1 Boring Old Man

It would be a gross understatement to say that I see psychiatry in need of reform. So I would’ve thought that on the last day of this particular year, the DSM-5 year, I would look back and feel like Job – sackcloth and ashes. The DSM-5 is many things, but a failed opportunity for reform is on the top of my list – though it’s not so bad as it tried to be. The APA leadership under Dr. Lieberman hasn’t been a plus either.

But when I think about what’s in need of reform, item number one would be the pharmaceutical industry’s invasion of academic and organized psychiatry and the willing collusion of the KOL Klan. They’ve taken major hits in the courts and in the press with more to come. The pipeline mirage has faded and the CNS drug machine is on sabbatical. The conduits for corruption, AKA Clinical Trials and distorted literature, are being plugged at a comforting rate. It’s been the year of escalating settlements, and palpable advances like AllTrials, RIAT, the EMA decision about data, etc. It feels like a healthy campaign. Psychiatry needs to re-locate itself, and the forces urging it to to do so are on the ascendency. Even all the attention focused on the DSM-5 has given the general populace a better view of the problems. Over-medication has become a frequently vilified topic in the press rather than only a spectator sport on Wall Street.

I would be reticent to declare it the dawn of a new day at this point, but a lot of the fog is definitely beginning to lift. So I’ll pass on the sackcloth and ashes this year and look for signs of the missing piece in 2014 – strong forces for change that are originating from within psychiatry itself…

Back in February 2012 [a book review…], I read an article by statistician Robert Gibbons et al that purported to be a meta-analysis showing that antidepressants are effective in adolescent depression and are not associated with suicidality as a side effect. It turned into a cause célèbre when I found that he made a habit of opposing any Black Box Warning. He’d done it with Neurontin® before. Since then, he’s done it with Chantix®. His pattern has been repetitive. He reports on data from the drug company given to him exclusively – not publicly available – attacking the FDA’s Black Box Warning. Then there’s a simultaneous media campaign that follows [very monotonous…]. The papers don’t show the data and are filled with so much statistic-ese that I can’t really vet them. My presumptive conclusion has been that he’s a PHARMA shill, specifically working for Pfizer/Wyeth [since their drugs are involved]. When confronted about his articles, he generally spits back.

In another thread, Dr. Gibbons has been developing some computerized psychometric screening tools for anxiety and depression, funded by the NIMH:

Development of the CAT-ANX:
A Computerized Adaptive Test for Anxiety

by Robert D. Gibbons, David J. Weiss, Paul A. Pilkonis, Ellen Frank, Tara Moore, Jong Bae Kim, and David J. Kupfer.

American Journal of Psychiatry. published on-line Aug 9, 2013

Conclusions: Traditional measurement fixes the number of items but allows measurement uncertainty to vary. Computerized adaptive testing fixes measurement uncertainty and allows the number and content of items to vary, leading to a dramatic decrease in the number of items required for a fixed level of measurement uncertainty. Potential applications for inexpensive, efficient, and accurate screening of anxiety in primary care settings, clinical trials, psychiatric epidemiology, molecular genetics, children, and other cultures are discussed.

The Computerized Adaptive Diagnostic Test for Major Depressive Disorder [CAD-MDD]:
A Screening Tool for Depression

by Robert D. Gibbons, Giles Hooker, Matthew D. Finkelman, David J. Weiss, Paul A. Pilkonis, Ellen Frank, Tara Moore, and David J. Kupfer.

Journal of Clinical Psychiatry. 2013 74[7]:669–674.

Conclusions: High sensitivity and reasonable specificity for a clinician-based DSM-IV diagnosis of depression can be obtained using an average of 4 adaptively administered self-report items in less than 1 minute. Relative to the currently used PHQ-9, the CAD-MDD dramatically increased sensitivity while maintaining similar specificity. As such, the CAD-MDD will identify more true positives [lower false-negative rate] than the PHQ-9 using half the number of items. Inexpensive [relative to clinical assessment], efficient, and accurate screening of depression in the settings of primary care, psychiatric epidemiology, molecular genetics, and global health are all direct applications of the current system.

Development of a computerized adaptive test for depression.

by Gibbons RD, Weiss DJ, Pilkonis PA, Frank E, Moore T, Kim JB, and Kupfer DJ.

Archives of General Psychiatry. 2012 69[11]:1104-12.

CONCLUSIONS Traditional measurement fixes the number of items administered and allows measurement uncertainty to vary. In contrast, a CAT fixes measurement uncertainty and allows the number of items to vary. The result is a significant reduction in the number of items needed to measure depression and increased precision of measurement.

Computerized Adaptive Test–Depression Inventory Not Ready for Prime Time

by Bernard J. Carroll, MBBS, PhD, FRCPsych

JAMA Psychiatry. 2013 70[7]:763.

[full text on-line]

In summary, it is very clear that Carroll is not a fan of multidimensional item response theory and computerized adaptive testing as applied to the process of psychiatric measurement. It is, however, completely unclear that his lack of enthusiasm is based on any scientifically rigorous foundation. Indeed, his knowledge of these methods seems lacking. Finally, Carroll is quick to point out the acknowledged potential conflicts of others as if they have led to bias in reporting of scientific information. In this case, it is Carroll who has the overwhelming conflict of interest. As developer,owner,and marketer of the Carroll Depression Scale–Revised, a traditional fixed-length test, it is not surprising that the paradigm shift described in our article would be of serious concern to him.

