1 Boring Old Man

U. will not support Keller retraction by Sahil Luthra February 3, 2012

The University will not support an effort to retract a controversial study co-authored by Professor of Psychiatry and Human Behavior Martin Keller, wrote Edward Wing, dean of medicine and biological sciences, in a recent letter to the global nonprofit Healthy Skepticism. The study — commonly referred to as Study 329 — identified the drug Paxil as an effective combatant of adolescent depression. Since its publication in 2001, the study has raised concerns due to findings that link Paxil to higher rates of suicidal tendencies.

Citing claims that Keller’s study intentionally misrepresented the effectiveness of Paxil by suppressing data, Healthy Skepticism asked the University to write to the Journal of the American Academy of Child and Adolescent Psychiatry and request a retraction of the findings, The Herald reported in November. Jon Jureidini, a co-author of the Healthy Skepticism letters and a professor at the University of Adelaide in Australia, received Wing’s most recent reply on Monday. In an email to The Herald, Jureidini wrote that Healthy Skepticism would not be discouraged by the University’s response, though he added he was unsure how the group would proceed. "One hopes that universities are leaders in moral and scientific integrity, but how can they expect students to acquire such values when their behavior directly contradicts their stated policies?" wrote Healthy Skepticism co-author Leemon McHenry in an email to The Herald. McHenry is also a researcher, lecturer and part-time professor at California State University in Northridge…

I find this profoundly disappointing. Study 329 is, in and of itself, pretty horrid in its scope, but has further come to be a symbol of academic integrity even beyond its obvious implications in the medical/psychiatric literature – because it is a lie. We all know it is a lie. I wonder if Dean Edward Wing has actually read it, and read the back story as it has emerged – about the ghost-writing, the data manipulation, the money changing hands. One has to ask, how is it to Brown University’s advantage to continue to leave this study "on the books," an embarassment to its students, professors, and Brown’s reputation in perpetuity? There will come a day when Study 329 will be retracted. Why not now? There are no extenuating circumstances for a lie, as this earlier student editorial makes very clear…

Accountable academics September 24, 2008

As students at Brown, we have grown accustomed to having professors and peers illumine our lives with insight and understanding. From the classroom to the gym and from the Ratty to the Main Green, we have all grown intellectually through our interactions with other members of the Brown community. Given the importance of this interaction, we expect professors to enrich our understanding with academic insight supported by unimpeachable scholarship. And we anticipate that our peers will be academically responsible as well. Consequently, it’s troubling to learn that Martin Keller, a professor of psychiatry and human behavior, has been accused of suppressing the link between the antidepressant Paxil and suicidal tendencies among adolescents in a drug study. Moreover, the fact that Keller may have taken money from GlaxoSmithKline, Paxil’s maker, without disclosing the amount is problematic to the Brown community and to the country more generally. While we do not pre-judge the allegations against Keller, we do believe that his actions directly affect the integrity of the University. What we do and who we are as a university is predicated upon an implied social contract of intellectual trust and personal reliability. As students, we expect our professors to act with integrity just as our professors demand that of us. And the obligations we owe to each other extend beyond Brown to the community at large. It is a troubling reality for students to realize that the work of their professors, let alone their peers, may lack integrity. After all, we understandably want our academic experience at Brown to enrich us. So students reject the prospect of anything that might undermine that experience. And they demand the bona fides of the information shared in lectures, seminars and even day-to-day conversation. Indeed, they recognize that the credibility of this information is the currency that underlies all the intellectual exchanges we make. However, as we consider the broader implications of the Keller allegations, we do think it is important to remember that professors are accountable for the honesty of their intellectual work and discourse as well. We suggest an edit to our academic code. The Academic Code as presented on the University’s Web site, states that in the case of "Misrepresentations of facts, significant omissions, or falsifications in any connection with the academic process … students are penalized accordingly." This code should be applied to both professors and students. For insofar as the Brown community is fostered by a direct dialogue between students and faculty, a demand for academic integrity should be imposed on all members of the University.

^{Q. Okay. So this — this notion of the — the cooperation and working together — between the research universities and the public sector?
A. That’s correct.
Q. What did that lead to?
A. And that had been going on, but this was my first kind of injection into dealing with that part of the department. So I went up to the Department of Psychiatry in Dallas, UT Southwestern, and met with Ken Altschuler and John Rush, who were the two people who – Ken Altschuler was the chair of the department at the time and John Rush a researcher there. And we met one afternoon and talked about what kind of projects we might focus on, because one cycle of the projects had come to an end and we were ready to start another cycle. So we kind of narrowed it down to a couple of areas. One was psychosocial interventions and the other was medication interventions. And it was out of that meeting that the decision was made to focus on improving the quality of medication prescribing. And that was one of the things that we had talked about because one of the things that I had seen as medical director in reviewing prescribing in our state, and it was really not different in California, was that prescribing could be fairly erratic. It was not consistent at all. One of the examples I would give as I gave talks is that if you had six people who had the same symptoms, everything was the same, perhaps they were clones and had the same psychiatric disorder, and they walked into six psychiatrists’ offices all lined up, chances were fairly high that they would walk out with six different medication programs.
Q. So this — this issue of the erratic or inconsistent prescribing of medications for mental illness, that’s — that’s the — that’s one of the topics that you discussed at this meeting at UT Southwestern?
A. Yes.
Q. And that was in what year?
A. At that meeting in ’95, ’96…}

^{…When requested, we at times would fund Dr. Shon to share his – his novel concept of TMAP with other states.
Q. And you say his novel concept?
A. I see him as the conductor or creator, main developer of TMAP.
…
Q. What do you recall your initial support being?
A. My recollection was that Dr. Rush said that he was approaching every company I believe for the amount of $75,000.
Q. Well, you knew from Janssen’s perspective that what Janssen was hoping to get from the support of TMAP was favorable Risperdal positioning within the TMAP algorithm; isn’t that right?
A. I think ultimately we supported TMAP because we totally believed in what TMAP stood for. Where — when we agreed to the $75,000, we had no idea where Risperdal or any of the atypicals would end up on the algorithm. But, again, it would only be natural – I work for a for-profit company, that it would be natural that if we had favorable positioning, it would ultimately help sales. But that was not our primary objective in looking at TMAP…}

