1 Boring Old Man

With the American Academy of Child and Adolescent Psychiatry meeting in San Diego right now, I’m having something of a remembrance of things past period. Of course there’s Paxil Study 329 which stands in my mind as a paradigm for an infamous era, along with a other less well known Clinical Trials suggesting that the SSRIs are effective and safe in the treatment of adolescent depression [ie more Wagner et al…]. It remains a major unresolved question in my mind why the Journal of the American Academy of Child and Adolescent Psychiatry is still unwilling to retract Paxil® Study 329, or for that matter, why the American Journal of Psychiatry didn’t [and still doesn’t] retract Wagner et al’s ghost written Citalopram [Celexa®] paper [collusion with fiction…]. And I continue to wonder why journals still publish the stream of papers attempting to discredit the Black Box Warning on these drugs about the uncommon but potentially fatal suicidality that the drugs sometimes cause [a betrayal…]. It’s like the ripples from that period when the pharmaceutical industry, complicit psychiatrists, and journals were publishing fiction-as-fact under the cover of darkness won’t die out.

There was one issue from that period that remains very sticky – Pediatric Bipolar Disorder. It’s sticky because the patients in question really exist, and the medications in question really work, and the treatment questions are really tricky for anyone who actually sees these cases. And whether these cases represent a distinct group or not is, itself, an open question in my mind. To use Dr. Joseph Biederman’s term, they are children with super angry, grouchy, cranky, irritability. They drive parents, teachers, siblings, psychiatrists, therapists, and themselves crazy. They usually have the clinical findings of ADHD [with a capital H] but there’s no cure with stimulants, and if you give them antipsychotics, they do become more manageable – but... These are among the kids that get drugged, often in response to pleas by parents, caretakers, psychologists, social workers, teachers, etc. – the exasperated people who deal with them. I’ll skip the many diagnoses invented for this maybe-group, except for one – Pediatric Bipolar Disorder.

When Risperda® was introduced, it came with a study of behavioral treatment for retarded children that was, of course, positive [genuinely positive] [see trial 93: a bad penny…]. Janssen’s application for FDA Approval was turned down. When Dr. Biederman began to say that these kids with super angry, grouchy, cranky, irritability had Pediatric Bipolar Disorder, this study was republished and repurposed under Dr. Biederman’s name [Risperidone for the treatment of affective symptoms in children with disruptive behavior disorder: a post hoc analysis of data from a 6-week, multicenter, randomized, double-blind, parallel-arm study] and the rest is history. Pediatric Bipolar Disorder took off like wildfire and the papers flowed from everywhere [I called it Biedermania].

I’ve reviewed all of this ad nauseum. And I ended up wondering if Pediatric Bipolar Disorder even exists, or if it does, thinking it’s uncommon. In my opinion, the reason Pediatric Bipolar Disorder caught on was that Child Psychiatrists and Pediatricians who were seeing these extremely difficult kids were previously guiltily treating them with antipsychotics for behavior control [unable to place them in the tough love token economy environments of the past], and that the diagnosis of a disease treated with a medicine for that disease took away the guilt. I was volunteering in a child clinic for a time, and I ultimately quit working there because of this very issue. The pressure to medicate with antipsychotics was overwhelming because there were no rational alternatives, and that’s just not my cup of tea. It’s simply a do no harm thing for me. But I felt some empathy for my colleagues who were and are in that double bind, and couldn’t just say, "No thanks."

1. Institute 1: An Update in Advanced Psychopharmacology for Practitioners
2. Institute 6: Early Recognition and Intervention for Youth at High Risk for Bipolar Disorder
3. Institute 9: Fundamentals of Practical Pediatric Psychopharmacology for the Primary Care Clinician
4. Symposium 9: Prodromal Symptoms in Bipolar Offspring: Cross-National Comparisons
5. Symposium 15: Psychosocial Treatment for Youth With Bipolar Disorder: Research Updates to Inform Clinical Practice
6. Symposium 23: Neural Markers of Risk and Resilience in Bipolar Disorde
7. Symposium 44: International Perspectives on Pediatric Bipolar Disorder: Is Research Leading to More Standardized Practice?
8. Genetics of Early Onset Bipolar Disorder: A Preliminary Analysis From the Treatment of Early Age Mania [TEAM] Study and Mayo Clinic Bipolar Bank