Failure to Report Financial Disclosure Information

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. doi:10.1001/jamapsychiatry.2013.3888

[full text on-line]

To the Editor: We apologize to the editors and readers of JAMA Psychiatry for our failure to fully disclose our financial interests in an article1 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.

WHEN IS DISCLOSURE NOT DISCLOSURE?

Hint: When it is made by the Chairman of the DSM-5 Task Force.

Healthcare Renewal

by Bernard Carroll

November 21, 2013

[full text online]

As I am not a person who suffers fools or insults gladly, their evasive response caused me to do some checking. I quickly learned that the gang of five are shareholders in a private corporation. Before their paper was accepted by JAMA Psychiatry, the corporation was incorporated in Delaware and soon after registered to do business in Illinois. Those facts were not disclosed in the original report or in the published letter of Reply to me. These omissions were acknowledged in the notice of Failure to Report that appeared on-line today.

It gets worse. Other things that I learned – and that I communicated to the journal – make it clear that the corporate train had left the station in advance of the letter of Reply. For instance, a professional operations and management executive [Mr. Yehuda Cohen] had joined the corporation. He had established the corporate website, where he was featured as a principal, along with the gang of five. The website also displayed a professionally crafted Privacy Policy, dated ahead of the letter of Reply. This document identified what appears to be a commercial business address for the corporation. The notice of Failure to Disclose is silent on these facts.

So, the published notice of Failure to Disclose still withholds pertinent information, which makes a mockery of the weasel words that they have not released any tests for commercial or professional use. Not yet, they haven’t. But they are under way, make no mistake. This prevarication creates the impression of a habitual lack of transparency. Considering that I gave the journal all this information, one has to be surprised that JAMA Psychiatry went along with this prevarication. Plus, would it have killed them to apologize for their foolish attempt to smear me, as I requested? In correspondence with me, the Editor in Chief of JAMA didn’t want to go there, and he refused to publish my letter that detailed the facts, citing the most specious of grounds. The Editor of JAMA Psychiatry has ducked for cover when I faulted him for publishing the ad hominem material in the first place.

It hasn’t been lost on any of us following the story that there’s something very suspicious about Dr. David Kupfer being part of this project. Why is he part of an effort to develop a product to screen for anxiety and depression in waiting rooms of doctor’s offices? That’s hardly his usual line of work. But lest one question his being a member of the PHARMA-friendly KOL set, one doesn’t have to look very far – like to the recent further assault on the antidepressant Black Box Warning [stories like the one told here…], published by the Journal of Psychiatric Research [with article authors and an editorial board that reads like a Who’s Who from this KOL Klan]. But what about Dr. Kupfer’s involvement with this psychometric CAT-DI/CAT-ANX business? That’s where the story is headed.

… But I have an even further complaint.

Throughout the whole DSM-5 process, they kept talking about adding a "cross-cutting" "dimensional" diagnostic system into the DSM-5. For a long time, I couldn’t even figure out what they were talking about. Towards the end, I finally got it that they were referring to symptoms that "cut" "across" the diagnostic entities – things like anxiety or depression. I was horrified, because I projected that the next step might be asking the FDA to approve medications for these "cross-cutting" diagnoses. Doing a clinical trial on symptomatic anxiety or depression seemed a sure road to rampant over-medication to me. But by the time I figured out what they were talking about, it was clear that the APA trustees weren’t going to approve adding this dimensional system, and I kept my fears to myself.

But when I saw these articles about quick screening tests for anxiety and depression, paid for with NIMH money, a part of a commercial development company, my conspiracy theory radar began to beep out of control. I’m no fan of diagnosis by a symptom list anyway. So the notion of waiting room screening for psychiatric symptoms leading directly to some symptomatic treatment with medications was bad enough. But for the leader of the DSM-5 Task Force who was pushing to make this dimensional system part of the DSM-5 to be involved in a commercial enterprise that would opportunize on the addition takes this story to the level of certifiable scandal.

DSM-5 – Dimensional Diagnoses – More Conflicts of Interest?

Behaviorism and Mental Health

by Phil Hickey

December 23, 2013

[full text on-line]

INTERPRETATION

It is difficult to put a benign interpretation on Dr. Kupfer’s role in this matter.  It is clear that he believed in the merits of the dimensional system, and that, in his role as DSM-5 Task Force Chair, he promoted this system with as much vigor as he could muster.  Even when the APA Board of Trustees voted in December 2012 to retain the categorical approach, he laid the structural groundwork for the introduction of dimensional assessment at a later time, and crafted a numbering system [5.1; 5.2; etc.] whereby the manual can be updated easily and at frequent intervals.

During the DSM-5 deliberations, it was obvious to anyone that if the APA replaced the categorical model with a dimensional model, then there would be a vastly increased market for dimensional rating scales, and that the profit potential was enormous. Given all of this, and given the lack of transparency in the Gibbons et al article, it is difficult to avoid the conclusion that Dr. Kupfer’s motivation was at least partly financial, and that he used his position as DSM-5 Task Force Chair to further his own financial agenda.