So Dr. Rush directed the TMAP program, a Depression researcher more involved with the depression algorithm with UT colleague, Dr. Madhukar Trivedi, than the Schizophrenia Algorithm itself [the focus of the Janssen Trial]. Presumably bolstered by his work with the TMAP Algorithms, in 1999 he received an NIMH grant to do the largest clinical trial of a sequenced treatment algorithm for Depression ever done, known as STAR*D, with Dr. Trivedi as his assistant P.I. [a thirty-five million dollar misunderstanding…]. As you can see in the opening graph, Dr. Rush’s publication rate soared during the period of TMAP and STAR*D [including his developing a rating scale (QIDS) specifically for this study].

But then things took a downward turn. Allen Jones filed his lawsuit alleging that Janssen had misbehaved badly in its involvement with TMAP and the State of Texas joined the suit. TMAP itself began to dissemble. The papers generated by STAR*D continued to flow, but the definitive results were not forthcoming. When they were finally published, they were, candidly, a garbled mess. Rush’s QIDS was used rather than the expected primary outcome variables, HAM-D. And while derivative STAR*D papers keep coming, the core findings remain unknown to this day. Rush’s fortune took a further downturn when he was listed by Senator Grassley as one of the psychiatric Key Opinion Leaders with unreported industry income. That year, he left UT and moved to the Duke medical graduate program in Singapore. A later study of his, CO-MED, using multiple antidepressants was a bust – no improvement. TMAP is now a largely forgotten program – except in litigation circles. And the results of STAR*D are still essentially unknown – a $35 M study that produced its own library of articles, but made no contribution to science that I’m aware of.

Dr. Rush has served as an advisor, consultant, or speaker for or received research support from Advanced Neuromodulation Systems, Inc.; Best Practice Project Management, Inc.; Bristol-Myers Squibb Company; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals, Inc.; Gerson Lehman Group; GlaxoSmithKline; Healthcare Technology Systems, Inc.; Jazz Pharmaceuticals; Merck & Co., Inc.; the National Institute of Mental Health; Neuronetics; Ono Pharmaceutical; Organon USA Inc.; Personality Disorder Research Corp.; Pfizer Inc.; the Robert Wood Johnson Foundation; the Stanley Medical Research Institute; the Urban Institute; and Wyeth-Ayerst Laboratories Inc. He has equity holdings in Pfizer Inc and receives royalty/patent income from Guilford Publications and Healthcare Technology Systems, Inc.
Dr. Trivedi has served as an advisor, consultant, or speaker for or received research support from Abbott Laboratories, Inc.; Akzo (Organon Pharmaceuticals Inc.); Bayer; Bristol-Myers Squibb Company; Cephalon, Inc.; Corcept Therapeutics, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica; Johnson & Johnson PRD; Meade Johnson; the National Institute of Mental Health; the National Alliance for Research in Schizophrenia and Depression; Novartis; Parke-Davis Pharmaceuticals, Inc.; Pfizer Inc; Pharmacia & Upjohn; Predix Pharmaceuticals; Sepracor; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories.
Dr. Wisniewski has received research support from the National Institute of Mental Health and served as an advisor/consultant for Cyberonics, Inc.
Dr. Nierenberg has served as an advisor, consultant, or speaker for or received research support from Bristol-Myers Squibb Company; Cederroth; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals Inc.; Genaissance; GlaxoSmithKline; Innapharma; Janssen Pharmaceutica; Lichtwer Pharma; the National Institute of Mental Health; the National Alliance for Research in Schizophrenia and Depression; Neuronetics; Organon, Inc.; Pfizer Inc; Sepracor; Shire; Stanley Foundation; and Wyeth-Ayerst Laboratories.
Dr. Stewart has served as an advisor, consultant, or speaker for or received research support from Eli Lilly & Company; GlaxoSmithKline; Organon USA Inc.; Shire; and Somerset.
Dr. Warden has received research support from the National Institute of Mental Health and has equity holdings in Bristol-Myers Squibb Company and Pfizer, Inc.
Dr. Thase has served as an advisor, consultant, or speaker for AstraZeneca; Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Forest Laboratories, Inc.; GlaxoSmithKline; Janssen Pharmaceutica; Eli Lilly & Company; Novartis; Organon, Inc.; Pfizer Pharmaceutical; Sanofi Aventis; Sepracor, Inc.; Shire US Inc.; and Wyeth Pharmaceuticals.
Dr. Lavori has served as an advisor, consultant, or speaker for or received research support from Bristol-Myers Squibb Company; Celera Diagnostics Inc; Cyberonics, Inc.; the Department of Veterans Affairs; Forest Pharmaceuticals, Inc.; Glaxo-SmithKline; Leaf Cabrezer Hyman and Bernstein; the National Institutes of Health; and Neuronetics, Inc.
Dr. McGrath has served as an advisor, consultant, or speaker for or received research support from Eli Lilly & Company; GlaxoSmithKline; Lipha Pharmaceuticals; the National Institute of Mental Health; the National Institute on Alcohol Abuse and Alcoholism; New York State Department of Mental Hygiene; Organon, Inc.; Research Foundation for Mental Hygiene (New York State); and Somerset Pharmaceuticals.
Dr. Rosenbaum has served as an advisor, consultant, or speaker for or received research support from Astra-Zeneca; Boehringer-Ingelheim; Bristol-Myers Squibb Company; Cephalon; Compellis; Cyberonics; EPIX; Forest; GlaxoSmithKline; Janssen; Lilly; MedAvante; Neuronetics; Novartis; Orexigen; Organon; Pfizer, Inc; Roche Diagnostics; Sanofi; Schwartz; Somaxon; Somerset; Sepracor; Shire; Supernus; and Wyeth. He has equity holdings in Compellis, Medavante, and Somaxon.
Dr. Sackeim has served as an advisor, consultant, or speaker for or received research support from Cyberonics, Inc.; Eli Lilly & Company; Magstim Ltd.; MECTA Corporation; Neurocrine Biosciences Inc.; Neuronetics Inc.; NeuroPace Inc.; and Pfizer Inc.
Dr. Kupfer has served as an advisor, consultant, or speaker for or received research support from Amersham; the Commonwealth of Pennsylvania; Corcept Corporated; Eli Lilly & Company; F. Hoffmann-La Roche Ltd.; Forest Pharmaceuticals; Lundbeck; the National Institute of Mental Health; Novartis; Pfizer, Inc; Servier Amerique; and Solvay/Wyeth. He has equity holdings in Body Media and Med Avante and receives royalty income from Oxford University Press.
Dr. Fava has served as an advisor, consultant, or speaker for or received research support from Abbott Laboratories; Alkermes; Aspect Medical Systems; Astra-Zeneca; Bayer AG; Biovail Pharmaceuticals, Inc.; BrainCells, Inc.; Bristol-Myers Squibb Company; Cephalon; Compellis; Cypress Pharmaceuticals; Dov Pharmaceuticals; Eli Lilly & Company; EPIX Pharmaceuticals; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals Inc.; GlaxoSmithKline; Grunenthal GmBH; J & J Pharmaceuticals; Janssen Pharmaceutica; Jazz Pharmaceuticals; Knoll Pharmaceutical Company; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck; MedAvante, Inc.; Novartis; Nutrition 21; Organon Inc.; PamLab, LLC; Pfizer, Inc; PharmaStar; Pharmavite; Roche; Sanofi/Synthelabo; Sepracor; Solvay Pharmaceuticals, Inc.; Somerset Pharmaceuticals; and Wyeth-Ayerst Laboratories. He has equity holdings in Compellis and MedAvante.
Dr. Niederehe, Dr. Lebowitz, and Mr. Luther report no competing interests.

