, Kevin Quinn, Charles Sanislow, and Philip Wang.}
American Journal of Psychiatry. 2010 167:748-751.
^{[full text online]}

^{Current versions of the DSM and ICD have facilitated reliable clinical diagnosis and research. However, problems have increasingly been documented over the past several years, both in clinical and research arenas. Diagnostic categories based on clinical consensus fail to align with findings emerging from clinical neuroscience and genetics. The boundaries of these categories have not been predictive of treatment response. And, perhaps most important, these categories, based upon presenting signs and symptoms, may not capture fundamental underlying mechanisms of dysfunction. One consequence has been to slow the development of new treatments targeted to underlying pathophysiological mechanisms…}

^{NIMH plans to maintain liaison with the American Psychiatric Association and the World Health Organization regarding mutual interests in psychiatric classification. As an initial step, representatives of the APA, WHO, and NIMH met in July 2009 to map out common ground. These organizations have also articulated the importance of adding molecular and neurobiological parameters to future diagnostic systems, but at our current state of knowledge this step seems more appropriate for research than for immediate clinical use. NIMH views RDoC as the beginning of a transformative effort that needs to succeed over the next decade and beyond to implement neuroscience-based psychiatric classification.…}

Neuroscience, Clinical Evidence, and the Future of Psychiatric Classification in DSM-5
^{by David J. Kupfer, M.D. and Darrel A. Regier, M.D., M.P.H.}
American Journal of Psychiatry 168:672-674, 2011.
^{[full text online]}

^{In the initial stages of development of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders,we expected that some of the limitations of the current psychiatric diagnostic criteria and taxonomy would be mitigated by the integration of validators derived from scientific advances in the last few decades. Throughout the last 25 years of psychiatric research, findings from genetics, neuroimaging, cognitive science, and pathophysiology have yielded important insights into diagnosis and treatment approaches for some debilitating mental disorders, including depression, schizophrenia, and bipolar disorder. In A Research Agenda for DSM-V, we anticipated that these emerging diagnostic and treatment advances would impact the diagnosis and classification of mental disorders faster than what has actually occurred…}

^{We realized from our Research Agenda conference series that we would not be able to accomplish by DSM-5′s deadline all of the things we set out to and, in fact, that portions of that agenda related to advances in neuroscience were already being addressed in other arenas. A logical extension of those discussions, as detailed in our Research Agenda  articles, is the Research Domain Criteria [RDoC] initiative recently launched by the National Institute of Mental Health [NIMH]. A commentary by Insel and colleagues  introduced readers to the working principles behind the RDoC, whose proposed reclassification of mental disorders for research purposes is predicated on a neuroscience-based framework that can contribute to a nosology in which disorders are grouped by underlying pathophysiological similarities rather than phenomenological observations…}

• 2002 was at the peak of the psychopharmacology era. The drugs were coming at a steady rate and business was booming. That year, Dr. Insel was a surprise pick to head the NIMH. It was a time of great enthusiasm, the dawn of a new millenium.
• While it probably should’ve started in 1996 when the Chairman of Psychiatry at Georgia [Dr. Richard Borison] was convicted, the realization that there was corruption afoot in psychiatry came later. In the mid-2000s, problems with conflicts of interest, unreported PHARMA income, and ghost writing increasingly came to the fore culminating in a U.S. Senate Investigation with several psychiatry chairmen "stepping down" and others in high places censured.
• Around the same time, the corruption in PHARMA reached the public eye. Allen Jones blew the whistle on TMAP, and elsewhere the civil suits began to pile up. In discovery, boxes of internal documents revealed the extensive connections between psychiatric authors a PHARMA, and the ubiquitous deceit in the publication of scientific data, along with a lot of shady drug promotion practices.
• People like Dr. David Healy and others began to report unmmentioned adverse effects like suicidality. The "black box" warning was added to the antidepressants. The reports of adverse effects were joined by charges of inflated efficacy.
• This was the era of large NIMH funded drug trials, and they were pretty disappointing. The new drugs hardly dazzled anyone.
• In that period, we learned the term "pipeline" [drugs headed for approval], and then that there weren’t any more "me too" drugs on the way or anything to replace them
• After a time of fretting over the "empty pipeline," the drug companies began to shut down their CNS drug development facilities – no candidates to work on.
• This was a remarkably non-productive time in research. Lots of new technology and hype, but little in the way of results.

My own read on this narrative is cynical. First, I don’t accept that the American Psychiatric Association, Academic Psychiatry, the DSM-5 Task Force, and the Director’s office of the National Institute of Mental Health are separate entities. I see then as a consortium of people in high places who see the future of psychiatry and mental health as a function of new CNS drug development. That means that the entity we call PHARMA is part of the consortium, whether officially or unofficially – it’s a big part of the mix.

What I think happened is that the consensus around the turn of the century was that they could make the move to a solid biological psychiatry that took its place among the medical professions as a solid member.  The DSM-III had opened the door, and the DSM-5 was going to complete the process. But as time moved on and the bad news began to accumulate, things weren’t going as planned, their DSM-5 conferences were going nowhere [I read them so trust me on this point], and they had to do something. The vision of their Research Agenda was handed over to the NIMH who launched the RDoC. Once that was in place and launched, they made their announcement that they couldn’t bring it off. In the meantime, they’d ignored the real business of the revision they’d been assigned, so they got involved in a lot of add-ons [Attenuated Psychosis, Mixed Anxiety Depression, etc]. The original impetus [the future is psychopharmacology] showed in the loosened criteria for any number of diagnoses the dropped bereavement exclusion. It was a lackluster showing at best, because it wasn’t what they were really aiming for in the first place. Why did Insel jump in at the 11th hour? My guess is that it lets the DSM-5 Task Force off the hook, changing their failed attempt at a biological system into something else – a noble try, but the clinical syndromes are just not a good-enough basis for drug development or biological discovery.

