1 Boring Old Man

I’ve been writing about Rapastinel, an NMDA receptor partial blocker touted to have Ketamine’s antidepressant effects without being a psychomimetic [see a touch of paralysis… and a block-buster-in-training…]. It was developed by a Northwestern University neuroscientist who formed a private company [Naurex], later purchased by industry giant Allergan for $560 M. They’ve recently registered four phase 3 clinical trials – all now recruiting. Before discussing these trials, here’s a bit of a review.

And so to the Rapastinel Phase 3 trials. Three of the four are virtual clones of each other, differing only in the number of subjects [why?] and one has a second dose level. They all have the same cohort – subjects in a Major Depressive Episode that "[h]ave no more than partial response [< 50% improvement] to ongoing treatment with a protocol-allowed antidepressant." These three trials call for 4589 total subjects who have failed to respond to SSRIs, documented by a less that 50% response on some unspecified rating scale after a course of an antidepressant from some unspecified list of drugs. That’s a huge cohort and it’s unclear why so many. There’s no power analysis included to explain it. Likewise, there’s a huge number of sites [134]. I even wondered if they are piggy-backing on the end of a bunch of somebody else’s antidepressant trials to get cases? Some kind of explanation would be welcome.

This is a medication that is given intravenously and the antidepressant effect lasts ~one week in the proof-of-concept study [see a block-buster-in-training…], so they call for weekly injections. Here’s all they have to say about the conduct of the study and the primary and secondary outcome variables:

• Primary Outcome Measure: Change from Baseline in Montgomery-Asberg Depression Rating Scale [MADRS] Total Score [Time Frame: Baseline and 1 Day]
• Secondary Outcome Measure: Change from Baseline in MADRS Total Score at the End of Study [Time Frame: Baseline and 3 Weeks]

How long does the study last? It doesn’t really say. I’m presuming three weeks based on that Time Frame comment in the Secondary Outcome Measure. They say the Primary Outcome Measure is the MADRS Score on day 1. After the first injection? or after each injection? And why day 1? After studying it a while, this was my best guess about what they were going to do,,,

Looking at the only published study [see a block-buster-in-training…], it seems important to take a look later in that week. That’s the whole reason the drug’s being given – for its presumed ability to last the week. And there are any number of Baselines. Which one is used? When? Is there a minimum MADRS score for entering the study? I could go on and on [and so could you].

And the 4th trial? RAP-MD-04? While it doesn’t say it in the ClinicalTrials.gov registration document, this trial apparently follows some subset of the subjects from the other three trials [responders?] on either continued Placebo or Rapastinel [weekly or every two weeks] as a relapse prevention trial for two years. And though it presumably follows some group from RAP-MD-01, RAP-MD-02, and RAP-MD-03, the criteria for that determination isn’t specified. Again, there’s no self rating depression scale, no PANSS, no adverse event plan mentioned.

Psychiatry was obviously ripe for the the medicalization ushered in by the neoKraepelinians and the DSM-III released two years after this article. Changes in reimbursement schedules, a burst of new psychotropic drugs certified by industry funded clinical trials, and a focus on neuroscience research soon followed. The disappearance of the public mental hospitals was matched by similar closings in the private sector. And the boundaries between academic psychiatry, guild organizations, and the pharmaceutical industry became increasingly indistinct.

In the period since this chapter was written, the large mental institutions closed for good, replaced, with the reinstitutionalization of many chronic mental patients in our jails and prisons. Psychiatry did indeed medicalize to the point that most psychiatrists became primarily involved in pharmacologic and other biological treatments. And the neuroleptic drugs used in the treatment of psychosis in Klerman’s time were for the most part forgotten, replaced by a string of new Atypical Antipsychotics.

What has been the influence of the disease approach on understanding schizophrenia? The neo-Kraepelinian answer has been another question: Does the concept of schizophrenia have any meaning, and if it does, what are the data that give it meaning? In other words, the concern has been with what one might call the epistemology of diagnosis; namely, what are the rules of the game? In the disease approach, there are six steps toward validating a concept of an illness such as schizophrenia.