^{Symptom remission is the desired goal of treatment for depression, given its implications for better daily functioning and better longer-term prognosis. Since no treatment is a panacea, several sequential treatment steps are often needed to obtain remission with a tolerated treatment. If a trial does not result in remission, it is an unsuccessful trial, whether due to lack of efficacy or intolerable side effects, as long as the treatment is vigorously dosed to tolerance and provided for a sufficient duration to achieve remission. The number of treatment steps needed to achieve an adequate benefit is typically used to gauge the degree of treatment resistance, usually with a focus on acute outcomes without reference to longer-term outcomes.}

^{After two treatment steps, it appears that over 50% of patients will achieve remission if they stay in treatment (i.e., 36.8% step 1 plus 30.6% of the remaining 63.2% of patients). Thereafter, the chances of subsequent remission are much lower. The theoretical cumulative remission rate after four acute treatment steps was 67%.}

Dr. Rush and I are within a year in age, and our careers roughly paralleled up until the time when the DSM-III was published and psychiatry changed so dramatically. As much as I’d like to demonize him for falling in with the whole PHARMA-driven deterioration of academic medicine and his participation in shady enterprises like TMAP and STAR*D, I still find myself wondering about his journey through the last twenty-five years in the main stream of modern psychiatry. What the hell happened? He followed every lead along the road of depression research – Cognitive Behavior Therapy, most of the Drugs, the DST and other neurochemistry, the VNS system, ECT, etc, etc. He worked and published with most of the luminaries in the world of academic psychiatry over his career. But what was the point of amassing all of those publications, presentations, etc? How did he end up administering a Public Health program like TMAP that was little more than a tawdry PHARMA scam? Or squeezing that stream of extra articles out of the STAR*D study without ever addressing what the study was about in the first place? Or abruptly heading for Singapore at the end of a thirty year career in Texas when he should’ve been getting a watch at a retirement party? Why did he sign on to the iSPOT study with the likes of Nemeroff and Schlatzberg, chasing the next depression research dead end?

Whistleblower Claims Forest Bribed Study’s Investigator to Favor Celexa
Bloomberg
By John T. Aquino
February 1, 2012

A whistleblower’s complaint from 2011 that was unsealed Jan. 20 in a federal district court alleged that Forest Pharmaceuticals paid the principal investigator of a federally funded antidepressant drug study to fix the results in favor of the company’s drug Celexa [United States ex rel. Pigott v. Forest Pharmaceuticals Inc., D. Md., No. 1:11-cv-00717, unsealed 1/20/12]. The whistleblower litigation was filed in the U.S. District Court for the District of Maryland by H. Edmund Pigott, a psychologist who resides in Clarksville, Md. The alleged False Claims Act violations occurred during the company’s management of the largest antidepressant drug trial ever conducted: the $35 million STAR*D [Sequenced Treatment to Relieve Depression] study, which was funded by the National Institute of Mental Health. The study enrolled 4,041 patients who were provided with 12 months of continuing antidepressant care.

In the article by J. Boren, A. Leventhal, and H.E. Pigott, “Just how effective are antidepressant medications? Results of a major new study,” Journal of Contemporary Psychotherapy, 39 (2), 93-100 [2009], Pigott had alleged there was bias in the STAR*D study in favor of Forest’s drug Celexa. In the litigation, he alleged that the bias was the result of kickbacks, bribes, and other improper financial inducements that were paid by Forest to Dr. John Rush, the principal investigator of the study, and to one or more of the project’s other investigators. The complaint alleged that this conflict of interest not only caused the selection of Celexa as the only antidepressant employed in the first part of the study, but also led to falsification and overstatement of the effectiveness of Celexa in the study’s published result. The end result of the kickbacks and bribes, Pigott claimed, was a significant increase in the sales of Celexa and its second generation version, Lexapro, to patients covered by federal and state health care programs in violation of the FCA, 31 U.S.C. §378, and comparable state statutes, which impose liability on persons and federal contractors who defraud government programs.