I think that all these people really do believe that the only avenue to follow is psychopharmacology and new drug development. What I object to is all the behind the scenes wheeling and dealing, presented to us in carefully prepared sound bytes. I object that they haven’t listened to Dr. Robert Spitzer, Dr. Allen Frances, and the rest of us who are trying to tell them that their monocular vision is obscuring everything. The roar of criticism about the DSM-5 has all said the same thing, "You’re supposed to be revising our clinical diagnostic manual! And you’re doing something else!" Everything has been wrapped around new drug development. It’s not even about biology because they’ve ignored repeated calls to reinstate our best candidate – Melancholia. It’s just about drug development, finding new targets to entice PHARMA back into the game. They say that outright.

and…

Then in the 1980s, that all changed. Because I was a psychiatrist, I was supposed to be a biologist. Well, I am a biologist, but that’s just a piece of what I am and what patients needed from me. And because I was a psychoanalyst, I was supposed to be … psychoanalytic, but that’s just a piece of what I am too and what patients needed from me. And so on and so on through the toolbox. And worse, I wasn’t supposed to meander from tool to tool until I found the one[s] that fit that patient on that day, I was supposed to have some consistent evidence-based position that could be validated by some third party to prove I wasn’t a charlatan or a I-don’t-know-what-but-it-was-a-bad-thing. I wasn’t up to it. I’d spent a long time refining my skills at doing it the other way which was some hard work, so I went off on my own and did what I’d learned to do until I retired. I’m so glad I did that.

Now it’s coming full circle. The psychologists are saying that the medical model psychiatrists are off the deep end. The biologists  are at war with each other over which biology is the correct biology. The humanists are after the robots. The analysts have learned to be quiet, but you can bet they’re thinking their thoughts. I’m sure all the existentialists in France and elsewhere are off being existential together. I know a lot of very talented and competent mental health types who come from a wide variety of backgrounds but they are unified by a few simple things – a deeply ingrained practice ethic, a suitable awe for the marvelous and monstrous variability in human beings, a genuine curiosity, broad training and life experience, and humility. If they can’t help you, they’ll at least be able to help you find someone who can.

When I think back on things, the most helpful piece of my training in mental health was becoming a hard science Internist first. The reason is that I knew a secret my psychiatric colleagues didn’t know. The hard science medicine I left was no more precise and assured than the loosy-goosy psychiatry I went to.  Sure there were more tests, more precise diagnoses, more drugs. But there was the wall of physical disease beyond which you couldn’t go. Once you found it, that was the end of the road. With mental illness, there’s no wall. Even with the worst cases of our most devastating illnesses, there’s still something that can be done, even if it is only a small thing. You may not find it, but it’s not because it’s not there.

NIMH vs DSM 5: No one wins, patients lose
Saving Normal: Psychology Today
by Allen Frances, M.D.
May 10, 2013

The flat out rejection of DSM 5 by National Institute of Mental Health is a sad moment for mental health and an unsafe one for our patients. The APA and NIMH are both letting us down, failing to be safe custodians for the mental health needs of our country. DSM 5 certainly deserves rejecting. It offers a reckless hodgepodge of new diagnoses that will misidentify normals and subject them to unnecessary treatment and stigma.

The NIMH director may have hammered the nail in the DSM 5 coffin when he so harshly criticized its lack of validity. But the NIMH statement went very far overboard with its implied promise that it would soon find a better way of sorting, understanding, and treating mental disorders. The media and internet are now alive with celebrations of this NiMH ‘kill shot’. There are chortlings that DSM 5 is dead on arrival and will perhaps take psychiatry down along with it.

This is misleading and dangerous stuff that is bad for the patients both institutions are meant to serve. NIMH has gone wrong now in the very same way that DSM 5 has gone wrong in the past – making impossible to keep promises. The new NIMH research agenda is necessary and highly desirable- it makes sense to target simpler symptoms rather than complex DSM syndromes, especially since so far we have come up empty. And the new plan will further, and be furthered, by the big, new Obama investment in brain research. But the likely payoff is being wildly oversold. There is no easy solution to what is in fact an almost impossibly complex research problem…

What Dr. Frances is talking about is, in my mind, the false dichotomy of this DSM-5/RDoC debate. The DSM-5 process and the RDoC hype both flounder in the same way, trying to knock the ball out of the park. What we needed from the DSM-5  was to just get on base. We need a cleaner, more accurate, clinical diagnostic system and we didn’t get it. They were so busy swinging for the fences that they didn’t make the simple changes that could’ve made a big [and helpful] difference.

So what is a patient or potential patient or parent to make of the confusing struggle between NIMH and DSM5 debacle? My advice is to ignore it. Don’t lose faith in psychiatry, but don’t accept psychiatric diagnosis or treatment on faith- particularly if it is given after a brief visit with someone who barely knows you. Be informed. Ask lots of questions. Expect reasonable answers. If you don’t get them, seek second, third, even fourth opinions until you do.

A psychiatric diagnosis is a milestone in a person’s life. Done well, an accurate diagnosis is the beginning of increased self understanding and a launch to effective treatment and a better future. Done poorly it can be a lingering disaster. Getting it right deserves the kind of care and patience exercised in choosing a spouse or a house. Remember that psychiatry is neither all good or all bad. Like most of medicine, it all depends on how well it is done.