1. Define the theoretical bases with clarity. It is very important to make explicit the assumptions on which the many conceptual views of schizophrenia are based. But unfortunately much of psychiatric discourse until the middle of this century* has never moved beyond these theoretical debates. In order to move psychiatry beyond philosophy and into science, the second step must be taken.
2. Translate the general concept into specific hypotheses that can be operationally tested. For example, what is the meaning of borderline schizophrenia? What are its components? How does it manifest itself?
3. Put the hypothesis to empirical testing to determine its reliability. How well do several observers agree that a borderline patient does have ego deficits, is using splitting or denial?
4. Subject the data to various statistical tests to determine whether we are dealing with one syndrome alone or a mixture of syndromes.
5. Attempt to validate the statistics by follow-up studies, family and genetic investigation, correlates in childhood development, and so on
6. Undertake epidemiological studies to ascertain the patterns of incidence and prevalence.

How well, then, does schizophrenia meet the criteria of a chronic disease in the medical model? It meets it well but not completely. Before one can conclude definitively that schizophrenia is a disease, conclusive evidence will have to be presented as to etiology and clinical course. While such evidence exists for many other disorders in psychiatry, it does not yet exist for schizophrenia — nor for many other clinical conditions with which medicine deals, such as hypertension, arthritis, and leukemia. That is to say, it is an obviously disordered state with multiple determinants in which there is not certainty as to the exact etiology. Moreover, schizophrenia as we now’ define it is similar to hypertension in that it is likely to comprise various disorders. As the specific etiological principles come into scientific investigation, we will probably reaffirm Bleuler’s concept of a group of schizophrenias. Nevertheless, it is likely that within this group of schizophrenias there is a core group that has a strong genetic component. This genetic factor creates a vulnerability that becomes manifest in psychosis when precipitated by environmental stresses.

His textbook was significant in tlie history of psychiatry not because it was the first textbook of psychiatry but because it was one of die first to approach mental illness in terms of causation and etiology, using the principles of modern scientific medicine.

After classifying as many cases of mental illness as possible by etiology — those due to infection, to endocrine disorders, and so on — Kraepelin was left with a large group of patients whose psychoses began in young adulthood and went on for many years but who had relatively few deaths… Kraepelin proposed that these psychotic conditions with no established etiology be further divided into two groups, which he called “dementia praecox” and “manic-depressive insanity.” He justified this division on the basis of clinical features during the acute illness, long term course, and outcome.

Most psychiatrists have traditionally accepted the disease model based on the syndromatic constellation and predictable course, suspecting a biological etiology to show itself sooner or later. The critics are less taken with the homogeneity of the syndromes [see a guest post from Sandy Steingard…], many seeing guild hegemony and medical training as unacknowledged complicating factors. That conflict is, if anything, more intense now than it was in 1978.

^{[continuing from an interesting read…, Schizophrenia: Science and Practice, Chapter 5: The Evolution of a Scientific Nosology, and Klerman 1978: on the medical model…].}

American, British, and Canadian psychiatry is today in the midst of a Kraepelinian revival that is becoming the dominant force among research and academic leaders, In contrast, the Meyerian school is currently in a phase of decline in American psychiatry. The Meyerian approach stresses the importance of personal experience and the uniqueness of the individual in his social context, in contrast to the Kraepelinian emphasis on categorizing diseases, an emphasis derived from continental European medicine, The neo-Kraepelinian credo includes nine propositions:

1. Psychiatry is a branch of medicine.
2. Psychiatry should utilize modem scientific methodologies and base its practice on scientific knowledge.
3. Psychiatry treats people who are sick and who require treatment for mental illnesses.
4. There is a boundary between the normal and the sick.
5. There are discrete mental illnesses. Mental illnesses are not myths. There is not one but many mental illnesses. It is the task of scientific psychiatry, as of other medical specialties, to investigate the causes, diagnosis, and treatment of these mental illnesses.
6. The focus of psychiatric physicians should be particularly on the biological aspects of mental 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 such criteria by various techniques. Further, departments of psychiatry in medical schools should teach these criteria and not depreciate them, as has been the case for many years.
9. In research efforts directed at improving the reliability and validity of diagnosis and classification, statistical techniques should be utilized.