According to the complaint, the NIMH initially entered into a contract for the STAR*D study with the University of Texas in September 1999 with Rush as the P.I. Celexa is a selective serotonin reuptake inhibitor or SSRI. SSRIs prevent the body’s reuptake or removal of a naturally-occurring neurotransmitter that it is believed to have a positive impact on mood. STAR*D was designed as a comparative effectiveness study of different treatment options for people with major depression and included 12 pre-specified research outcome measures and a detailed analytical plan for evaluation. According to the complaint, Celexa was selected for the study even though it was the least prescribed of all SSRIs. Pigott argued that the least-prescribed status was either because Celexa was less effective than other SSRIs or had a greater risk continuation syndrome or drug-to-drug reaction. Patients in the study were first given Celexa and, if they failed to get relief from Celexa, they received one of three other antidepressant treatments.

The complaint stated that even after the passage of four years since the publication of STAR*D’s major summary article and the publication of over 70 peer-reviewed articles on the STAR*D findings, none of the articles published by the STAR*D authors have reported the outcomes of any of the 12 pre-specified measures of the study, nor have they reported any findings in a manner consistent with the study’s analytical plan as presented in STAR*D’s research protocol. The authors’ articles also did not discuss the main purpose of the study, which was to evaluate the cost-effectiveness of the various antidepressant treatments, Pigott claimed.

The article for which Pigott was coauthor, the complaint stated, documented that, in contrast to the positive results in STAR*D’s published findings, only 108 of STAR*D’s 4,041 patients [2.7 percent] had an acute-care remission and neither relapsed nor dropped out during the 12 months of continuing care that followed. The article also documented how STAR*D changed its research outcome measures and analyses, which resulted in an inflation of STAR*D’s remission rates by 44.9 percent. The complaint reported that 10 of STAR*D’s authors, including Rush, have disclosed in journal articles that they had received money from Forest and that in the summer of 2008 Rush left the University of Texas, moved to Singapore, and was replaced as the STAR*D P.I.

The complaint stated, “The relator has concluded and therefore alleges that the only reasonable explanation for the false and biased reporting of the study results is that Dr. Rush received significant financial remuneration from Forest that Forest paid to him for the purpose of influencing his actions”…

Hat Tip to AEK… 

In response to a request from Senator Grassley, the Government Accountability Office did a survey [12/01/2011] of the medication of Medicaid covered children with psychotropic drugs in five States [Florida, Texas, Oregon, Michigan, and Massachusetts], separating Foster Children and non-Foster Children:

They also looked at some parameters that would be indicators of irrational medication:

Conclusions:

^{The higher rates of psychotropic drug prescriptions among foster children may be explained by their greater mental health needs and the challenges inherent to the foster care system. However, thousands of foster and nonfoster children in the five states we analyzed were found to have prescriptions that carry potential health risks. While doctors are permitted to prescribe these drugs under current laws, increasing the number of drugs used concurrently and exceeding the maximum recommended dosages for certain psychotropic drugs have been shown to increase the risk of adverse side effects in adults. Prescriptions for infants are also of concern, due to the potential for serious adverse effects even when these drugs are used for non-mental health purposes. Comprehensive oversight programs would help states identify these and other potential health risks and provide caregivers and prescribers with the information necessary to weigh drug risks and benefits. The recently enacted Child and Family Services Improvement and Innovation Act requires states to establish protocols for monitoring psychotropic drugs prescribed to foster children. Under the act, each state is authorized to develop its own monitoring protocols, but HHS-endorsed, nationwide guidelines for consent, oversight, consultation, and information sharing would help states close the oversight gaps we identified and increase protections for this vulnerable population.}
Recommendations for Executive Action:
^{In our draft report, we recommended that the Secretary of HHS evaluate our findings and consider endorsing guidance to state Medicaid and child welfare agencies on best practices for monitoring psychotropic drug prescriptions for foster children, including guidance that addresses, at minimum, informed consent, oversight, consultation, and information sharing. We have received written comments on our draft report from HHS and relevant agencies in 6 states. In written comments, HHS agreed with our recommendation and provided technical comments, which we incorporated as appropriate. In written comments and exit conferences, staff from state Medicaid and foster care agencies provided comments on key facts from the report. Agency comments will be incorporated and addressed in a written report that will be issued in December 2011.}

But it’s the APA response that bugs me [below]. This statement, "New research on alleged overuse of psychotropic medications in both nursing-home and foster-care settings signals a need for better training of nonpsychiatric physicians and increased funding to bolster the mental health workforce" puts the blame on others. I expect that there’s plenty of blame to go around but that we psychiatrists and child psychiatrists own a significant share in our own right. And I didn’t care much for this one either, "While APA acknowledged in its statement in conjunction with the Senate hearing that children in foster-care systems experience high rates of mental illness, it voiced support for the GAO’s recommendation that HHS issue formal guidance to state Medicaid and child-welfare agencies on best practices for monitoring the prescription of psychotropic medications for foster children." Medicine has been traditionally self regulating. I don’t hear the APA’s response as having any acknowledgement of that function. It’s a politically correct response with all the forcefulness of a feather.

