an explanation and a surprise…

Posted on Sunday 25 December 2016

So, picking up from explanation would be welcome… and looking at the enrollments in RAP-MD-01, RAP-MD-02, and RAP-MD-03 that seem so high in those Rapastinel Clinical Trials. The way trialists pick their sample size is to do a Power Analysis. Using the Standard Deviation from a previous similar study, then pick the difference in means between the control and experimental values you would consider meaningful, and it spits out a sample size. Here’s the formula:

These studies use Montgomery-Asberg Depression Rating Scale [MADRS], and I can’t find any data to give me a Standard Deviation for Rapastinel using MADRS, nor do I know that scale well enough to select a mean difference. But, if you’ll allow me a bit of numeric mojo, I can use the Z Scores for p=0.05 and an 80% power [both standard], si I simplified the equation. I noticed that it has a clause that contains the formula for the Cohen’s d Effect Size so I substituted and come up with a formula that calculates the sample size for the group for any given Effect Size [could that be right?]. The table on the right gives some example values:

Looking at the group sample sizes for RAP-MD-01, RAP-MD-02, and RAP-MD-03, we have 700÷2 = 350, 2333÷3 = 778, and 1556÷2 = 778 respectively. Applying the formula, that gives Cohen’s d values of 0.21, 0.14, and 0.14. So if my formula works, using Cohen’s rough guidance [0.25 is a weak Effect, 0.50 is moderate Effect, and 0.75+ is a strong Effect] these studies are powered to detect statistically significant differences at Effect Sizes that are for all intents and purposes no Effect at all, clinically insignificant. By this read, these studies are dramatically overpowered.

And as to the question, why three different clinical trials that are close to identical? That one’s easy. They need two statistically significant RCTs to be eligible for an FDA Approval. Instead of doing a trial, and if it’s positive, trying to replicate it, they are doing them simultaneously because it’s faster. Sinilarly, why so many sites? I really speeds up recruitment.And how are they going to come up with 4589 depressed subjects that are treatment failures [<50% response to an SSRI] and get this study done in two years? I haven’t a clue. But the point is clear, this is a race to the finish line, to be the first company to have a Ketamine-like product on the market.

Surprise/Flash: So I just went to ClinicalTrials.gov to look up something about RAP-MD-04 that I was about to write about, and there’s another whole trial! posted on Christmas Day! It’s called Long-term Safety Study of Rapastinel as Adjunctive Therapy in Patients With Major Depressive Disorder [RAP-MD-06]. And this is what I had just typed, "But those things aren’t the most alarming piece of this suite of clinical trials. The fourth trial [RAP-MD-4] is a longer term clinical trial looking at relapse prevention…" I was about to talk about the potential harms. They were talking about an extension study where they were giving an intravenous drug weekly that is a kissing cousin to Ketamine, a hallucinogen. They’ve reported that Rapastunel isn’t a hallucinogen based on one published single shot trial. Now they’re going to give it weekly for up to two years as a preventative, but there’s no contingency for any continued monitoring over the long haul. And Flash, there’s appears a safety analysis. Thought broadcasting? I hope not. Anyway, here’s the new study…

which looks for all the world like yet another trial using that same cohort. Is that kosher? Basing multiple trials on a single group of subjects? I guess the right thing to do at this point is to back off until Allergan settles down and lands on a scenario that suits them. Is this their first CNS drug trial? They’re sure making one fine mess of things so far…

So Merry Christmas already!…
Mickey @ 6:00 PM

season’s greetings…

Posted on Sunday 25 December 2016

Mickey @ 12:01 AM

explanation would be welcome…

Posted on Friday 23 December 2016

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.