… In this country the neo-Kraepelinian point of view has been most strongly identified with the group at Washington University in St. Louis, whose leading spokesman are Eli Robins, Sam Guze, and George Winokur. Recently, they have been joined by a New York contingent including Donald Klein, whose book on diagnosis and drug treatment has probably been the most influential textbook of psychopharmacology in this country.  Klein has repeatedly asserted that psychiatrists cannot prescribe drug treatment appropriately without a careful description of the patient’s symptoms and syndromes.  Another New York investigator identified with the neo-Kraepelinian approach is Robert Spitzer, chairperson of the American Psychiatric Association Task Force that is drafting the third edition of the Diagnostic and Statistical Manual. The first draft of this volume has been met with controversy over the strongly descriptive approach it takes to psychopathology…

How could a professional organization engineer a scientific revolution that changed its core? According to conventional wisdom, organizations respond; they do not initiate By Ihe 1970a psychiatry in the United States had begun to undergo massive changes. The postwar glow had been replaced by the new pressures for accountability on all of medicine. Many leaders in psychiatry deplored the ideological rifts that had divided the field and they called far a more unified, scientifically based profession. They deplored the "demedicalization" of psychiatry and its severe loss of credibility . I was one of the young leaders who had criticized the ideological divisions within psychiatry and had been searching for ways to improve its scientific status throughout my career. The field’s ideological schisms had weakened us serious, and psychiatrists bitter public disagreements were self-destructive To cover up these differences or to act solely because of the criticism was not in itself sufficient; psychiatry had to adopt a genuine commitment to science rather than to ideology, It needed to change the profession fundamentally if it was to become a respected part of medicine. To accede to the pressures without radical modifications of the field would not have convinced others that the profession had changed. A new strategy was essential! Producing the DSM-llI stated emphatically that psychiatry in America chose an evidence-based practice rather than ideology.

The Kraepelinian revival is part of the general movement of psychiatry towards greater integration with medicine. This movement has multiple sources, professional, economic, social, scientific. Whatever its sources, the consequence for psychiatry is a greater concern for medical identity Applied to schizophrenia, there is greater attention to diagnosis in the classical medical tradition and to biological causes and treatments of this disorder.

The medical model has become a code word for controversy and debate, a slogan with which to rally one’s allies or to castigate one’s enemies. To psychiatrists concerned about defending their health insurance prerogatives, the medical model is an umbrella to justify continued support from Blue Cross, Blue Shield, or Aetna. To psychologists and other nonmedical practitioners anxious to be included under health insurance, the medical model refers to a narrow biological approach to the treatment of psychological problem. To behavior therapists, who apply the methods of B. F. Skinner, the medical model applies to dynamic psychotherapy and psychoanalysis, which they attack for postulating “underlying conflicts” of which symptoms are only manifest behaviors [It is ironic that this extension of the medical model to psychoanalysis would be rejected by a substantial group of nonpsychiatric physicians]. To black militants in an urban ghetto, the medical model is a term of contempt for the futile attempt of the community mental health center to treat social ills by treating individuals, whom the militants regard as victims rather than patients.

[1] The disease concept. This is a theory of illness that evolved in the eighteenth century and is now held throughout Western industrial civilization.

[2] The sick role. As sociologists such as Parsons [1951] and Fox [1968] and anthropologists such as Fabraga [Fabraga et al. 1968] have pointed out, every known society has a category of the “sick role” for a special class of deviance, even non-Western societies that do not have modern notions of biology such as bacteriology or catecholamines. The sick role carries with it a set of rights and prerogatives, and mechanisms are specified whereby this role can legitimately be conferred on certain individuals by another group within society, the “healers.”