If a more benign interpretation can be put on these events, I would be interested in hearing it.  But it’s clear that psychiatric credibility has taken yet another hit.  Dr. Kupfer is a graduate of Yale’s medical school.  He joined the University of Pittsburgh in 1973, and became chairman of the psychiatry department in 1983.  He continued as department chair until 2009, and is now a professor of psychiatry at that establishment.  He has published more than 800 articles, books, and book chapters, and has served on the editorial boards of various journals.  And, of course, as mentioned earlier, he served in the prestigious position as chair of the DSM-5 Task Force.  He is, in every sense of the term, an eminent psychiatrist.

So I am left with two questions:  Firstly, why hasn’t Dr. Kupfer issued some kind of explanation for the lack of transparency?  The JAMA Psychiatry letter of apology was just a stark statement of fact, which leaves a huge cloud of doubt not only over Dr. Kupfer, but also over DSM-5 and psychiatry generally.  Secondly, why are we not hearing widespread expressions of concern from psychiatry about this matter?  To the best of my knowledge, the only psychiatrists who have spoken out on this are Bernard Carroll, who exposed the matter in the first place, and Mickey Nardo, who has been retired for ten years.

This kind of silence in these kinds of situations has become characteristic of psychiatry, through scandal after scandal, in recent years. It is very difficult to avoid the impression that neither psychiatry’s leadership nor its general body has any interest in ethical matters. There is only one agenda item in modern American psychiatry: the relentless expansion of psychiatric turf and drug sales. They’ve promoted categorical diagnoses and chemical imbalances strenuously for the past five decades.Now that these spurious notions are on the point of expiration, psychiatry is developing dimensional diagnoses and neurocircuitry malfunctions as the rallying points of the “new and improved” psychiatry.

But the bottom line is always the same: turf and money.  Something is truly rotten in the state of psychiatry.

Things like that last two paragraphs always make me wince. I feel defensive and always wish "organized psychiatry" had been substituted for "psychiatry." But I have to admit that I agree with everything Phil says including that "Something is truly rotten in the state of psychiatry." This is more than a scandal. It’s about a concerted effort to build the entire specialty of psychiatry around psychopharmacology; to make the change to diagnosis by symptom [anxiety and depression]; and to create a screening instrument for waiting rooms that skips even taking a history, wasting the doctor’s valuable time. Look at the printout, prescribe a psychotropic.

As an aging computer type and technocrat, I read the neuroimaging studies in our journals when I run across them. My reaction is hardly similar to that described above. I’m impressed with the MRIs and CAT scans of the brain in a neurological setting – tumors, strokes, atrophy. It’s a diagnostic tool of extraordinary merit. But when I look at the PET scans and fMRIs being studied in psychiatric research, I always think about what a long way they have to go. And in most of the papers, I become a doubting Thomas. If I can’t see the results, I’m unconvinced. And in most of the papers, there are a few selected images with graphs and tables so far removed from the data that I tend to glaze over. I feel like I’m being asked to take the author’s word for the results – and that’s not okay in psychiatry these days, at least not for me.

Toward a neuroimaging treatment selection biomarker for major depressive disorder.

by McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, and Mayberg HS.

JAMA Psychiatry. 2013 70[8]:821-829.

Currently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact.

OBJECTIVE: To identify a candidate neuroimaging "treatment-specific biomarker" that predicts differential outcome to either medication or psychotherapy.

DESIGN: Brain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment Men and women aged 18 to 60 years with currently untreated major depressive disorder.

INTERVENTION: Randomized assignment to 12 weeks of treatment with either escitalopram oxalate [10-20 mg/d] or 16 sessions of manual-based cognitive behavior therapy.

MAIN OUTCOME AND MEASURE: Remission, defined as a 17-item Hamilton depression rating scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment.

RESULTS: Positive and negative predictors of remission were identified with a 2-way analysis of variance treatment [escitalopram or cognitive behavior therapy] × outcome [remission or nonresponse] interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups [effect size = 1.43]. Insula hypometabolism [relative to whole-brain mean] was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy.

CONCLUSIONS AND RELEVANCE: If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression.

There is wide agreement that the category MDD [Major Depressive Disorder] is not an entity, not a disease, and is used clinically to code almost any depressed person. There is presumptive evidence that there is a genetic/biological basis for some depressions, by no means the majority, certainly not the category of MDD. The search for biomarkers among the depressions themselves is at a standstill,  Added to that, there is no compelling evidence that the antidepressants have specificity for anything clearly etiologic in depression. Since time long past, we know that CBT+Antidepressant is a bit more effective that either CBT or Antidepressant alone, and all three beat nothing. We know that simultaneous antidepressants aren’t better than a single drug. So why are we doing studies like this one? What are we looking for?

“An obvious next step is to see whether we can improve remission rates if we assign treatment based on the brain type,” Mayberg told Psychiatric News. “The subjects with high insula activity would get the drug, and the subjects with low insula activity would get CBT. We have a competitive grant renewal application currently under review at the National Institute of Mental Health…?This would be a prospective testing of the utility of the insula biomarker.”