I wish I knew the contents of numbers 1 and 3, just wondering what they’re saying about Pediatric Bipolar Disorder and the use of the SSRIs in depressed adolescents. But that roster is not intended to be an indictment of the AACAP. Compared to my remembrance of things past, it’s a remarkable improvement. Even the topics are more benign and rational. But they’re all ripples nevertheless. It’s time for the ripples from that time in our history to stop…

Senate Lawmaker Eyes Hearing on the Cost of Hepatitis C Treatments

Pharmalot: WSJ

By Ed Silverman

October 20, 2013

Responding to the ongoing controversy over the prices for new hepatitis C treatments, U.S. Sen. Bernard Sanders [I-Vt.] will probably hold a hearing – possibly before the year ends – to examine how the cost is affecting the U.S. Department of Veterans Affairs, according to his spokesman. Sanders is chairman of the Senate Committee on Veterans’ Affairs.

His interest in a hearing comes as the expense of these medicines helps fuel a national debate over the rising cost of prescription drugs. New hepatitis C treatments, in particular, have caused a ruckus, because they promise cure rates exceeding 90%, which is prompting a sudden surge in prescribing – and subsequent concerns over the effect on insurance budgets. For the past several months, pharmacy benefit managers and state Medicaid programs have complained that the cost of Sovaldi, a treatment sold by Gilead Sciences, may become unsustainable. Sovaldi costs $1,000 a pill, or $84,000, for a 12- week regimen. Gilead maintains the treatment is a cheaper alternative to older forms of care that may be less successful and involve costly hospitalization.

Federal programs may feel the pinch, as well. A recent forecast from the Veterans Department indicated that Sovaldi will cost the department about $1.3 billion over the next two years. And that’s after a discount the VA receives that brings the cost per pill down to about $543, according to department documents provided earlier this year to the U.S. Senate Committee on Veterans’ Affairs. A Veterans Affairs spokeswoman writes us that the department added Sovaldi to its national formulary, or list of drugs for which coverage is provided, last March. As of October 1, more than 5,300 veterans have received treatment with Sovaldi, she writes, adding that about 225 patients are started on the treatment each week.

And so, Sanders “is interested [in holding a hearing,] among other reasons, because of the impact on the VA,” his spokesman tells us. The timing for a hearing, however, remains uncertain. The spokesman says a hearing may occur following the upcoming midterm elections on Nov. 4, “but it’s really up in the air.” This is not the first time Congress has responded to concerns over the cost of hepatitis C medicines. Last July, two members of the U.S. Senate Finance Committee asked Gilead to provide financial information about the $11 billion deal in which it acquired the treatment, R&D costs and subsequent pricing forecasts. A committee spokesman tells us the probe remains under way, but could not offer an update.

We asked Gilead, which has more recently received FDA approval to sell a newer, fixed-dose combination treatment called Harvoni that includes Sovaldi and another compound, for comment and will update you accordingly. [UPDATE: A A Gilead spokeswoman later sent us this note: "We are not aware of a hearing but we are cooperating with the Committee and responding to their questions."] This is the second time in recent weeks that Sanders has indicated concerns about prescription drug costs. Earlier this month, he was one of two members of Congress who launched an investigation into generic drugs and asked 14 drug makers to provide data on what was called the “escalating prices they have been charging” for some medicines.

Finding Middle Ground Between Psychiatry and Anti-Psychiatry

Mental health civil wars leave patients in desperate lurch

Psychology Today: Saving Normal

by Allen J. Frances, M.D.

October 20, 2014

[full text on-line]

Pipeline and Innovation for Psychotropic Drugs Are Limited, Study Finds

PsychiatricNews

October 17, 2014

As development of drugs to treat psychiatric disorders lags behind that of drugs for other illnesses, a recent study published in Psychiatric Services in Advance sheds light on why the pipeline for psychotropic medicines is nearly empty.

Researchers from Brandeis University and Truven Health Analytics led an investigation of the current state of psychotropic drugs in the pipeline and potential barriers that may keep these drugs from reaching distribution in the United States… The analysis showed that the pipeline for psychotropic drug development — 99 clinical trials were included — is limited, with little product innovation evident. Most of the examined drugs were a combination of existing of U.S. Food and Drug Administration-approved medicines or individually approved medicines that were being tested for new indications or delivery-system approaches [such as an injectable version that is similar to an approved oral form]. Only three drugs differed substantially from existing drugs…