[3] The health care system. As society becomes more specialized and differentiated, the roles of both the sick and the healer become more complex. In modern industrial society there is a complex health care system that includes various kinds of specialists among healers, such as nurses, doctors, technicians, as well as complex institutions such as hospitals and universities and, recently, fiscal mechanisms such as health insurance and Social Security. In part, the debate over whether or not schizophrenia or anxiety are “diseases” is a conflict over whether individuals exhibiting such behaviors are legitimately to be given the rights and prerogatives of the sick role and whether or not the complex and powerful apparatus of the health care system shall serve their needs…

Looked at in these terms, mental illness and the medical model are social constructs; they are inventions of modern society that attempt to make sense of and deal with the real phenomena of pain, distress, anguish, and disability experienced by certain individuals. However, to say that the medical model or the concept of mental illness is a social construct is not to say that it is a myth or that it is invalid. All social constructs are not myths and they are not necessarily untrue. After all, “the rights of man,” the electron, and the university are also social constructs. They are not facts given in nature, but rather are complex ideas developed by historical forces and legitimated by consent. The concept of illness is not arbitrary but reflects areas of shared consensus, embodying truths arrived at by rules of evidence.

The application of the medical model to mental illness was an achievement of the nineteenth century, when Philippe Pinel at the Salpetriere was responsible for bringing medical leadership to the asylums. For centuries Western Europe had had institutions for lunatics, but these asylums had not been considered appropriate for medical supervision. Usually they were run by religious orders or were parts of jails or prisons. Furthermore, the courts had not distinguished “madness” and “badness” as clearly as became the norm in the early part of the nineteenth century, as a result of the eighteenth century Enlightenment. This distinction between being mad and being bad was regarded as a major humanitarian gain, motivated by humane and benevolent intents.

Historical and Philosophical Perspectives
1. Approaches to Understanding Schizophrenia – John C. Shershow
2. The Manifest and the Scientific Images – Etiology: The Nature-Nurture Interaction
3. Heredity and Environment – Seymour Kety
4. A Developmental Theory – Theodore Lidz
Bioscientific Research
5. The Evolution of a Scientific Nosology – Gerald L. Klerman
6. Biochemical Investigation – Ian Creese and Solomon II. Snyder
7. Psychopharmacology – Leo Hollister
Care and Treatment: The Human Dimension
8. The Patient and the Community – Jonathan F. Boras and Elaine Hatow
9. Psychotherapy – Daniel P. Schwartz
10. The Surrogate “Family,” an Alternative to Hospitalization – Loren II. Mosher and Alma Z. Menn

I came to psychiatry from practicing Internal Medicine with something specific in mind to learn about – and it wasn’t psychiatric patients. It was the subset of medical patients whose problems were clearly mental – and there were plenty of them. But in a psychiatry residency, that’s not where you start. It’s on the wards of a beleaguered City/County hospital populated with psychotic people and an emergency room called the Crisis Intervention Service [throw in that it was the end of the de-institutionalization period]. I found myself in the middle of interesting times, to say the least. By 1978, I was one year out of residency, in a psychoanalytic training program, in charge of that Crisis Intervention Service, and having a fine time. There was a book published that year that I didn’t know about, but it was a harbinger of a really big change coming to psychiatry:

Schizophrenia: Science and Practice, Edited by J. C. Shershow. [Pp. 248]; Harvard University Press: Cambridge, Massachusetts. 1978. Chapter 5: The Evolution of a Scientific Nosology by Gerald Klerman.

A couple of years later [1980], there was another book that nobody missed [the DSM-III], ushering in that big change – the medicalization of psychiatry.

I’ve quoted Klerman’s neoKraepelinian Tenets frequently but never had the whole chapter in hand. Some time back, I ran across a dogeared copy of the Shershow book for $2.53 online and ordered it. In the holiday, post-election lull, I opened it up and ended up reading the whole book. It was a window into to state of psychiatry at the dawn of the new era, the dawn of my own psychiatric career. The Klerman chapter was a lot more that just the neoKraepelinian Tenets. I’m going to write about it some, but I thought others of you might want to read what he had to say, so I Scanned/OCR’d it, and it can be downloaded here as a .doc file.