Dorthea Dix [1802 – 1887]_Wikipedia

She was born in the town of Hampden, Maine, and grew up first in Worcester, Massachusetts, and then in her wealthy grandmother’s home in Boston. She fled there at the age of twelve, to get away from her alcoholic family and abusive father. She was the first child of three born to Joseph Dix and Mary Bigelow, and had deep ancestral roots in Massachusetts Bay Colony. Her father was an itinerant worker.  About 1821 she opened a school in Boston, which was patronized by the well-to-do families. Soon afterwards she also began teaching poor and neglected children at home. But her health broke down, and from 1824 to 1830 she was chiefly occupied with the writing of books of devotion and stories for children. Her Conversations on Common Things [1824] had reached its sixtieth edition by 1869. In 1831 she established in Boston a model school for girls, and conducted this successfully until 1836, when her health again failed. In hopes of a cure, in 1836 she traveled to England, where she had the good fortune to meet the Rathbone family, who invited her to spend a year as their guest at Greenbank, their ancestral mansion in Liverpool. The Rathbones were Quakers and prominent social reformers, and at Greenbank, Dix met men and women who believed that government should play a direct, active role in social welfare. She was also exposed to the British lunacy reform movement, whose methods involved detailed investigations of madhouses and asylums, the results of which were published in reports to the House of Commons.

After she returned to America, in 1840-41, Dix conducted a statewide investigation of how her home state of Massachusetts cared for the insane poor. In most cases, towns contracted with local individuals to care for people with mental disorders who could not care for themselves, and who lacked family and friends to provide for them. Unregulated and underfunded, this system produced widespread abuse. After her survey, Dix published the results in a fiery report, a Memorial, to the state legislature. "I proceed, Gentlemen, briefly to call your attention to the present state of Insane Persons confined within this Commonwealth, in cages, stalls, pens! Chained, naked, beaten with rods, and lashed into obedience." The outcome of her lobbying was a bill to expand the state’s mental hospital in Worcester. Henceforth, Dix traveled from New Hampshire to Louisiana, documenting the condition of pauper lunatics, publishing memorials to state legislatures, and devoting enormous personal energy to working with committees to draft the enabling legislation and appropriations bills needed to build asylums. In 1846, Dix travelled to Illinois to study mental illness. While there, she fell ill and spent the winter in Springfield recovering. As she recovered, she worked on research, and submitted a report to the January 1847 legislative session, which adopted legislation to establish Illinois’ first state mental hospital.

 

In 1848, Dorothea Dix visited North Carolina and called for reform in the care of mentally ill patients. In 1849, when the North Carolina State Medical Society was formed, the construction of an institution in the capital, Raleigh, for the care of mentally ill patients was authorized. The hospital, named in honor of Dorothea Dix, opened in 1856. She was instrumental in the founding of the first public mental hospital in Pennsylvania, the Harrisburg State Hospital, and later in establishing its library and reading room in 1853. The culmination of her work was the Bill for the Benefit of the Indigent Insane, legislation to set aside 12,225,000 acres of Federal land, 10,000,000 acres for the benefit of the insane and the remainder for the "blind, deaf, and dumb", with proceeds from its sale distributed to the states to build and maintain asylums. Dix’s land bill passed both houses of Congress, but in 1854 President Franklin Pierce vetoed it, arguing that the federal government should not commit itself to social welfare, which was properly the responsibility of the states…

The big institution, Central State Hospital in Milledgeville Georgia, finally closed for good in 2010 [at age 166 years]. Some pictures from then and now:

I said I came in at a time when things were in obvious decline, but in retrospect, in 1974 I made it just under the wire. The system at that time was oriented towards short term hospitalization and community liason. I was lucky to be on Unit where that system worked. We had enough time to manage the acute problems that lead to hospitalization and could insure solid placement in communities with adequate resources and follow-up. It was challenging rewarding work. Not many years later, my office as Director of Residency training was on the campus. I visited that same Unit and saw that it had been essentially destroyed by the excessive admission rate from the closing of too many State facilities. It had become a warehouse. I had to pull my residents off of that Unit where I had learned so much. They were being misused and only learning to be bitter. I involuntarily teared up that day. It seemed so utterly pointless.

We used to be called Alienists, reflecting an outside view of the psychotic patients. But after an early period of adjustment, one doesn’t feel like that. There’s a way that these patients think and  approach living that’s difficult for them and others, but it’s just the way things are. Once you learn it, it’s no longer alien, and there’s a great deal you can do for them. There are some wonderful recoveries, some tragedy, and a lot in between. The idea of Asylum is that it’s the somewhere else [“just a mental health patient living on the street”…] they need to come back to when the world at large becomes impossible. That’s what they’re looking for in those ERs in Raleigh. It doesn’t have to be a hospital. But it does need to be. If you work in a functional version, you know that medication is helpful, but hardly the answer, particularly long term. In my experience, over-medication is a direct result of not having appropriate resources for effective care and Asylum.

E.R. Costs for Mentally Ill Soar, and Hospitals Seek Better Way

New York Times

By JULIE CRESWELL

December 25, 2013

As darkness fell on a Friday evening over downtown Raleigh, N.C., Michael Lyons, a paramedic supervisor for Wake County Emergency Medical Services, slowly approached the tall, lanky man who was swaying back and forth in a gentle rhythm. In answer to Mr. Lyons’s questions, the man, wearing a red shirt that dwarfed his thin frame, said he was bipolar, schizophrenic and homeless. He was looking for help because he did not think his prescribed medication was working. In the past, paramedics would have taken the man to the closest hospital emergency room — most likely the nearby WakeMed Health and Hospitals, one of the largest centers in the region. But instead, under a pilot program, paramedics ushered him through the doors of Holly Hill Hospital, a commercial psychiatric facility. “He doesn’t have a medical complaint, he’s just a mental health patient living on the street who is looking for some help,” said Mr. Lyons, pulling his van back into traffic. “The good news is that he’s not going to an E.R. That’s saving the hospital money and getting the patient to the most appropriate place for him,” he added.