In an interview with Psychiatric News, Alan Schatzberg, M.D., a professor of psychiatry at Stanford University and former APA president, said that the departure by pharmaceutical companies to develop innovative psychotropic medicines could result in serious problems for the field of psychiatry, especially for patients. “There is a number of initiatives by various organizations to help with this problem, including the European College of Neuropsychopharmacology, which is working with companies to provide investigators with compounds that have been shelved, and NIMH’s Research Domain Criteria [RDoC], which promotes research on specific [and new] biological targets," he said. Schatzberg emphasized that it will take a concerted effort on the parts of governmental agencies, industry, as well as APA to advocate for investment and innovative psychiatric drug development. “Silence will not be helpful to our patients,” he concluded…

Re-engineering Translational Sciences
• NIH Chemical Genomics Center
• Repurposing Drugs
• Tissue Chip for Drug Screening
• Extracellular RNA Communication
• Identifying and Validating Drug Targets
• Toxicology in the 21st Century
• Illuminating the Druggable Genome
Strategic Alliances for Technology Transfer

Med Check

NIH Initiates Program to Find Potential Drug Targets

PsychiatricNews

by Vabren Watts

October 17, 2014

According to the National Institutes of Health [NIH], as many as 3,000 genes express proteins whose molecular actions could be altered by medicines, yet only 10 percent of these “druggable genes” are targeted by drugs that have been approved by the Food and Drug Administration [FDA].

The NIH recently announced the launch of Illuminating the Druggable Genome [IDG], a three-year pilot project to explore poorly understood genes that have the potential to be modified by medicines. The IDG will target understudied genes of four important protein families that may be affected by medications — nuclear receptors, ion channels, protein kinases, and G-protein coupled receptors.

“We have a gap in the drug-development pipeline between what gene activities we know could be modified by medication and what currently is targeted,” said James Anderson, M.D., Ph.D., director of the NIH Division of Program Coordination, Planning, and Strategic Initiatives. “By focusing on understudied genes, we hope to find potential targets for medications to treat or cure some of our most burdensome diseases — and then share what we learn so that all can build on this knowledge.”

Primary funding for pilot awards is coming from the NIH Common Fund, which supports high-impact pioneering research in all divisions of NIH. Institutions granted awards will thoroughly investigate potential gene targets and share what they learn on a public resource that will help the larger scientific community build on the findings through basic research and clinical translation.

Illuminating the Druggable Genome

Results from the Human Genome Project revealed that the human genome contains 20,000 to 25,000 genes. A gene contains [encodes] the information that each cell uses to make [express] a protein, which is essential for the body to function properly. Abnormal protein expression is associated with many human diseases, which makes proteins key targets for therapeutic agents…

Approximately 3,000 genes are considered part of the “druggable genome”, a set of genes encoding proteins that scientists can or predict they can modulate using experimental small molecule compounds. Yet, only about 10 percent of these genes encode proteins that have been targeted successfully by an approved drug. Therefore, a large number of proteins remain for scientists to explore as potential therapeutic targets. The vast majority of the druggable genome encodes four key protein families: G-protein-coupled receptors, nuclear receptors, ion channels and kinases…

By expanding the potential therapeutic space through the IDG program, NIH is clearing a path for more efficient disease-related research and more effective treatments for patients.

I did notice along the way that the last new better drug became the next old obsolete drug with some regularity. And with that came the illusion that the drugs were improving [I would now see it as more determined by patent life and advertising]. And in those salad days, psychiatry had developed a sizable commentator class – a group of academics who commented on the drugs, talked about what was coming next, wrote about the neurobiology of this or the psychobiology of that regularly. In my mind, I called it future-think, with the good stuff always lying just around the corner, but it never occurred to me that a house of cards might tumble if the march of the new ever came to an end. So now we’re illuminating the druggable genome, repurposing existing drugs, building neuro-chips for in vitro assays, and revising diagnoses to fit drug effects [RDoC] in an attempt to revitalize the previous flow of new treatments.

There was another quote in that article about the 2012 Pipeline Summit that has also stayed with me:

I thought that was an incredibly naive comment. One could say that about a million things in medicine. The comment implies that "if you need it, it will come". Most scientific discovery doesn’t work that way. It’s closer to, "don’t push the river, it runs by itself." There are places where mounting a huge effort in science speeds up the process, but those are areas where there’s a clear direction, and the task is working out the practical details [Manhattan Project, NASA, Salk Vaccine, DARPA, etc]. Their quest for genuinely new psychopharmacology starts from near zero. And the pharmaceutical industry has a tremendous interest; has been at it for years; and just couldn’t find a thread to pull that lead them anywhere. So whether you agree that new symptomatic CNS drugs are a critical national priority or not, the likelihood of locating them [if they indeed exist] may not be enhanced by NCATS, the RDoC, or any other directed research under NIH/NIMH martial law. In fact, this forced march might squeeze out the guy who would notice something odd on a dirty petri dish [Alexander Fleming Discovers Penicillin].