^{Looking through the December American Journal of Psychiatry, there was a small study in the Letters section, Effect of a Novel NMDA Receptor Modulator, Rapastinel [Formerly GLYX-13], in OCD: Proof of Concept. They had given intravenous Rapastinel [GLYX-13] an NMDA receptor partial blocker to seven patients with severe OCD. Remember Rapastinel [GLYX-13]? It’s the Ketamine-like drug touted to have Ketamine’s short-term antidepressant effect without any of the Psychodelic "Club Drug" effect. In this series, Rapastinel did have an acute effect on the OCD Sx, but unlike in depression, at one week the effect was gone. But enough about that. This Letter just reminded me that I had unfinished business with Rapastinel.}

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

by D. Jeffrey Newport, Linda L. Carpenter, William M. McDonald, James B. Potash, Mauricio Tohen, and Charles B. Nemeroff, The APA Council of Research Task Force on Novel Biomarkers and Treatments

American Journal of Psychiatry. 2015 172:950–966.

[full text on-line]

I wrote about it in [a touch of paralysis…]. Dr. Nemeroff had already gone out of his way to say he was not connected with Naurex, the company behind GLYX-13 [Rapastinel] here, [between 5:40 and 6:40]. That APA review article was enthusiastic about Rapastinel, in spite of the fact that there was only one trial [Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent][NCT01234558] with all authors being involved with Naurex [founded by Joseph Moskal, PhD]. Sure enough, shortly after that review article came out, Allergan bought Naurex for $560 M [Dr. Nemeroff is definitely financially involved with Allergan]. Positively reviewing drugs without acknowledging his own COI was Dr. Nemeroff’s M.O. in the past [see supplement·a·tion: a strange kind of sense…], and frankly I suspected he might be up to his old tricks again – though in a more untouchable way. So I flagged Rapastinel as a trial to take a look at. As I said, the letter in the American Journal of Psychiatry this month just reminded me.

Dr. Moskal and his colleagues have certainly put in the time with their GLIX-13 NMDA partial agonist [now Rapastinel]. He is a neurobiologist at Northwestern [see Northwestern’s $560 million man] who tested his molecule in a wide range of animal models. His articles about GLIX-13 are worth looking over [at least the titles], as he predicts from his basic research many possible clinical applications. But these two titles state clearly where the eagle landed – GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists and GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects [both available on-line].

• Single IV Dose of GLYX-13 in Patients With Treatment-Resistant Depression
  Condition: Major Depressive
  NCT Number: NCT01234558
  Study Start: May 2011
  Study Completion: July 2012
• Efficacy and Safety of GLYX-13 in Subjects With Inadequate/Partial Response to Antidepressants
  Condition: Major Depressive Disorder
  NCT Number: NCT01684163
  Study Start: November 2012
  Study Completion: June 2014
• Open Label Extension for GLYX13-C-202, NCT01684163
  Condition: Major Depressive Disorder
  NCT Number: NCT02192099
  Study Start: February 2015
  Study Completion: December 2017
• Open Label Trial of GLYX-13 in Individuals With Obsessive-Compulsive Disorder
  Condition: Obsessive-Compulsive Disorder [OCD]
  NCT Number: NCT02267629
  Study Start: October 2014
  Study Completion: February 2016

Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent.

by Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM; and GLYX-13 Clinical Study Group.

Journal of Psychiatric Practice. 2015 21[2]:140-149.

[NCT Number: NCT01234558]

BACKGROUND: … Studies have demonstrated that high affinity N-methyl-Daspartate [NMDA] receptor blockers [eg, ketamine] can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist.

METHOD: In this double-blind, randomized, placebo-controlled study, a single intravenous [IV] dose of GLYX-13 [1, 5, 10, or 30 mg/kg] or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 [Ham-D17], which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration.