The experiment in Raleigh is being closely watched by other cities desperate to find a way to help mentally ill patients without admitting them to emergency rooms, where the cost of treatment is high — and unnecessary. While there is evidence that other types of health care costs might be declining slightly, the cost of emergency room care for the mentally ill shows no sign of ebbing. Nationally, more than 6.4 million visits to emergency rooms in 2010, or about 5 percent of total visits, involved patients whose primary diagnosis was a mental health condition or substance abuse. That is up 28 percent from just four years earlier, according to the latest figures available from the Agency for Healthcare Research and Quality in Rockville, Md. By one federal estimate, spending by general hospitals to care for these patients is expected to nearly double to $38.5 billion in 2014, from $20.3 billion in 2003.

The problem has been building for decades as mental health systems have been largely decentralized, pushing oversight and responsibility for psychiatric care into overwhelmed communities and, often, to hospitals, like WakeMed. In North Carolina, the problem is becoming particularly acute. A recent study said that the number of mental patients entering emergency rooms in the state was double the nation’s average in 2010. More than 10 years after overhauling its own state mental health system, North Carolina is grappling with the consequences of a lost number of beds and a reduction in funding amid a growing outcry that the state’s mentally ill need more help.

In Raleigh, where the Dorothea Dix Hospital — a state psychiatric institution that served the area for more than 150 years — was closed in 2012, mentally ill patients began trickling into hospital emergency rooms. Hospitals, which cannot legally turn away any patient seeking care, say the influx of psychiatric patients is straining already busy E.R.’s and creating dangerous conditions. This spring, University Medical Center of Southern Nevada in Las Vegas declared an “internal disaster,” shutting its doors to arriving ambulances for 12 hours, after mental patients filled up more than half of its emergency room beds. A suicidal patient took out a gun and shot herself in the head while in a hospital emergency room in New Mexico in January…

Despite Law, Fewer Than One In Eight Completed Studies Of Drugs And Biologics Are Reported On Time On ClinicalTrials.gov

Health Affairs

by Michael R. Law, Yuko Kawasumi and Steven G. Morgan

December 2011

Clinical trial registries are public databases created to prospectively document the methods and measures of prescription drug studies and retrospectively collect a summary of results. In 2007 the US government began requiring that researchers register certain studies and report the results on ClinicalTrials.gov, a public database of federally and privately supported trials conducted in the United States and abroad. We found that although the mandate briefly increased trial registrations, 39 percent of trials were still registered late after the mandate’s deadline, and only 12 percent of completed studies reported results within a year, as required by the mandate. This result is important because there is evidence of selective reporting even among registered trials. Furthermore, we found that trials funded by industry were more than three times as likely to report results than were trials funded by the National Institutes of Health. Thus, additional enforcement may be required to ensure disclosure of all trial results, leading to a better understanding of drug safety and efficacy. Congress should also reconsider the three-year delay in reporting results for products that have been approved by the Food and Drug Administration and are in use by patients.

How often do US-based human subjects research studies register on time, and how often do they post their results? A statistical analysis of the Clinicaltrials.gov database

by Christopher J Gill

British Medical Journal – Open. 2012 2:001186.

[full text on-line]

Context: The Food and Drug Administration Modernization Act of 1997 [FDAMA] and the FDA Amendment Act of 2007 [FDAAA], respectively, established mandates for registration of interventional human research studies on the website clinicaltrials.gov [CTG] and for posting of results of completed studies.

Objective: To characterise, contrast and explain rates of compliance with ontime registration of new studies and posting of results for completed studies on CTG.

Design: Statistical analysis of publically available data downloaded from the CTG website.

Participants: US studies registered on CTG since 1 November 1999, the date when the CTG website became operational, through 24 June 2011, the date the data set was downloaded for analysis.

Main outcome measures: Ontime registration [within 21 days of study start]; average delay from study start to registration; proportion of studies posting their results from within the group of studies listed as completed on CTG.

Results: As of 24 June 2011, CTG contained 54,890 studies registered in the USA. Prior to 2005, an estimated 80% of US studies were not being registered. Among registered studies, only 55.7% registered within the 21-day reporting window. The average delay on CTG was 322 days. Between 28 September 2007 and June 23 2010, 28% of intervention studies at Phase II or beyond posted their study results on CTG, compared with 8.4% for studies without industry funding [RR 4.2, 95% CI 3.7 to 4.8]. Factors associated with posting of results included exclusively paediatric studies [adjusted OR [AOR] 2.9, 95% CI 2.1 to 4.0], and later phase clinical trials [relative to Phase II studies, AOR for Phase III was 3.4, 95% CI 2.8 to 4.1; AOR for Phase IV was 6.0, 95% CI 4.8 to 7.6].

Conclusions: Non-compliance with FDAMA and FDAAA appears to be very common, although compliance is higher for studies sponsored by industry. Further oversight may be required to improve compliance.