A properly conducted clinical trial has a number of essential elements related to the efficacy analysis:
  1. Subjects are assigned to the various arms at random.
  2. It is blinded – neither subject nor rater knows the subject’s assigned arm.
  3. The outcome variables [primary and secondary] are declared a priori [before the study begins] as is the plan for later analysis.
Many clinical trials have been misreported in journal articles, and a common modus operandi for distorting the results has been to base the report on the outcome variable that give the most favorable results rather than those declared a priori. Since the pharmaceutical companies that sponsor these trials insist that the raw data is proprietary [a secret], we don’t have the IPD [Individual Participant Data], the CRFs [Clinical Report Forms], the Protocol, or the SAP [Statistical Analysis Plan]. So our only shot at knowing what outcome variables were designated primary and secondary a priori is the registration on ClinicalTrials.gov. And even registration is only useful if it’s before the study starts and the outcome variables are clearly stated.

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]
That’s it for RAP-MD-01, RAP-MD-02, and RAP-MD-03. Bear in mind that this is a medication that’s going to be given weekly intravenously to over 4000 subjects for several years [explained below]. It’s a cousin to Ketamine [Special-K], a drug that people take to hallucinate, certainly not with anything like this kind of chronic frequency. Based on a single one injection proof-of-concept trial, the claim is that it has the antidepressant effect of  Ketamine, but not the club drug effects. But we have no idea if that holds true with long term use. And yet there’s no plan about how harms are to be assessed, no PANSS to look for subtle psychotic symptoms, no global well-being scale, no "self assessment" by the subjects themselves mentioned. Safety should come before efficacy.

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.

In September, the NIH, FDA, ad ClinicalTrials.gov announced their long studied reforms for ClinicalTrials.gov and its place in our clinical trial reporting system [see a blast off… and The Final Rule]. If this is an example of what they had in mind, they failed. To be continued
Mickey @ 9:16 PM

Klerman 1978: schizophrenia…

Posted on Monday 19 December 2016

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.

Although The Evolution of a Scientific Nosology] is a broad commentary about nosology in general, it’s in a book called Schizophrenia: Science and Practice, sandwiched among a number of different perspectives [though it would soon become the dominant point of view]. Here’s what Klerman had to say about Schizophrenia in 1978:
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.
In his introduction to the chapter, Klerman had said of Emil Kraepelin…
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.
and
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.
… capturing the conundrum that continues to haunt these discussions – from among the psychotic cases with no established etiology, Kraepelin was a pioneer for approaching them in terms of causation and etiology. In the snippet from his section Schizophrenia as a Disease quoted above, he lays out a pathway to define such Diseases.

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.

Gerald Klerman and the neoKraepelinians had an unprecedented impact on the subsequent course of psychiatry itself. On the other hand, the plight of the patients with the schizophrenias, particularly those with its chronic forms, have not seen much change in the four decades that followed.
Mickey @ 3:21 PM

Klerman 1978: the critics…

Posted on Saturday 17 December 2016

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

In 1978, criticism of psychiatry was in full bloom. At the radical pole were people like R. D. Laing and Thomas Szasz who questioned whether psychiatry should even exist. In 1974, Thomas Szasz had published The Myth of Mental Illness, asserting that Mental Illness was a made-up construct used to control aberrant behavior eg an agency of the  State. And there were other criticisms to deal with. In the US as opposed to the rest of the world, psychoanalytic training was largely limited to physicians. They were prominent in academic and organized psychiatry, and had exerted a strong influence on the DSM-II classification of non-psychotic mental illness. The criticism from both within psychiatry and at large was that psychoanalytic theory and practice was subjective without an evidence or research base; that precise classification was of little interest with no distinction between normal and abnormal; that psychoanalysts were elitist; and that they were charging long therapies on the walking wounded to medical insurance carriers. All of these criticisms were obviously strong influences on Klerman’s neo-Kraepelinian Credo:
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…
Note: While Adolf Meyer’s thinking had indeed heavily influenced the original DSM [1952], it was the psychoanalytic influence in the DSM-II [1968] that was the target to be supplanted here. Another omitted major player was Mel Sabshin, Director of the American Psychiatric Association from 1974-1997, who initiated and shepherded many of the changes being discussed here. To change sources for just a moment, this is a quote from Dr. Sabshin’s book, Changing American Psychiatry: A Personal Perspective, about the task they had undertaken:
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.
So now back to the Klerman chapter. Klerman is clear on where this was all headed:
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.
This chapter by Gerald Klerman and the release of Robert Spitzer’s DSM-III two years later became the rallying texts of record for the dramatic changes in psychiatry that soon followed. The point of this post is to flesh out some of the criticisms of that time that helped shape what happened and what came to be…
Mickey @ 5:13 PM