The problem here is not that people need just "formal guidance to state Medicaid and child-welfare agencies on best practices for monitoring the prescription of psychotropic medications for foster children." What’s needed is active censure of these practices with consequences from the APA on its members, the Certification Boards on their practitioners, and Licensing Boards on licensed physicians. Chronic, unjustified, overmedication of children is malpractice, not ignorance of guidelines. And, by the way, what is the APA for if not to set the tone for rational practice? If the APA doesn’t do it, sooner or later someone else will [and actually should]. There is outrageous information in this report that needs to be dealt with…

APA Responds to Reports on Antipsychotic Prescribing
^{APA cites a need to use practice guidelines when prescribing antipsychotics in nursing homes and foster-care facilities.}
Psychiatric News
by Jonathan Wolfe
January 6, 2012

New research on alleged overuse of psychotropic medications in both nursing-home and foster-care settings signals a need for better training of nonpsychiatric physicians and increased funding to bolster the mental health workforce, stated APA in recently submitted congressional testimony. On November 30, 2011, the Senate Special Committee on Aging held a hearing exploring an audit issued earlier in the year by the Department of Health and Human Services’ (HHS) Office of Inspector General (OIG). The report found that 14 percent of nursing-home residents were prescribed an atypical antipsychotic during the first six months of 2007. One day later, the Senate Homeland Security and Government Affairs’ Subcommittee on Federal Financial Management, Government Information, Federal Services, and International Security heard testimony from the Government Accountability Office (GAO) that foster children are prescribed psychotropic drugs at a significantly higher rate than children not in foster care.

Conducted at the request of Sen. Charles Grassley (R-Iowa), the OIG’s report evaluated the extent to which nursing-home residents over age 65 receive atypical antipsychotics, as well as the cost to Medicare associated with these prescribing practices. Grassley had voiced concern about prescription of these drugs for off-label conditions and/or in the presence of dementia…

Are Foster Children Overmedicated?
On another issue related to concerns about use of antipsychotics, the GAO in recent congressional testimony compared the number of foster children being prescribed psychotropic medications in 2008 with the rate of prescriptions for nonfoster children and examined state oversight of psychotropic prescriptions for foster children through October 2011. While APA acknowledged in its statement in conjunction with the Senate hearing that children in foster-care systems experience high rates of mental illness, it voiced support for the GAO’s recommendation that HHS issue formal guidance to state Medicaid and child-welfare agencies on best practices for monitoring the prescription of psychotropic medications for foster children.

“APA strongly believes psychotropic medications must be prescribed only when appropriately deemed necessary, and must form part of a larger customized treatment plan that includes both psychopharmacologic and psychosocial interventions,” Scully said in his testimony.

 

This introduces a gigantic topic, polarizing at first breath, the source of a divisiveness that reaches into antiquity – what to do about Schizophrenia. But first, are these drugs efficacious? Are these drugs safe?

FDA Medical Review
FDA Letter of Approval
Clinical Trials

FDA Medical Review
FDA Letter of Approval
Clinical Trials

When it comes to the question of the psychotic Schizophrenic person, one has to always question whether you are doing something for the patient, with the patient, or to the patient. And often times, the patient himself isn’t much help, particularly under the sway of active hallucinations or compelling delusions. This is not, to me, something to be considered in a general way sitting in an armchair in your study. It’s something that has to be dealt with in proximity to the patient in question. Most people go through life neither experiencing nor being around active psychosis, and so thinking about the topic is uninformed by the disease in question – and in its more florid form, it’s a show-stopper. I remember my early days in psychiatry training in Grady Hospital in Atlanta. I thought of it as "Fort Apache, the Bronx" the name of a contemporary television show. On call at night, first he elevator bell would sound, and here would come a family or the police with some out of control, delusional person fighting and screaming. The staff who had been there for decades would settle things down, then I was supposed to do something definitive – like make a diagnosis, decide on a course of action, maybe sign commitment papers to force hospitalization. No matter what I did, somebody didn’t like it – the patient, the family, the police, the ward staff, sometimes even me.

After a time, it became easier, or at least clearer. The criteria were simple. Was the person mentally ill? yes/no. Was the person immediately dangerous to himself or other people?  yes/no. That decision was going to be reviewed on the next day by someone higher up, and in a few days by a judge. I could answer those questions and didn’t have to deal with the fact that I was depriving a person of their civil liberties without due process of law for a day. I didn’t like doing it. Was I doing something for the patient, with the patient, or to the patient? In those days, there was Dr. Thomas Szasz and a host of antipsychiatrists who said I was being an agent of the State, not a doctor. And on those long nights, it seemed like I was always riding against the waves. If I thought the patient needed hospitalization, they didn’t agree. If I thought the patient didn’t need to be hospitalized, they wanted in. The on-call room was next to the nursing station with a window overlooking I-75/85. On several of those nights, I dreamed that it was falling off of the building and smashing onto the highway – a testimony to both what it’s like to be around that many psychotic people and my own wish to escape.

In the scope of things, those decisions that felt so cataclysmic in those early days were really not a problem for me. I could see that I was doing something for the patients after all. For one thing, they continued to be my patients and when they got better, we got on just fine. And I knew that had I seen them thirty years earlier, they would’ve ended up in Central State Hospital where way too many might have spent the majority of their lives suffering the kind of deterioration I read about in the older psychiatry texts and occasionally saw. I could see with my own eyes that the acute treatment of florid psychosis with neuroleptic medication was doing something for the patient. And even though I never particularly liked being in the situation of signing those papers, I came to agree that better someone like me than someone who didn’t know this strange illness called Schizophrenia inside and out [though I'll admit to heavy reliance on the staff who had been there forever and just "knew" what to do].

But I never got there with the treatment of Chronic Schizophrenia. Schizophrenic patients are notoriously "non-compliant" in taking medication long term. There are plenty of reasons. The side effects or just how the stuff makes you feel is a rational reason. The medicine may ablate psychotic symptoms, but it doesn’t do much for the anhedonia [lack of pleasurable feelings] or other "negative" symptoms. But there are plenty of other reasons, like being controlled, poisoned, etc. And you don’t have to be around too long to realize that the florid symptoms have a positive "feel." A delusion explains the confusing world. Or as a patient once said, "You want to hear my voices? They keep me from feeling lonely out there on the road." So the treatment of acute psychosis had turned a chronic progressive illness for many into an illness where the psychotic symptoms remit, then return with another psychotic episode. And there’s little question that staying on medication lowers the frequency of relapses. And as the literature review here [RISPERDAL® CONSTA®] says, being on depot medication lowers the recurrence rate even more than counting on the patients to take it themselves. I expect that’s true. But I’m not sure we have the right to push constant medication. The courts don’t think so either.