Non-publication of large randomized clinical trials: cross sectional analysis

by Christopher W Jones, Lara Handler, Karen E Crowell, Lukas G Keil, Mark A Weaver, and Timothy F Platts-Mills

British Medical Journal. 2013 347:f6104.

[full text on-line]

Objective To estimate the frequency with which results of large randomized clinical trials registered with ClinicalTrials.gov are not available to the public.

Setting Trials with at least 500 participants that were prospectively registered with ClinicalTrials.gov and completed prior to January 2009.

Data sources PubMed, Google Scholar, and Embase were searched to identify published manuscripts containing trial results. The final literature search occurred in November 2012. Registry entries for unpublished trials were reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database.

Main outcome measures The frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database.

Results Of 585 registered trials, 171 [29%] remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299 763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. Non-publication was more common among trials that received industry funding [150/468, 32%] than those that did not [21/117, 18%], P=0.003. Of the 171 unpublished trials, 133 [78%] had no results available in ClinicalTrials.gov.

Conclusions Among this group of large clinical drug trials, non-publication of results was common and the availability of results in the ClinicalTrials.gov database was limited. A substantial number of study participants were exposed to the risks of trial participation without the societal benefits that accompany the dissemination of trial results.

A year or so ago, I reviewed the results database on clinicaltrials.gov [starts with eyes wide shut open I…]. It’s kind of thin – more summary than raw data. But still, it would’ve been helpful. It would’ve given us the outcome of all those unpublished studies like Seroquel Study 15 [15 years of study 15 [and counting]…], the two negative trials of paroxetine in adolescents that weren’t published until the patent expired [an addendum…], or the missing Zoloft studies [zoloft: the approval I… etc.]. I doubt it would help us vet studies like Paxil Study 329. For that one, you’d need the raw data to confirm suspicions. But that’s all speculation as the listed articles above show. The requirements for results publication on clinicaltrials.gov have been essentially ignored [without consequence].

Will the U review or whitewash a research subject’s death?

Star Tribune

by MATT LAMKIN

December 18, 2013

As scholars of medical ethics and proud alumni of the University of Minnesota, we have been pained by the cloud that has hung over our alma mater in the decade since Dan Markingson killed himself while enrolled in a university-sponsored drug trial. Many prominent voices have called for an independent investigation into Markingson’s death, including editors of the world’s most prestigious medical journals and more than 250 other ethicists, physicians and scholars.

Unfortunately, rather than working to be accountable and transparent, the university administration has taken a relentlessly defensive posture — hiding behind its lawyers, targeting its critics and distorting the facts. Most notably, the administration has dismissed the need for an independent investigation by claiming that the university’s treatment of Markingson “has been exhaustively reviewed by federal, state and academic bodies since 2004,” in the words of the university’s general counsel. However, some of these claimed reviews simply did not occur, while others did not examine the most troubling aspects of the Markingson case. For example, the administration has repeatedly claimed that the Hennepin County District Court exonerated the university in a lawsuit brought by Markingson’s mother. In fact, the university convinced the court that it had legal immunity from the suit and could not be held liable no matter how badly it may have treated Markingson.

The administration’s refusal to commission an independent investigation of the Markingson case has tainted the university for far too long. That began to change recently when the Faculty Senate responded to a letter signed by more than 175 scholars asking for an external, independent investigation into the Markingson case. By an overwhelming margin, the Faculty Senate voted to approve a “Resolution on the Matter of the Markingson case” and endorse an inquiry into clinical research practices at the university. Yet University of Minnesota President Eric Kaler appears intent on continuing the university’s efforts to avoid scrutiny. In a recent interview with the Minnesota Daily, Kaler said that the inquiry will not look at Markingson’s death at all, but rather will focus solely on “what we are doing now and what we’re going to do moving forward.” Such a limited inquiry would defeat the purposes of the Senate’s action. Although the resolution does call for an inquiry into the university’s current practices, the Senate left no doubt that the aims of that investigation included resolving “questions [that] continue to be raised about the policies and procedures followed in the Markingson case” and addressing the harm to the university’s reputation “in consequence of this tragic case and its aftermath”.

Any inquiry that merely considers the university’s forms and policies without examining the experiences of actual research subjects would only further erode confidence in the institution and compound the harm to its reputation. In addition to seeking to limit the scope of the investigation, Kaler seems intent on handpicking the investigators. Any involvement by the administration in selecting the members of the investigative panel would destroy the body’s credibility. The offices of the president, the general counsel and the Academic Health Center are all important players in the Markingson controversy whose roles must be examined by the investigative panel. It would be a clear conflict of interest for the targets of this inquiry to select their own investigators…

They seem to still be trying to blow this case off as no big deal. And while I feel the same outrage about that as everyone else, there’s something that nags at me. I figured it out today, but I’m not sure I can articulate it. I think of acute first break cases of psychosis much differently from patients with chronic illness. I see the first episode cases as psychiatric emergencies. The patients are experiencing bizarre and confusing symptoms, often not seen as an illness but as a reality in need of immediate response. They’re volatile, often terrified, and capable of desperate actions in response to their symptoms. There’s nothing routine about those cases. In patients with chronic illness who have an exacerbation or increase in psychotic symptoms, I feel less worried. The symptoms may be compelling, but they’re not unknown. They’ve been here before. I’m much more comfortable being softer with medications. Things just feel safer and less pressing.