"We look forward to welcoming you to sunny San Diego for AACAP’s 61st Annual Meeting!

Gabrielle Carlson, MD, AACAP’s Program Chair, welcomes you to San Diego from the USS Midway, the site of the Welcome Reception on Wednesday, October 22. All are invited to attend!"

In the spirited video from the deck of the USS Midway, Gabrielle Carlson sporting a sailor’s cap, welcomes us to the AACAP Annual Meeting, ending with the words, "Get here however you can!" You may not recognize her name right off. Here’s a reminder:

The Dramatic Rise in Neuroleptic Use In Children:
Why Do We Do It and What Does It Buy Us?
Theories from Inpatient Data 1988-2010

by Gabrielle A. Carlson, MD

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY 2013 23[3]:144-147.

[full text on-line]

…It is ironic that the most noxious and impairing behavior, namely explosive outbursts in children, has no ‘‘home’’ in the DSM no- sology. Recognizing that explosions can occur in many conditions, neither intermittent explosive disorder nor, if it is accepted into DSM-V, DMDD, allows the diagnosis if the explosions are ‘‘better explained by’’ another condition. There is not even a consistent way in which one can find information about rage outbursts. In PubMed, there are almost completely different databases for terms like rages, rage outbursts, anger outbursts, rage attacks, explosive outbursts, and meltdowns. Irritability, the term that seems increasingly to be adopted, like aggression, may sub- sume these behaviors, but is not synonymous. Therefore, we speculate that the behavior that most drives the most use of AAPs does not even have a label that can be consistently used, and will certainly, without a "home," never be an indication for FDA approval….

In conclusion, the meteoric rise in the use of AAPs in children with ADHD and ODD reflects the fact that the traditional evidence-based treatments (stimulants and parent training/behavior modification) are either unsupported by providers and insurance (at least in terms of the intensity they require) or that these treatments are insufficient, because of the severity of the conditions being treated.

AAPs may be expensive, and clearly have important adverse effects. The question is whether society (and insurance companies) want to support the alternatives. If they do not, I feel that the rhetoric is disingenuous. I, for one, would be grateful if the AAPs could compensate for what we have lost in terms of other treatments, and were as powerful as the media imply.

However, I not only think that haunting these authors is justified, but is actually an imperative. Twenty of the twenty-two authors of Study 329 are still alive, six are in significant leadership positions in the American Academy of Child and Adolescent Psychiatry, and others dot the by-lines of other ghost-written industry-funded experimercials like this one. Gabrielle Carlson is AACAP’s Program Chair welcoming the attendees to the meeting. It is likely that many of the named authors were on the by-line of that article only because they were site primary investigators for the clinical trial itself and little involved in the writing or the extensive data manipulation involved in creating this masterpiece of deceit – now a monument to an era yet to be fully acknowledged.

In the case of Dr. Carlson, Stony Brook was in the group of sites added to Paxil Study 329 late because of slow recruitment and accounted for only 11 subjects in the trial. She’s not mentioned in any of the subpoenaed documents that I know of. Apparently it was simply a source of revenue for Stony Book, and another paper to add to her CV. But that’s the whole point. Other than the two SKB/GSK employees who directed the show creating the paper with ghost-writer Sally Laden, the actual non-involvement was true for the twenty academic authors whose names were on that author‘s list. They lent their academic credentials and the reputations of their institutions to the paper, a ticket insuring that it would be accepted in a prestigious journal and read by colleagues who respected those honorifics, without really participating in its creation. But even worse, in the decade during which the paper has been universally vilified, not one of those authors has come forward and said a word. They continue to occupy high places, adding an obvious irony to Carlson’s comment, "Get here however you can!"

Sure, Managed Care bureaucrats have pushed atypical antipsychotics over more intensive and expensive interventions [keeping the cost of medical care down]. Of course the Pharmaceutical Industry has promoted antidepressant medications for treatment of adolescent depression [in the business of selling FDA approved drugs]. Yes the professional organizations have created guidelines that recommend these practices [evidence-based medicine from peer-reviewed journals]. But without those names on the by-line certifying the articles, the papers wouldn’t have been published that allowed those things to happen. And when the authors sit in silence in their own careers even after it becomes clear, as in this case, that they lent their names, positions, and institutions to a fictional publication, they are the main force in the center of perpetuating what’s wrong.