So enter stage left, Janssen Pharmaceuticals who is offering to teach doctors how the be compliant with the injunction to keep people on medication by getting the patients to be on Long Acting Injectable Therapy [VITAL™], and thereby get the Schizophrenic Patients to be more compliant. They’ve even put together a program to make it easier for patients [Janssen® Connect™ Launches In California].

Of course INVEGA® SUSTENNA® is a patent extender. Of course Janssen® Connect™ and VITAL™ are attempts to sell more drugs. That goes without saying. That’s their right. It’s what Janssen does. But there are other considerations. Even if neuroleptics were completely benign, I’m not sure I’d agree with "forcing the issue" of medication. Maybe people with Schizophrenia need a fling with psychosis every once and a while as relief from the blandness of their experience otherwise, who knows? I sure don’t, but I don’t have to think about such questions because neuroleptics [no matter what generation] are not benign. That part is clear as a bell. So if you are a Chronic Schizophrenic, is the injunction to always be on medication something that is being done for you, with you, or to you? I can think of only a few situations where it’s that clear that it’s  for you. And, by the way, these two drugs are targeted towards the Public Mental Health systems where most Schizophrenic patients receive treatment. There, it’s only clear that it’s good for the bean counters who do cost accounting in public medicine. Keep them on meds, lower hospital costs.

I just sat through a trial in Texas about a company named Janssen Pharmaceuticals who took a drug called Risperdal that by all rights was only indicated in Adult Schizophrenia and turned it into a blockbuster yielding $30+ billion in profit by invading Public Health Systems and Child Psychiatry [even though there were essentially no FDA approvals for children] using methods that were criminal – jury-rigged guidelines, hired KOLs, off label promotion by Sales Reps. Now, I’m reading about a company called Janssen with a drug called something very like Risperdal [9-hydroxy-risperidone] that is only for a few people in Public Health Systems who have an uncommon illness [Schizophrenia] – a company who is off and running with a new, peculiar marketing campaign. I find that disturbing. I can see them pitching this stuff to Formulary Administrators and Public System upper eschelon. Steven Shon has already given it a shot with RISPERDAL® CONSTA® in the TMAP guidelines. I can see this being touted to people treating Foster kids and other kids. I called my last post déjà vu because it reminded me of the 1970s, but I’m also having TMAP déjà vu because it reminded me of the very recent weeks as well.

Janssen® Connect™ Launches In California
^{New Service Helps Practitioners Coordinate Care for Patients Receiving Company’s Long-Acting Injectable Therapies}

Titusville, NJ (January 31, 2011) – Janssen®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., announced today the launch in California of Janssen® Connect™, a new service for psychiatrists and other healthcare professionals and their patients who have been prescribed a Janssen® long-acting injectable atypical antipsychotic medicine. These medicines are INVEGA® SUSTENNA® (paliperidone palmitate), for the treatment of schizophrenia, and RISPERDAL® CONSTA® (risperidone), for the treatment of schizophrenia and longer-term treatment of Bipolar I Disorder.

Janssen® Connect™ is a service designed to help make it easier for patients to access Janssen® long-acting injectable therapies. Janssen® partners with treatment teams that request to be a part of the program and works directly with them to provide their patients with support and resources, including: alternate injection sites of care, such as pharmacies; trained healthcare professionals to provide injections; facilities that may be more conveniently located for patients; access and reimbursement services; appointment reminders; and scheduling of future injection appointments.

“We are pleased to offer this program to prescribers and patients, as part of our long-standing commitment to people with mental illness,” said Denice Torres, president of Janssen®.

The move from an inpatient to an outpatient setting may be complicated for some people with mental illness, and this transition is critical to the process of recovery. Janssen® Connect™ assists with this transition by keeping inpatient and outpatient healthcare professionals and planners informed about timing of injections, doses of medication, adverse events or patient concerns. Healthcare professionals also will be notified if a patient has missed an appointment or was not given medication for any reason, which can help identify situations in which a physician may need to intervene.

Janssen® Connect™ reimbursement-support services and care-coordination services are provided as a service by Proherant Health Inc., under contract for Janssen®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. These support services are made available as a convenience to patients, and no additional compensation is required from or paid to patients or prescribers. Proherant Health, Inc. and other providers are responsible for the services they provide.

Incidence of extrapyramidal symptoms and tardive dyskinesia in schizophrenia: thirty-six-month results from the European schizophrenia outpatient health outcomes study.
^{Lilly Research Centre, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.}

by Novick D, Haro JM, Bertsch J, and Haddad PM.

Journal of Clinical Psychopharmacology. 2010 30(5):531-40.

^{The incidence of treatment-emergent extrapyramidal symptoms (EPSs) and tardive dyskinesia (TD) in schizophrenic patients, and the clinical characteristics associated with an increased risk of developing EPSs and TD were examined. Patients (N = 7728) in the 3-year, prospective, observational Schizophrenia Outpatient Health Outcomes study were examined according to baseline antipsychotic drug exposure. At baseline, 4893 patients (63.3%) had no EPS, and 6921 (89.6%) had no TD. Extrapyramidal symptoms and TD were assessed separately during follow-up: frequency and time to appearance from Kaplan-Meier survival curves and factors associated with time to appearance using Cox proportional hazard regression models. The cumulative incidence of EPS ranged from 7.7% (olanzapine) to 32.8% (depot typical drugs). Compared with olanzapine, patients taking depot typical drugs, oral typical drugs, risperidone, and amisulpride had a significantly higher risk of developing EPS. Differences from clozapine were marginally significant. High baseline clinical severity was associated with a significantly higher risk of developing EPS. The incidence of TD ranged from 2.8% (olanzapine) to 11.1% (depot typical agent). Compared with olanzapine, patients taking depot typical agents, oral typical agents, and risperidone had a significantly higher risk of developing TD. Baseline factors associated with a significantly higher risk of developing TD were age, EPS, a higher negative Clinical Global Impression score, and presence of gynecomastia. In summary, patients treated with typical antipsychotic agents (oral and depot) and risperidone had a higher risk of developing EPS and TD than patients treated with olanzapine. Higher baseline clinical severity was associated with EPS development, whereas age, presence of EPS, a higher negative Clinical Global Impression score, and presence of gynecomastia were associated with TD development.}