I haven’t read that difference anywhere and honestly wasn’t even aware I thought it until I tried to figure out what was bothering me about this case. I realized that the way they were approaching him was as if he were a person with a chronic psychosis with an exacerbation. Putting him some standard dose of medications and following him in a minimum security halfway house. There was none of the close attention and medication adjustment I’m personally used to in a first episode case. It just seems strange to me – a recipe for the disaster it became. I started looking over the increasingly voluminous material available and I found myself honing in on the fact that at the time, there were two Clinical Trials of the Atypical Antipsychotics that overlapped – CATIE [Clinical Antipsychotic Trials of Intervention Effectiveness] and CAFE [Comparison of Atypicals in First Episode of Psychosis][CAFE Protocol]. I hadn’t paid sufficient attention to the fact that they were targeted at two different study populations:

I had noticed, as had everyone else, that Jeffrey Lieberman was the Principle Investigator in both studies and that they overlapped in time. What I hadn’t realized is that the University of Minnesota was a site for both studies and that Dr. Stephen Olson, Dan’s physician, was the site investigator for both. In fact, the majority of CAFE sites were CATIE sites. The CATIE study was run by the Quintiles CRO. And while the CAFE study was listed as administered by UNC [where Dr. Lieberman was at the time], the Protocol has 45 instances that mention Quintiles being involved in various aspects of the trial. And the protocol of the CAFE study refers directly to CATIE as a resource:

Although Mary’s lawsuit was unsuccessful, it revealed some disturbing fnancial arrangements at the university. As a patient on public assistance, Dan’s treatment would have normally generated little income for the university. Under its arrangement with AstraZeneca, however, the psychiatry de-partment earned $15,648 for each subject who completed the cafe study. In total, the study generated $327,000 for the department. In fact, during the months before Dan was enrolled, the department was apparent-ly feeling pressure from Quintiles, the CRO that managed the study, to step up recruitment. According to emails written by Jean Kenney, the university’s study coordinator,the site had been placed on probation for its recruitment problems, and they were still “struggling to get patients.” In November 2002, Olson had managed to recruit only one subject in six months. That began to change in April 2003, when the psychiatry department established a specialized inpatient unit at Fairview hospital called Station12, in which every patient could be evaluated for research. By December, Olson had recruited 12 more subjects, including Dan, and Olson had been featured in a cafe study webcast for “turning an underperforming site into a well-performing site.” [Quintiles refused to give comment on the case.]

So it looks to me as if AstraZeneca [and Dr. Lieberman, and Quintiles] just cloned the NIMH’s CATIE to create CAFE [easy to do with the same CRO and Principle Investigator]. The reason it looked like a study for chronic patients is because that’s exactly what it was – or that’s how I’m thinking about it now. On reflection, I can’t imagine putting a first episode psychotic person on a fixed dose of a randomly chosen antipsychotic and seeing him once a month to see how he’s getting along. That’s what has been nagging at me. No matter what medication I picked, I’d want to assess his status frequently to make adjustments in either dose or choice of medication. I’d want to also look into his psychosocial situation, his resources, his family connectedness and plan for the future, including trying to establish whatever treatment alliance is possible. I don’t want to preach here, but I see the careful management of the first episode as a powerful determinate of the future course of the illness. I expect most clinicians share my feeling. This CAFE approach is too casual, too routine. That’s not to say that psychosis is ever business-as-usual, but there’s a real issue of degree.With chronic patients, one is often trying to restore the equilibrium and prevent deterioration.

So I’m thinking that CAFE had a fundamental design flaw. It appears to be an extrapolation of another study designed to manage chronic illness with medication compliance as its outcome parameter inappropriately repurposed for these acute cases. Acute psychosis isn’t a stabilization issue, it’s something much more than that. I can’t find anything that tells me about Dan’s clinical state in the months in the halfway house on a fixed dose of the then unknown medication except that he stayed in his room and his mother was alarmed at his state. What I hypothesize is that the study team had become used to following the chronic patients in CATIE, and approached the first break patients in the same way. Dan and many with acute illness needed much more attention than that. The people at the University of Minnesota still don’t seem to get that.

Moving from left to right, first there was TMAP [1998], the PHARMA scheme originating in Texas that had seventeen States paying top dollar for psychotropic drugs instead of using the equivalent generics – finally busted by Allen Jones blowing the whistle. It was followed by STAR*D [2001], the $35 M sequencing study of antidepressants that produced hundreds of papers – none of which were the actual results of the study. IMPACTS [2003] followed, a study using computer generated algorithms for doctors in the State of Texas to follow treating depressed patients. It never got off the ground because the doctors wouldn’t follow instructions. CO-MED [2008] was something of a quickie, trying various combinations of antidepressants. Drs. Rush and Trivedi actually finished and reported that one [it was a bust].

If you’re following this, there’s a theme here – getting more out of antidepressants by following some kind of rules in the way they’re given. Except for TMAP, they’ve all been financed by the NIMH and have taken a bite out of the public money going for research. In 2008, when Senator Grassley added his name to the list being investigated, John Rush who was the leader left it to his assistant, Madhukar Trivedi, to finish things up and took off for China to head the Duke program there.