Klerman 1978: on the medical model…

Posted on Friday 16 December 2016

Some of Gerald Klerman’s comments from 40  years ago [an interesting read…, Schizophrenia: Science and Practice, Chapter 5: The Evolution of a Scientific Nosology] could’ve been written yesterday, and you wouldn’t see any difference. After reviewing the oft told history of diagnosis and treatment of psychotic illness and discussing the neoKraepelinian Credo, he turns to the medical model:
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.
That is the way it felt in 1978. I’d never even heard the term medical model of disease as an internist – first encountering it as a psychiatry resident as I was being berated by a behaviorist trainee for believing in it. Klerman goes on to say how he understands the term:
[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…
1978 was a very different time from the days of Emil Kraepelin when psychiatry was still associated with the asylum whose population who could be classified by the syndromes he so carefully described. By 1978, there were a treatments for a broad range of behavioral and emotional conditions  that had unclear boundaries and didn’t easily groups treated by psychiatrists, psychoanalysts, psychologists, social workers, etc. Those in non-medical specialties were not reimbursed by medical insurance and were vocal about being excluded. Also, the insurance carriers balked at including these patients in the "sick" role along with those with physical ailments or even the classic psychiatric syndromes. Thus, Klerman’s comments about legitimacy – an issue that was very much on the front burner in those days. Klerman goes on:
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.
The psychiatry of 1978 was also very different from the 2016 version. Psychoanalysts at that time were all physicians and heavily represented in the upper levels of the Departments and Professional Organizations. Schizophrenia was one of the least conflicted areas, but even then, you can see the difference just by looking at the chapter headings of this book.
    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
  5. Bioscientific Research
  6. The Evolution of a Scientific Nosology – Gerald L. Klerman
  7. Biochemical Investigation – Ian Creese and Solomon II. Snyder
  8. Psychopharmacology – Leo Hollister
  9. Care and Treatment: The Human Dimension
  10. The Patient and the Community – Jonathan F. Boras and Elaine Hatow
  11. Psychotherapy – Daniel P. Schwartz
  12. The Surrogate “Family,” an Alternative to Hospitalization – Loren II. Mosher and Alma Z. Menn
And while Klerman’s chapter was about Schizophrenia, it was also about nosology for the whole of mental illness. Reading this section about the medical model, I doubt that many psychiatrists or physicians would disagree with much of it. It certainly fits my understanding [then and now], though it wouldn’t sit well with psychiatry’s critics – then or now. They would argue that to call something a Disease, you needed a known cause and a biomarker. They would likely see his notion of a social construct as a rationalization or worse, and go on to talk about why it’s harmful to think that way. So on to the critics in 1978 in the next post…
Mickey @ 4:31 PM

an interesting read…

Posted on Thursday 15 December 2016

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.