^{From Eli Lilly and Company, Windlesham, Surrey, United Kingdom; †Departament de Psiquiatrı´a, Universitat Auto`noma de Barcelona, Spain; ‡Sant Joan de De´u-SSM, CIBERSAM; §Sant Joan de De´u-SSM, Fundacio Sant Joan de De´u, Sant Boi, Barcelona, Spain; and ||Greater Manchester West Mental Health NHS Foundation Trust and University of Manchester, Manchester, United Kingdom.
Received September 14, 2009; accepted after revision July 9, 2010.
Reprints: Diego Novick, MD, Lilly Research Centre, Eli Lilly and Company,
Erl Wood Manor, Sunninghill Rd, Windlesham, Surrey, GU20 6PH, United Kingdom
The Schizophrenia Outpatient Health Outcomes study was funded by Eli Lilly and Company.
Copyright * 2010 by Lippincott Williams & Wilkins}

^{AUTHOR DISCLOSURE INFORMATION
Diego Novick is a Lilly employee. Josep Maria Haro has acted as a consultant, received grants, or acted as a speaker in activities sponsored by the following companies: AstraZeneca, Eli Lilly, GlaxoSmithKline, and Lundbeck. Jordan Bertsch was a statistical consultant for the SOHO study. Peter M. Haddad received honoraria for lecturing and consultancy from the manufacturers of several antipsychotic agents including AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen-Cilag.}

Admittedly this is an Eli Lilly funded and conducted study, but I have no reason to doubt their Tardive Dyskinesia findings. It’s that faint yellow line at the bottom that caught my attention [I wasn't in love with those blue and gray lines either]:

It makes perfect intuitive sense that the constant exposure to a neuroleptic afforded by LAT [Long Acting Therapy][Depot] would be more likely to cause neurological complications – and that does seem to be the case. On might extrapolate this data for Risperdal in Depot form or imagine what weight gain and metabolic effects one might see with these preparations [INVEGA® SUSTENNA® (paliperidone palmitate) and RISPERDAL® CONSTA® (risperidone)].

I want to linger for a moment on that ad [“no is the beginning of yes”…]. It’s not an ad for their products [INVEGA® SUSTENNA® and RISPERDAL® CONSTA®]. It’s not even an ad for the services in that announcement up there [Janssen® Connect™]. It’s an ad for ways a doctor can get patients to use their products. In the third video [Importance of the Therapeutic Alliance], we’re told how to get to know our patients, gain their trust, then use it to "guide the patient" into using these injectables – "use the therapeutic alliance" they say. They even quote an APA blurb about the Therapeutic Alliance [see top graphic]. If I may allow my inner analyst to speak, that really pisses me off. The concept of the Therapeutic Alliance was Freud’s, though it was named later by Edward Bibbering. It is an alliance between the patient’s healthy ego and the analyst against the destructive forces in the patient’s mind. It is not make friends with the patients so they’ll trust you and do what you want them to do. And speaking of trust, why does the psychiatrist want the patient to use Long Acting Therapy? It’s because the psychiatrist doesn’t trust the patient to take the medication. Freud’s and Bibbering’s Therapeutic Alliance is built on mutual trust, hard earned. Janssen’s Therapeutic Alliance is a con job. So Janssen’s marketing target is psychiatrists, not patients – in fact, it’s doctors who see their task as keeping Schizophrenic patients medicated by making friendly [and apparently need to be taught how to do that].

But there’s more. What are [INVEGA® SUSTENNA® (paliperidone palmitate) and RISPERDAL® CONSTA® (risperidone)]? Why were they approved?

APA Should Delay Publication Of DSM-5
Pschiatric Times
By Allen Frances, MD
January 31, 2012

^{My three criticisms of DSM-5 have been:}

1. risky suggestions;
2. bad writing;
3. poor planning and disorganization.

^{I have pretty much failed to have any real impact other than perhaps getting APA to delay publication from May 2012 to May 2013. The one-year extension was wasted, the risky suggestions and bad writing remain, and my constant warnings that missed deadlines would lead to a mad and careless race at the end were ignored. With less than a year remaining before DSM-5 is scheduled to go to print, the signs are clear that it cannot possibly be completed on time unless we are willing to settle for a third rate product. The unmistakable red flag is the recent embarrassing admission that DSM-5 will accept diagnoses that achieve reliabilities as unbelievably low as 0.2-0.4 [barely beating the level of chance agreement two monkeys could achieve throwing darts at a diagnostic board]. This dramatic departure from the much higher standards of previous DSM’s is a sure tip-off that many DSM-5 proposals must be failing to achieve adequate diagnostic agreement in the much delayed and yet to be reported field trials. Unable to meet expected standards, the DSM-5 Task Force is drastically and desperately trying to lower our expectations…}

^{The wise, safe, and responsible thing for APA to do now is to delay publication of DSM-5 until the missing second stage of rewriting and retesting can be completed. The wordings that do poorly in the first stage of field testing should be rewritten to finally attain the clarity and consistency necessary in an official manual of psychiatric diagnosis. The newly revised (and hopefully final) versions should then undergo the second stage of field testing as originally envisaged to ensure that they now work. The extra time will also allow for the independent scientific reviews of controversial DSM-5 proposals called for in a petition that has already been signed by more than 11,000 mental health professionals and is endorsed by 40 professional organizations (including many divisions of the American Psychological Association, the American Counseling Association, and the British Psychological Society)…}