Black Box Warning Should Remain on Chantix®: Panel

WebMD

October 17, 2014

A black box warning about suicide risks should remain on the anti-smoking drug Chantix® until it can be reevaluated using findings from thorough scientific studies, a U.S. Food and Drug Administration panel of experts said Thursday. Chantix® has carried the FDA’s strongest warning label since 2009 after it was linked to violent or suicidal behavior among some patients taking the drug.

Pfizer asked the FDA to drop the boxed warning, citing recent studies suggesting that patients taking Chantix® were not at increased risk for psychiatric problems, the Associated Press reported. However, the 11-member FDA advisory panel voted to retain the black box warning on Chantix®. One member voting in favor of removing the warning and six favored slight changes to the label. The FDA does not have to follow the advice of its expert panels, but typically does.

Pfizer Loses a Bet on Removing Serious Warnings From its Chantix® Pill

Pharmalot

by Ed Silverman

October 17, 2014

…
“I think Pfizer took quite a chance trying to get the box deleted. They obviously wouldn’t have done it if they thought they could convince people, but they failed completely,” says Diana Zuckerman, the president of the National Center for Health Research, a non-profit advocacy group.

“They had the best presentation money could buy – very good analyses and complicated statistics to prove their point. And the company trotted out these studies and tried to make a very strong case for why the Black Box should be deleted, but only one person voted their way."

“Pfizer took a big chance, but I think they did so because they were afraid the next study wouldn’t be so favorable and maybe they could get rid of the Black Box warning now. Remember, if it were removed, it would be hard to get it reinstated later, even if a post-marketing study showed risk.”

Pfizer is not flinching. “The completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication,” says Steven Romano, a Pfizer senior VP who heads the medicines development group.

But there’s something else to say. Pfizer’s sales of Chantix® are down. They obviously think it has something to do with the Black Box warning in the labeling. So they are spending tons of money trying to get the label removed – thinking more patients will "ask their doctor if…" and that more doctors will not be afraid to prescribe it. It’s a sign of their inflated sense that they can influence and control the world if they just play their cards right. It doesn’t occur to them that maybe their sales are down because Chantix® is only for the hardy. If you’ve prescribed it yourself, you know that it does exactly what that Black Box label says it does, and maybe more often than the label suggests. They can’t change that with a label eraser or even a piece of Robert Gibbons statistical sleight of hand [see way past time…].

I know I sometimes get kind of hung up on numbers, and it just happened. I was looking at Wagner et al in the last post because it was ghost-written, but I did read the abstract and something stuck with me. It’s highlighted in red below, "[effect size=2.9]". The effect size is a measure of the strength of an effect and is the simplest of calculations: it’s the difference in the means of the two groups divided by the standard deviation. Besides being an index of the strength of an effect, it also normalizes things so different studies can be compared. The usual range is 0.25 = weak, 0.50 = moderate, and 0.75 = strong. So what’s with effect size=2.9? It doesn’t make any sense. So I went back and pulled the whole paper to calculate it myself. Curious George, I guess…

A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents.

by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE.

American Journal of Psychiatry. 2004 161[6]:1079-1083.

OBJECTIVE: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric patients with major depression.

METHOD: An 8-week, randomized, double-blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children [ages 7-11] and adolescents [ages 12-17] with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Patients [N=174] were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children’s Depression Rating Scale-Revised; the response criterion was defined as a score of < 28.

RESULTS: The overall mean citalopram dose was approximately 24 mg/day. Mean Children’s Depression Rating Scale-Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study [effect size=2.9]. The difference in response rate at week 8 between placebo [24%] and citalopram [36%] also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups [5.9% versus 5.6%, respectively]. Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.

CONCLUSIONS: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.

… Mean Children’s Depression Rating Scale Revised scores at baseline were 58.8 [SD=10.9] and 57.8 [SD=11.1] in the citalopram and placebo groups, respectively, indicative of moderately severe illness.