RESULTS: GLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychotomimetic or other significant side effects.

CONCLUSION: In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned.

^{[redrawn for clarity]}

There was a substantial placebo response in this study with subjects in the placebo group showing an average 45% reduction in Ham-D17 scores at 24 hours post dose…

The subjects who received 1 mg/kg of GLYX-13 had numerically but not statistically sig- nificantly greater reductions in mean Ham-D17 scores compared to those who received placebo. However, the subjects who received 5 and 10 mg/kg of GLYX-13 showed reductions in mean Ham-D17 scores that were both numerically and statistically significantly greater than those that occurred in the placebo group [p < 0.05 for the ANCOVA drug effect of 5 and 10 mg/kg]. While the effect of GLYX-13 differed significantly from placebo at Day 7 after dose administration, the difference between the effect of GLYX-13 and placebo was not significant at Day 14. Differences from placebo on the Ham-D17 ranged from -2.8 units for 5 mg/kg and -2.5 units for 10 mg/kg at day 1 after dosing to -3.1 to for 5 mg/kg and -4.3 units for 10 mg/kg at day 7 following dosing. The effect sizes [Cohen’s ds] at days 1, 3 and 7 were 0.56, 0.41, and 0.39 for the 5 mg/kg dose of GLYX-13 and 0.37, 0.36, 0.60 for the 10 mg/kg of GLYX-13. However, when the dose of GLYX-13 was raised to 30 mg/kg, there was no antidepressant effect… None of the response or remission percentages in subjects receiving GLYX-13 was statistically significant compared to placebo, due to the large placebo effect observed during the first 24 hours after dosing…

Since this POC was done, a multiple dose study has been recently completed. That study demonstrated sustained antidepressant efficacy in patients whose depressive episode had not been responsive to available biogenic amine antidepressants. Based on the results of this POC study and the subsequent multiple dose study, GLYX-13 is entering phase 3 development…

… The literature search identified one randomized clinical trial of rapastinel, evaluating the anti-depressant efficacy of a single intravenous infusion at four doses [1,5,10, and 30 mg/kg] with treatment effects assessed at 2, 4, 8, and 12 hours and 1, 3, 7, and 14 days postinfusion.

No statistically significant differences were observed in rates of treatment response or symptom remission associated with placebo [64% and 42%, respectively] versus rapastinel at any dose [up to 70% and 53%, respectively]. However, statistically significant differences in the reduction of the 17-item HAM-D scores were observed for the 5-mg/kg dose at all intervals except day 14 [peak 17-itcm HAM-D reduction 3.1 points greater than placebo] and the 10-mg/kg dose at day 1 and day 3 [peak 17-itcm HAM-D reduction 4.3 points greater than placebo]. Neither the low [1 mg/kg] nor high [30 mg/kg] rapastinel doses were associated with significant greater 17-item HAM-D score reduction than placebo, leading the authors to posit an inverted U-shape dose response curve.

Psychotomimetic and dissociative side effects. The BPRS positive symptom subscale was administered in this trial with no differences observed between the placebo group and any of the four rapastinel treatment groups. The Clinician-Administered Dissociative States Scale was not administered in this study.

• Recruiting
  A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder [RAP-MD-01]
  Condition: Depressive Disorder,
  Number Enrolled: 700
  NCT Number: NCT02932943
  Study Start: October 2016
• Recruiting
  A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder [RAP-MD-02]
  Condition: Depressive Disorder,
  Number Enrolled: 1050
  NCT Number: NCT02943564
  Study Start: October 2016
• Recruiting
  A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder [RAP-MD-03]
  Condition: Depressive Disorder,
  Number Enrolled: 700
  NCT Number: NCT02943577
  Study Start: October 2016
• Not yet recruiting
  A Study of Rapastinel as Adjunctive Therapy in the Prevention of Relapse in Patients With Major Depressive Disorder
  Condition: Depressive Disorder,
  Number Enrolled: 1500
  NCT Number: NCT02951988
  Study Start: November 2016

"Subjects were recruited from investigator practices and via newspaper, radio and Internet advertisements."