Trust me. It’s an interesting read [11 pages]…
Mickey @ 2:02 PM

blockbuster-in-training addendum…

Posted on Tuesday 13 December 2016

We say that the reason that new drugs are given such a generous period of patent-exclusivity is to compensate the pharmaceutical company for its long and expensive research and development process taken at great risk. But ever since the Bayh-Dole Act of 1980, universities and/or their faculty can be granted unencumbered patents even if federal funding was used for research and development. Naurex was such a company that arose in the university; received grant and venture capital to develop GLYX-13; obtained the drug patent; then sold itself with the patent rights to Allergan for $560 M [well below the estimated cost of developing a new drug from scratch]. Allergan’s task is getting FDA Approval and marketing the drug at today’s inflated prices. In this increasingly common scenario, Allergan is more in the role of being a drug broker than scientific innovator or developer [or even much of a risk taker]. The government [of the people] pays part of the freight, assumes some of the risk, patents and approves the drug, and the costs [including the lobbying expenses] are rolled into the exorbitant price the people [remember them?] pay for the drug.
Mickey @ 7:13 AM

a block-buster-in-training…

Posted on Monday 12 December 2016

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.

A year ago, the American Psychiatric Association Council on Research published a review article with senior author Dr. Charlie Nemeroff:
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.

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].

While there is a gaggle of basic science articles in the literatiure, there are only a few pertinent Clinical Trials registered on ClinicalTrials.gov [none with Results posted]…
…only one of which has been published other that this month’s OCD Letter to the Editor [at least this is the only one I could find]. :
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]
This study was completed in July 2012 but not published until March 2015. A month later, the Nemeroff review article came out, and several months after that, Allergan bought Naurex for $560 M. Their abstract is skimpy on details so I’ve included snippets from the full text. To be honest, the text wasn’t so very forthcoming either. Expected data tables weren’t in attendance – just the graphs:
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…
And this comment from the discussion was perplexing…
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…
…because I couldn’t find any such multiple dose study, either registered on ClinicalTrials.gov or published in PubMed. I’m not saying it doesn’t exist, but it has certainly eluded me [if you know of it, let me know]. This is what they had to say about this trial in Ketamine and Other NMDA Antagonists…:
… 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.
It’s hard for me to believe that Allergan would pay that kind of money based on just one Clinical Trial., but, looking at Clinical Trials.gov, they’ve already registered and started four of their own Phase III Clinical Trials – all focused on Rapastinel as an Adjunctive Therapy in MDD cases:

There are adverse effects with all psychiatric drugs, but we’ve traditionally reserved the more radical empirical treatments for patients who are desperately ill – ECT, antipsychotics, etc. The patients involved in the study reviewed here have a made-up version [Treatment Resistant Depression] of a made-up clinical entity [Major Depressive Disorder].
"Subjects were recruited from investigator practices and via newspaper, radio and Internet advertisements."
They don’t strike me as desperately ill and for that reason, I’ve personally recoiled from the Ketamine fervor altogether. A weekly intravenous injection of a hallucinogenic drug feels like falling prey to therapeutic zeal, one of the traditionally great dangers in medical practice [along with the other head of that dragon – commercial zeal]. But here we are being offered a partial solution to my objection. It’s still an intravenous drug, but at least it’s not heir to Timothy Leary’s fifty year old injunction "turn on, tune in, drop out." GLYX-13 is being advertised as a non-psychedelic version of Ketamine that has its antidepressant properties [they were working on an oral version – NRX-1074 [AGN-241660]. But this blog isn’t really focused on my opinions as an aging psychotherapist [though I certainly have opinions]. It’s about the scientific malfeasance that has bombarded psychiatric medication reporting for the last thirty years. The promise offered by this drug is obvious, but there’s a lot here that deserves a good dose of skepticism…
  • 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].
… for starters. So from where I sit, this one deserves our closest scrutiny all along the way. It’s a block-buster-in-training, and our history with such drugs hasn’t made any of us proud…
Mickey @ 3:17 PM

speaking of bottoms…

Posted on Wednesday 7 December 2016

HealthNewsReview
by Trudy Lieberman
December 6, 2016
hat tip to AA… 
Kaiser Health News
By Sydney Lupkin
November 28, 2016
hat tip to Mark Wilson… 
Excellent summaries of the problem. My commentary to follow.
Mickey @ 9:35 AM