• Child psychopharmacology, effect sizes, and the big bang. [Am J Psychiatry. 2005]
• Child psychopharmacology, effect sizes, and the big bang. [Am J Psychiatry. 2005]
• Child psychopharmacology, effect sizes, and the big bang. [Am J Psychiatry. 2005]

Dr. Martin and colleagues inquire about the value of 2.9, which was calculated as the quotient of the least square mean, divided by the common standard error of the mean for each treatment group. With Cohen’s method, the effect size was 0.32.

… Citalopram treatment showed statistically significant improvement compared with placebo on the Children’s Depression Rating Scale — Revised as early as week 1 [F=6.58, df=l,150, p<0.05], which persisted throughout the study. At week 8, the effect size on the primary outcome measure, Children’s Depression Rating Scale-Revised [last observation carried forward], was 2.9. Additionally, at endpoint more citalopram-treated patients [36%] met the prospectively defined criterion for response than did placebo-treated patients [24%], a difference that was statistically significant [x²=4.178, df=l, p<0.05]. The proportion of patients with a CGI improvement rating <2 at week 8 was 47% for the citalopram group and 45% for the placebo group [last observation carried forward values]. For the CGI severity rating, baseline values were 4.4 for the citalopram group and 4.3 for the placebo group, and endpoint values [last observation carried forward] were 3.1 for the citalopram group and 3.3 for the placebo group.

We believe that the results of our study, which demonstrated a significant difference between citalopram and placebo beginning at week 1, is clinically meaningful, particularly at a time when there have been so few antidepressants shown to have superiority to placebo for depressed children.

That final comment is pretty bizarre, given that by the time it was written, Dr. Wagner herself had authored three previous articles claiming the effectiveness of SSRIs in youth [collusion with fiction…].

How was that for a wild goose chase? Actually, I kind of enjoyed it. I had originally just looked at the graph in Wagner et all and assumed it was a positive study. Coming back to it after seeing that [effect size=2.9] value and realizing how shaky it really was was a good reminder that with these clinical trials, "all that glitters is not gold." It was only a positive study by the letter of the law, not by direct observation [CGI].

A Review of Escitalopram and Citalopram in Child and Adolescent Depression

by Carlo Carandang, Rekha Jabbal, Angela MacBride, and Dean Elbe

Journal of the Canadian Academy of Child and Adolescent Psychiatry. 2011 20[4]: 315–324.

[full text on-line]

FDA Approval Process & Legal Action
While only one RCT for escitalopram was statistically superior to placebo on the primary outcome measure, according to Forest Laboratories, Inc. [US manufacturer of Lexapro] the FDA decision to approve escitalopram was based on two RCTs – the escitalopram RCT with positive results and an earlier trial with citalopram. “Escitalopram is the only active enantiomer of the racemic drug citalopram, so we considered it reasonable to [deem] the positive citalopram study along with the positive escitalopram study as sufficient evidence to support the approval,” said Karen Mahoney, an FDA spokesperson. A 2002 application for a pediatric indication for citalopram had previously been rejected by the FDA, and the US patent for citalopram expired in 2003.

The FDA approval decision for escitalopram came shortly after filing of a federal civil suit alleging Forest Laboratories, Inc. had illegally marketed escitalopram and citalopram for off-label use in children and adolescents from 1998 to 2005. The suit also alleged the company suppressed publication of a negative citalopram trial, and reports of increased suicidality in pediatric patients. This lawsuit was joined with another lawsuit regarding another Forest Laboratories, Inc. product levothyroxine, and was eventually settled in September 2010 for the sum of $149 million.

The citalopram trial [Wagner et al., 2004] that formed part of the basis for escitalopram FDA approval was alleged to have been written and submitted by a medical “ghost-writer” on behalf of Forest Laboratories, Inc. In April 2009, one month after the FDA approval for escitalopram in adolescents was granted, Forest Laboratories, Inc. admitted that a medical communications company, Prescott Medical Communications Group was not acknowledged as a contributor to the article at the time of publication. This practice is not allowed by the American Journal of Psychiatry, and an editor’s note regarding correction of this matter was published in August 2009…

At this point, I will admit that I had lost interest in my initial quest [FDA Approval of Celexa/Lexapro] because I’d run across something that was far more interesting. So let’s start over. The new topic is the 2009 Editor’s Note in the American Journal of Psychiatry about their earlier 2004 article on Celexa:

I’d never seen this before. It’s like a picture window into how much competition there was for the adolescent depression market, and how corrupt the whole enterprise had become. While we can respect Editor Robert Freedman for publishing this Editor’s Note, his certification of authorship is, of course, a sham – as is Dr. Wagner’s claim that she knew nothing of the ghost authoring. In the first place, the paper was presented to her already drafted. Whether it was written by Forest senior study director Dr. William Heydorn or someone else, it certainly wasn’t Wagner’s or her co-investigator’s work. And since she was in the author role in multiple other ghost-written trial reports at that time, her claim of naïveté about hired professional writers holds no water. She was everywhere in those days – Paxil, Prozac, Zoloft, Celexa – an author on each of these of ghost-written journal articles – all four claiming efficacy and safety in depressed adolescents for their respective drug:

• 2001: Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial. "Paroxetine is generally well tolerated and effective for major depression in adolescents."
  by Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, and McCafferty JP
• 2002: Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial. "Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression."
  by Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, and Jacobson JG
• 2003: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. "…sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD."
  by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
• 2004: A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. "…treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated."
  by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, and Heydorn WE

• 2006: ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth.
by Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D, and Wagner KD

A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. The manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

As for the specific suit that brought this particular bit of ghost-writing into the public eye? The case against Forest Laboratories ultimately settled [see September 15, 2010: Drug Maker Forest Pleads Guilty: Will Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations]. But even in this instance where the ghost-writing was exposed and admitted, the American Journal of Psychiatry, official journal of the American Psychiatric Association, chose to collude with the fiction that the academics on the by-line were genuine authors, and the journal left the study in place.

The American Psychiatric Association seems to be poised to engineer yet another identity shift in psychiatry [the prequel…, anything but over…, the sequel I…], apparently intending to proceed without acknowledging the misadventures of the last makeover, without participating in the reform efforts like Data Transparency or revised Conflict of Interest policies, without correcting or at least flagging the large fiction sections of our journal libraries. The American Academy of Child and Adolescent Psychiatry meeting in San Diego next week appears to be moving along the same silent path. Beside the obvious moral and ethical tangles involved, it seems to me that there’s an enduring liability being assumed by the professional organizations, the academic community, and our peer reviewed journals when they incorporate this attitude of denial and rationalization. The active participants in the deceit and corruption that accompanied the industrial invasion of academic and organized psychiatry actually represented only a segment of psychiatrists, albeit a segment in high places. Many of their names are already on this page, most are cataloged throughout this blog. And while too many in the specialty followed their lead, it was also the only major highway open to traffic, and it’s easy to forget how little many of us knew of this before the last six or seven years. That’s not intended as an excuse, but rather a commentary on the state of play.

Prozac Is No Magic Pill, but It Works

New York Times

by Robert Gibbons and J. John Mann

October 7, 2014

The changes in treatment and attitude brought on by Prozac prompted two colliding points of view. One was that antidepressants were overprescribed and people were encouraged to turn to a pill to solve all their problems. Another viewpoint was that major depression was one of the most debilitating illnesses in the world and was mostly untreated or undertreated, and even though we were now prescribing a lot of antidepressants there were still too many people with moderate to severe depression that remained untreated.

A third claim intruded into this debate, namely that the efficacy of antidepressant medications is overstated and the best evidence of effectiveness was in only the most severely ill patients. In an effort to shed light on this question, we obtained much of the world’s complete longitudinal data on randomized controlled trials of the antidepressants fluoxetine [Prozac] and venlafaxine [Effexor] in depressed patients conducted by Lilly, Wyeth and the National Institute of Mental Health. We included studies regardless of whether they demonstrated the medications were effective in order to get the clearest picture possible of the efficacy of these widely used antidepressants.

From the statistical model that synthesized these data across all studies separately for each age category, we computed estimated response and remission rates. We found an improvement in depression regardless of age in both medications relative to a placebo pill. Interestingly, the greatest benefit in terms of response and remission rates was seen in children, followed by adults, and then by more modest effects in the elderly. There was no evidence that severity of depression made a difference to how well the antidepressant medication worked. Based on these findings we concluded that antidepressants work across the lifespan, in patients with moderate or severe depression.

Antidepressant treatment and suicide attempts and self-inflicted injury in children and adolescents

by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA

Pharmacoepidemiologic Drug Safety. 2014 Sep 29. doi: 10.1002/pds.3713. [Epub ahead of print]

PURPOSE: In the 2004, FDA placed a black box warning on antidepressants for risk of suicidal thoughts and behavior in children and adolescents. The purpose of this paper is to examine the risk of suicide attempt and self-inflicted injury in depressed children ages 5-17 treated with antidepressants in two large observational datasets taking account time-varying confounding.