But the legacy lives on. Dr. Trivedi received an NIMH grant for yet another shot at improving the outcome of antidepressants. One might have thought that since CO-MED said that even in combination, the results aren’t better, the notion of some kind of discriminatory administration might improve things would finally die out – but hope springs eternal. And so to EMBARC [2010], an attempt to predict who will respond to which antidepressant by measuring all possible things neuro-something and locating predictors. It’s called "personalized medicine" and it was all the rage there for a while, but it’s died off in recent years. Though it may be gone from the stage, it’s not forgotten [about to go over the $10 M mark]:

• Biological psychiatry. 2013 73[2]:111-118.
• The British journal of psychiatry. 2013 203:310-301.
• Psychological medicine. 2012 42[7]:1417-1428.

• the track record above
• very poor study design
• highly unlikely base hypothesis
• switching to an SSRI that is possibly inert

  1. zoloft®: the approval I…
  2. zoloft®: the approval II…
  3. zoloft®: the approval III…
  4. zoloft®: beyond the approval I…
  5. zoloft®: beyond the approval II…
  6. zoloft®: the epilogue…

A New Focus on Depression

New York Times

By RICHARD A. FRIEDMAN, M.D.

December 23, 2013

When will we ever get depression under control?

Of all the major illnesses, mental or physical, depression has been one of the toughest to subdue. Despite the ubiquity of antidepressant drugs — there are now 26 to choose from — only a third of patients with major depression will experience a full remission after the first round of treatment, and successive treatments with different drugs will give some relief to just 20 to 25 percent more. About 30 percent of people with depression have some degree of treatment resistance. And the greater the degree of resistance, the more likely a future relapse, even if the patient continues taking the drug.

Although we have learned much about depression — for example, the recent research showing that the successful treatment of insomnia in depressed patients essentially doubles their response to a drug like Prozac — we still don’t understand its fundamental cause. The old idea that the disease results from a deficiency of a single neurotransmitter like serotonin or dopamine is clearly simplistic and wrong… Not long ago, I sat in at a meeting of the Hope for Depression Research Foundation. Audrey Gruss, the knowledgeable and energetic philanthropist who started the foundation, has corralled a group of senior basic and clinical neuroscientists to look for solutions. [It is not the first to try a collaborative approach; others are being sponsored by the MacArthur Foundation and the Pritzker Consortium.]

“A complex problem like depression is much larger than one scientist or lab can handle,” said the leader of the group at the Hope foundation, Huda Akil, a professor of neurosciences and psychiatry at the University of Michigan. “What is great about our collaboration is that we can think about big ideas and take risks without worrying about what grant reviewers” — like the National Institute of Mental Health, the major source of federal funding for psychiatric research — “might think.” A major goal is to understand which brain circuits and genes are altered by depression, how the environment interacts with these genes, and how to reverse the accumulated biological assaults of this disease. That will require the integration of a wide range of tools, she said: genomics, epigenetics, electrophysiology, animal models, clinical psychiatry.

A major drawback of our current antidepressants is that they rely on animal models that have been used for decades, yielding drugs that all work the same way. Novel drugs require identification of new targets in the brain and better animal models in which to screen them. So one member of the group, Dr. Joshua Gordon, an associate professor of psychiatry at Columbia, studies new animal models of depression by recording activity in select brain regions in mice that are engaged in depressionlike behavior.

After talking with another group member, Dr. Helen S. Mayberg, a neuroscientist at Emory University, Dr. Gordon modified his approach. Dr. Mayberg has identified a target for deep brain stimulation in patients with treatment-resistant depression: a region called the subgenual cingulate cortex. When it is directly stimulated with electrodes in depressed patients who have failed to respond to nearly all other treatments, many show a brisk positive response. Dr. Mayberg urged Dr. Gordon to extend the region of his recording to include the mouse analog of this human brain region, so he could more fully capture activity in these different areas of the cortex and understand how they individually contribute to depressionlike behavior in mice. Another group member, Bruce McEwen, a neuroscientist at Rockefeller University who has done pioneering work on the effects of stress on the brain, is studying rats from Dr. Akil’s lab that have been genetically selected for their propensity to show anxiety and depressionlike behavior.

Among other things, Dr. McEwen is using these rats to study the efficacy of drugs with the potential to act rapidly against depression. Such a drug would be a major boon to psychiatry: We need treatments that can ease the symptoms of depression, and its attendant risk of suicide, in far less time than the two to six weeks that all current antidepressants require to do their work.

Even a high-powered collaboration like this one offers no guarantee of finding effective weapons against intractable depression. After all, it took 50 years to smoke out the Higgs boson, and even at that, there are huge unanswered questions. But at a time when federal research funds are shrinking and major drug companies have all but shuttered their brain research programs, enlightened philanthropists and entrepreneurs are helping to open a promising new pathway for neuroscience research: collaboration among researchers willing and able to take thoughtful risks and solve big problems.

The point of any taxonomy is to iterate large categories towards increasingly homogeneous  subgroupings that can be researched in pure culture. The creation of Major Depressive Disorder with the DSM-III thirty-three years ago did the opposite, destroying that process and setting the stage for one of medicine’s all time misadventures with its monotonous waves of new foci. But that’s old news [as is this article about a new focus on depression]. Nothing new up there we haven’t heard for years. Just the inertia of a generation of academic psychiatrists who have known nothing else. But they unfortunately threw out many of the clinicians who form the backbone of any medical specialty, and psychiatry became increasingly experience distant from patients [often treated more like subjects in an endless clinical trial]. But that’s old news too.