• This is an unreplicated lone study of a drug [financed with venture capital].
• All authors have loud conflicts of interest.
• There are no "Results" posted on clinicaltrials.gov even though it was completed 4½ years ago.
• The expected Mean and Standard Deviation data for the raw HAM-D outcome variable by dose by time isn’t in the paper. All we see are the point differences in a graph [with no way to assess variance]. It can’t be vetted…
• There is a very peculiar plummet in depression scores two hours after the injection and their speculations about "the why?" just don’t pass muster. This drug isn’t supposed to have a "druggie" effect, but it sure seems to have something that smells suspiciously like that!
• There are at least two other GLYX-13 studies mentioned, but nowhere found eg the Clinical Trial registered as NCT01684163 completed 2½ years ago, and the multiple dose trial mentioned in the text of this paper.
• The shout-out in an APA AJP Review article has a first author [Newport] with COI with the developing company [Naurex] reporting for a panel lead by a notoriously tarnished KOL [Nemeroff] with COI with the company that just bought the drug [Allergan].

With media watchdogs on the sidelines, pharma-funded advocacy groups pushed Cures Act to the finish line 

HealthNewsReview

by Trudy Lieberman

December 6, 2016

^{hat tip to AA…} 

A Frenzy Of Lobbying On 21st Century Cures

Kaiser Health News

By Sydney Lupkin

November 28, 2016

^{hat tip to Mark Wilson…} 

New Report Exposes “Patient Advocacy” Groups as a Big Pharma Scam

The Intercept

by David Dayen

December 1, 2016

DRUG MONEY: PART I

FDA Depends on Industry Funding; Money Comes with “Strings Attached”

POGO

by David Hilzenrath

December 1, 2016

DRUG MONEY: PART II

In FDA Meetings, "Voice" of the Patient Often Funded by Drug Companies

POGO

by David Hilzenrath

December 1, 2016

Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial

by Gerardo Villarreal, Mark B. Hamner, José M. Cañive, Sophie Robert, Lawrence A. Calais, Valerie Durklaski, Yusheng Zhai, and Clifford Qualls

American Journal of Psychiatry. 2016 173[12]:1205-1212.

	Received:	July 27, 2015
	Accepted:	May 02, 2016
ClinicalTrials.gov Identifier: NCT00237393
	Study Start Date:	August 2003
	Study Completion Date:	December 2007

Objective: This was a 12-week randomized, placebo-controlled trial to assess the efficacy of quetiapine monotherapy in the treatment of posttraumatic stress disorder [PTSD].

Method: Eighty patients were randomly assigned to treatment with either quetiapine or placebo. The primary outcome measure was the Clinician-Administered PTSD Scale [CAPS]. Secondary efficacy measures included the CAPS subscales, the Davidson Trauma Scale, the Positive and Negative Syndrome Scale [PANSS], the Clinical Global Impressions [CGI] scales for severity of Illness and improvement, the Hamilton Depression Rating Scale [HAM-D], and the Hamilton Anxiety Rating Scale [HAM-A]. Safety measurements included adverse events, vital signs, the Abnormal Involuntary Movement Scale, the Barnes Akathisia Scale, the Simpson-Angus Scale, and the Arizona Sexual Experiences Scale.

Results: After a 1-week placebo run-in, quetiapine was started at a daily dosage of 25 mg and increased to a maximum of 800 mg; the average was 258 mg [range, 50–800 mg]. Reductions in CAPS total, re-experiencing, and hyperarousal scores were significantly greater for the quetiapine group than for the placebo group. Greater improvements were also observed for quetiapine in scores on the Davidson Trauma Scale, CGI severity and improvement ratings, PANSS positive symptom and general psychopathology subscales, HAM-A, and HAM-D than for placebo. Adverse events were generally mild and expected based on prior studies of quetiapine in this and other patient population. There were no differences in safety measures between groups.