METHODS: We analyzed two large US medical claims databases (MarketScan and LifeLink) containing 221,028 youth (ages 5-17) with new episodes of depression, with and without antidepressant treatment during the period of 2004-2009. Subjects were followed for up to 180 days. Marginal structural models were used to adjust for time-dependent confounding.

RESULTS: For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses. Marginal structural models revealed that the majority of the association is produced by dynamic confounding in the treatment selection process; estimated odds ratios were close to 1.0 consistent with the unadjusted and simple covariate adjusted association being a product of chance alone.

CONCLUSIONS: Our analysis suggests antidepressant treatment selection is a product of both static and dynamic patient characteristics. Lack of adjustment for treatment selection based on dynamic patient characteristics can lead to the appearance of an association between antidepressant treatment and suicide attempts and self-inflicted injury among youths in unadjusted and simple covariate adjusted analyses. Marginal structural models can be used to adjust for static and dynamic treatment selection processes such as that likely encountered in observational studies of associations between antidepressant treatment selection, suicide and related behaviors in youth.

1. There is no strong evidence that SSRIs are even effective in adolescent depression. Only Prozac was approved, and that was early on before these questions were raised. So the notion that effective treatment is being withheld is unsubstantiatable.
2. This syndrome is not common, but once you see it, you have no question of causality [at least I didn’t]. It’s not a population study thing, it’s a case report thing. And there are plenty of cases of completed suicides among those reports. I don’t even treat adolescents, but I personally know of several such cases. The cases are substantiatable.
   

"For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses."

Impact of publicity concerning pediatric suicidality data on physician practice patterns in the United States.

by Nemeroff CB, Kalali A, Keller MB, Charney DS, Lenderts SE, Cascade EF, Stephenson H, and Schatzberg AF.

Archives of General Psychiatry. 2007 64[4]:466-72.

News coverage of FDA warnings on pediatric antidepressant use and suicidality

by Barry CL and Busch SH.

Pediatrics. 2010 125[1]:88-95.

[full text online]

• PHARMA: Depressed adolescents are common – a lucrative market for the sale of antidepressants.
• PHARMA: The suicidality Adverse Event was downplayed in the original reports – a litigation liability.
• Managed Care: The cost of delivering care other than drugs to depressed teens would be expensive.
• Psychiatry: The KOL psychiatrists have based their reason d’etre on the effectiveness of the SSRI drugs, talking about ‘depression’ as if it’s a ‘disease entity’ and the SSRIs as the ‘treatment’ for that ‘disease entity’. They essentially define psychiatry by this disease/treatment dyad. 

The top graph tells the story. The relative cost of medical care in the United States has doubled [since the days I first heard of Managed Care around the late 1970s]. And the reasons are obvious everywhere you turn. Fee churning Emergency Rooms in for-profit Hospital Corporation owned facilities; Direct-to-Consumer ads increasing drug sales six-fold; inflated guidelines fueling unnecessary testing and treatment; controlling Managed Care monitors demanding evidence of efficacy but giving no evidence of their own [efficacy]; abusive pharmaceutical advertising and pricing; the constant whirr of the MRI machines in the background pouring out normal studies. The sick and those of us who treat them are a captive audience with no clear alternatives in sight. We’ve been an easy mark for decades. And it’s as if there’s an inertia from a more benevolent time, memories of a different ethic – something that keeps us naive about the impact that the business·i·fi·ca·tion of medicine has had on our lives and our healthcare. And speaking of evidence, the bottom graph is one of the many that make the same indictment – it hasn’t been worth it.

It’s funny, the cynicism in that last two paragraphs is evanescent. I can get to feeling it in spades, work myself up into a righteous froth – and then watch it evaporate within minutes. It happened today. I hadn’t worked in a couple of weeks – weddings, funerals, other things – but when I went to the clinic today, the cynical gloom lifted and I had fun. Maybe that’s not the right word. I got into the problems that came my way and did what I’ve learned to do. Some might say I wrote too many prescriptions. Others might say I didn’t write near enough. Some would say I didn’t need all those years of training to do what I actually spent my time doing today. Since I don’t get paid, it would be hard to say I didn’t earn my keep. My point is that I felt none of that uncomfortable cynicism I can feel at other times. The Licensed Professional Counselor I worked with and I saw several cases together we pass back and forth in our version of Collaborative Care, the same with the Internist and the Nurse Practitioner.