^{… The May 2013 publication date appears to be completely unrealistic unless we are to settle for a DSM-5 so poorly done that its reliabilities will return us to the dark ages of DSM II. DSM-5 is in a very deep hole with very few remaining options. My recommendations:}

1. Make the publication date flexible and contingent on delivery of a quality product that the field can trust;
2. Subject the current drafts and texts to extensive editing for clarity and consistency;
3. Drop the controversial suggestions that risk harmful unintended consequences or at least subject them to external scientific review;
4. Have the rewritten drafts reviewed word for word by many experts in the clinical, research, and forensic uses of DSM-5;
5. Field test again to make sure the new versions work adequately.

^{One last point. Many critics use the obvious failures of DSM-5 as justification to attack psychiatry as a whole. I strongly disagree. DSM-5 is no more than an unfortunate aberration reflecting the temporary state of weak and misguided APA leadership. The work on DSM-5 went off track because of unrealizable ambitions; a closed and secretive process; and insufficient attention to the day to day details of prudent planning, efficient organization, and careful writing. Because of its poor performance on DSM-5, APA has probably forfeited its right to sole control of future revisions. But all this represents only the specific failure of DSM-5, not a general reflection on what psychiatry is and what it can accomplish. Done well and within its reasonable limits, psychiatry is an extremely helpful, indeed essential profession. It would be a shame to throw the valuable baby out with the bath water or discourage patients from getting the psychiatric help they need and can benefit from. Admittedly, DSM-5 is an embarrassment and a serious hit to our credibility, but we will recover and our patients should not lose faith.}

I worked in the clinics today. In the morning, I saw adults – a lot of them. I had three patients where the central issue was unrecognized anti-depressant withdrawal syndromes. I had three patients who’d been told to they were "bipolar" [who weren't]. I had a patient who had been labeled a drug seeking "character disorder." He was, instead, a 49 year old guy who had been thrown through a car window in a wreck at age six, been in a coma for six months, been passed through the seventh grade in Special Education [social promotion], and could sort of read using his finger, one word at a time [all the short words]. He’s never worked ["can't be still"] and lives with aging parents worrying about what he’ll do when they are gone. Given the scrambled brain he lives with, I thought he was doing the best he could. It was that kind of morning – frustrations. In the afternoon, I was at a children’s clinic – doing ADHD med checks, arguing with Medicaid providers, the stuff of modern medicine that I do as a volunteer [but wouldn't do if paid]. My last patient was an adult, a woman with persistent PTSD from a terrible event eight years ago that involved the death of her son. The tension of undoing bad diagnoses and bad treatments all day just disappeared as I talked to this woman about her illness, something I know about. I felt like a doctor instead of someone putting out brush fires, a case-worker in a social agency, or a med-check doctor. As one of my patients once quipped, "I felt my efficacy."

On the way home, I was thinking about why I’m at volunteer clinics in my retirement doing things I refused to have anything to do with as a practitioner – talking to some young guy working for Medicaid Managed Care getting "pre-cert" for medication, calling Social Security Disability about Mr. non-character-disorder’s real diagnosis, talking to a special ed teacher about a school plan for a teenager with a crippling social phobia who was in trouble for truancy [rather than being "served" by the school system]. It’s not that such things aren’t needed – the need is yawning. But why me? There are several reasons I do it. One is if I don’t, it won’t get done. But another is that there’s never a clinic day when I don’t see one or more people who help me remember why I did this in the first place – like the lady with PTSD. And there’s never a day when I don’t see some case that’s being mis-managed or mis-diagnosed, and I can get things on a better track. But an important side effect is that these clinic days are an antidote to reading and writing in this blog about the DSM-5 Task Force, or the Pharmaceutical intrusions into academia, or the "weak and misguided APA leadership", or the overvaluing of some dreamed-of future for "clinical neuroscience", or the insightful but painful truths in Dr. Healy’s Pharmageddon.

Balancing Immediate Needs with Future Innovation
NIMH Director’s Blog
by Thomas Insel
January 26, 2012

NIMH, like all Institutes at NIH, has an advisory council that meets three times each year. The National Advisory Mental Health Council [NAMHC] is a distinguished group of scientists, advocates, clinicians, and policy experts. Each of our meetings includes a closed session to review individual grants considered for funding and a session open to the public that engages this diverse group in discussions about the larger issues that guide NIMH funding.

At last week’s session, we heard a recurrent tension around one such larger issue. Some members of Council bear witness to the poor quality of care, the unmet medical need, and the diminishing investments by states on behalf of people with mental disorders. They reasonably ask, “How are we ensuring that the science that NIMH has produced is implemented where the need is greatest?” They also question on the pay-off of genetics research. After all, two decades after the gene for Huntington’s disease was identified, we still have no effective treatments, and Huntington’s disease is genetically far simpler than schizophrenia or bipolar disorder. In contrast to so many neurological diseases, we have effective treatments for schizophrenia and bipolar disorder. NIMH should be investing to ensure these are available.

The opposing argument runs something like this. There has been no major innovation in therapeutics for most mental disorders since 1960. Current treatments are not good enough for too many. Rather than investing scarce dollars for incremental improvements or increased dissemination of mediocre interventions, we need invest in the fundamental science of brain and behavior so that we can understand how to develop better treatments.

While I may have oversimplified the two sides of this debate, the divide is substantial. Some advisors want more funds in services research; other advisors want more funds in basic neuroscience. Some are thinking of the immediate needs; others are focused on the paradigm shifts that may be revealed by another decade of research. And with the NIMH budget stretched, tough choices must be made…