Conclusion: Quetiapine monotherapy was efficacious in the treatment of PTSD. These findings suggest quetiapine as a single agent is effective in treating military PTSD.

---

Presented at the 29th Annual Conference of the Anxiety Disorders Association of America, Santa Anna Pueblo, N.M., March 12–15, 2009, and the 2009 CINP Thematic Meeting, Edinburgh, April 25–27, 2009.

Funded by an investigator-initiated grant from AstraZeneca to Dr. Hamner.

Dr. Hamner has current research support from Alkermes and Pfizer; he has been the recipient of research grant support or honoraria and/or has served as a consultant for the following pharmaceutical companies: Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen, Lundbeck, Organon, Otsuka, and Sanofi-Synthlabo. Dr. Cañive has received research grant support or honoraria and/or has served as a consultant for the following pharmaceutical companies: Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Organon, Otsuka, and Sanofi-Synthlabo. The other authors report no financial relationships with commercial interests.

Editorial

Adjusting to Traumatic Stress Research

by Murray B. Stein

American Journal of Psychiatry. 2016 173[12]:1165-1166.

…the study by Villarreal et al., also in this issue, digs up a topic thought to be long dead: the efficacy of atypical antipsychotics for PTSD. Whereas some early, small trials had suggested that atypical antipsychotics, such as olanzapine or risperidone, might be useful adjunctive [to selective serotonin reuptake inhibitors] treatment for PTSD, a large VA Cooperative Study seemed to put the nail in the coffin of that treatment option by failing to show a benefit of adjunctive risperidone on global severity of PTSD. That trial, it should be noted, did show statistically significant [though, it was argued, clinically modest] beneficial effects on hyperarousal symptoms and, in a more recent secondary analysis, sleep disturbance. Moreover, meta-analysis suggests that atypical antipsychotics can be useful in treating PTSD, and clinicians continue to believe they are efficacious and continue to prescribe them for many [up to 20% of] patients with PTSD.

Against this backdrop of high antipsychotic prescribing for PTSD in the face of limited evidence of efficacy comes this new randomized placebo-controlled trial of quetiapine as monotherapy for military-related PTSD [by Villarreal et al]. Well, not really a new study, but an old study — completed in 2008 — newly published. It is unclear why it took nearly a decade to publish the results of this positive study, but it is timely nonetheless. Albeit a fairly small trial that enrolled 80 patients, the results suggest that quetiapine can be useful in the treatment of PTSD, though the authors remind readers that adverse effects of this class of drugs must be considered in the risk-benefit ratio of whether to treat a given individual.

Whereas clinical practice should rarely be influenced by findings from a single trial, the results of this study should hasten a reinvigoration of research into the safety and efficacy of atypical antipsychotics for the treatment of PTSD. Though we yearn for a future where better and safer drugs for PTSD can be targeted for precisely the patients most likely to benefit from them with the fewest adverse effects, we are constrained to practice medicine in the present. Call it imprecision medicine if you must, but if atypical antipsychotics — administered as monotherapy or as adjunctive therapy — can help some patients with PTSD — then let’s shore up the evidence base for their utility so that we practitioners can feel less stressed about using them.

A Silenced Drug Study Creates An Uproar

Washington Post

By Shankar Vedantam

March 18, 2009

The study would come to be called "cursed," but it started out just as Study 15. It was a long-term trial of the antipsychotic drug Seroquel. The common wisdom in psychiatric circles was that newer drugs were far better than older drugs, but Study 15’s results suggested otherwise.

As a result, newly unearthed documents show, Study 15 suffered the same fate as many industry-sponsored trials that yield data drugmakers don’t like: It got buried. It took eight years before a taxpayer-funded study rediscovered what Study 15 had found — and raised serious concerns about an entire new class of expensive drugs. Study 15 was silenced in 1997, the same year Seroquel was approved by the Food and Drug Administration to treat schizophrenia…