Tag Archives: antipsychotics

CAFÉ Study: Real Science or Marketing Exercise?

BACKGROUND

On December 8,  I received the following question from a reader:  (The subject matter is the controversial CAFÉ – Comparisons of Atypicals in First Episode of Psychosis – study.  This was the study in which Dan Markingson committed suicide.)

“It appears that there was no head-to-head with a control group taking a placebo pill. Nor was there a control group featuring ‘old’ types of ‘antipsychotic’. If that was the case then it is very poor study. If you are just looking at 3 ‘new’ subtypes of a ‘new’ class – then what on earth can you hope to show from the data.”

I started to write a response, but the subject is complex, and my response became the following article.

******************************

Any discussion of CAFÉ must begin with a review of CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness).

CATIE was a randomized trial funded by the US government (NIMH).  It was written up in three phases:  Phase 1 (Lieberman J et al, 2005); Phase 2 Part a (McEvoy JP et al, 2006) and Phase 2 Part b (Stroup TS et al, 2006);  and CATIE Phase 3 (Stroup TS et al, 2009).  CATIE’s purpose was to compare old neuroleptics with new neuroleptics.  There was no placebo.  This reflected the belief/assumption that the efficacy of neuroleptics generally had already been established.  The researchers compared the old drug perphenazine with the second generation neuroleptics olanzapine, quetiapine, risperidone, and ziprasidone.  The conclusion:

“Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone.  Olanzapine was associated with greater weight gain and increases in measurers of glucose and lipid metabolism.” (Phase 1, p 1209)

So, a kind of mixed result; but notice that quetiapine was shown to be no better than the old drug.

In CATIE phase 2, clozapine was introduced.  One of the findings was:

“At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine.” ( Part a, p 600)

and

“…risperidone and olanzapine were more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation for any reason.” (Part b, p 611)

Again, a mixed result.  Clozapine is most effective but known to have even more serious adverse effects than other neuroleptics.  But notice again that quetiapine isn’t looking too good.

CATIE also had a placebo-controlled arm that addressed the use of neuroleptics in “treating” aggression and agitation in patients with Alzheimer’s Disease (CATIE-AD, Schenider et al 2006).  Even here, quetiapine didn’t do so well.  It had the lowest “improvement” rate, though the differences were not statistically significant.  The researchers also noted that:

“Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.” (p 1525)

It was also found in CATIE Phase 1 that the individuals who had received quetiapine had the highest rate of hospitalization during the study.  The comparative figures were:

Olanzapine –    11%
Quetiapine –    20%
Risperidone –   15%
Perphenazine – 16%
Ziprasidone –   18%
(Table 3, p 1220)

These differences were statistically significant at the 0.001 level (i.e. there’s less than one chance in a thousand that the differences could have occurred by chance).

CAFÉ

Which brings us to CAFÉ, a multi-site study of neuroleptic treatment of first episode psychosis, funded by AstraZeneca, manufacturer of quetiapine (Seroquel).  CAFÉ was written up in two parts in the American Journal of Psychiatry.  CAFÉ has been criticized as little more than a marketing ploy by AstraZeneca to rescue their baby from the CATIE fall-out.

There were two main hypotheses:

“…that quetiapine was not inferior to olanzapine or risperidone in the rate of all cause treatment discontinuation in early psychosis patients.” (p 1050)

and

“…that the three agents would be equivalent in their effects on various neurocognitive measures.” (p 1061)

The researchers concluded:

“Olanzapine, quetiapine, and risperidone demonstrated comparable effectiveness in early-psychosis patients, as indicated by similar rates of all-cause treatment discontinuation.” (p 1050)

and

“Olanzapine, quetiapine, and risperidone all produced significant improvement in neurocognition in early-psychosis patients.  Although cognitive improvements were modest, their clinical importance was suggested by relationships with improvements in functional outcome.” (p 1061)

So, quetiapine is just as good, as measured by rates of treatment discontinuation, in early stage psychosis as the other second-generation neuroleptics.  The rate of treatment discontinuation, however, is a fairly minimal outcome criterion.  The usual rationale for using it in these kinds of studies is the assumption that it is inevitably associated with poor outcome generally.  This assumption has been critiqued widely in recent years, but is still generally accepted by psychiatrists.

But the most serious critique launched against CAFÉ is that the researchers administered the rival drugs at reduced dosages.  Olanzapine and risperidone were administered at about 60% of the CATIE dose, while quetiapine was administered at about 90% of the CATIE dose.  Here’s what the researchers wrote:

“Previous studies suggesting that first-episode patients receive therapeutic benefit from antipsychotic doses lower than those required for chronic patients and that first-episode patients develop unnecessary extrapyramidal side effects at higher doses led us to use lower dose ranges of olanzapine and risperidone in this study than those used in the Clinical Antipsychotic Trials of Intervention effectiveness (CATIE). However, given quetiapine’s low extrapyramidal side effects liability, we expected that the quetiapine doses used in CATIE would be tolerable in our study population.” (p 1058)

This seems questionable.  Neuroleptics, at least initially, reduce agitated thoughts and behavior.  And the higher the dose, the greater the “improvement.”  The authors themselves acknowledged this interpretation:

“This may have been a factor in the comparable effectiveness demonstrated by quetiapine.  In the CATIE phase 1 and phase 2 schizophrenia trials…higher mean modal doses of olanzapine and risperidone but similar mean modal doses of quetiapine were used; in these trials, olanzapine and less consistently risperidone proved to be more effective than quetiapine.  It remains an empirical question whether higher doses will improve the relative effectiveness of quetiapine in chronic patients.” (p 1058)

But this is buried in the text of a 20-page article.  As mentioned earlier, the article is written up in two parts in the American Journal of Psychiatry, 2007 (p 1050-1060 and p 1060-1071).  The above quotes appear on page 1058, but are not reflected in the conclusions.

The authors’ assertion of “low extrapyramidal side effect liability” for quetiapine is also of interest.  Firstly, they cite no reference in support of this assertion.  Secondly, CATIE had reported the following percentages for extrapyramidal effects: olanzapine 2%; quetiapine 3%; risperidone 3%; ziprasidone 4%.  The actual numbers are too small to draw firm conclusions, but there is nothing to suggest that quetiapine has a particularly low liability.

Another item of interest that was buried in the text, but did not appear in the conclusions, was:

“A total of 18 serious adverse events occurred, four in the olanzapine group and seven each in the quetiapine and risperidone groups.  These events included two suicide attempts and one alleged homicide in the olanzapine group, two completed suicides and one case of suicidal ideation in the quetiapine group, and one suicide attempt in the risperidone group.” (p 1057)

Further indications of the researchers’ agenda are suggested by the following quote:

“Our findings in this study suggest that the effect of quetiapine on cognition may be as beneficial as that of olanzapine or risperidone, and thus this agent may be another evidenced-based alternative for clinicians who focus on cognitive outcomes. (p 1069)

Even one of the primary conclusions was tenuous.  In the second part of the write-up, as mentioned earlier, the authors had concluded:

“Olanzapine, quetiapine and risperidone all produced significant improvements in neurocognition in early-psychosis patients.” (p 1061)

Buried in the text, however, on page 1069-1070, they wrote:

“In this study, patients with early psychosis who demonstrated cognitive improvement at 52 weeks also demonstrated functional benefit in social and occupational domains, which suggests a functional relevance for cognitive improvement.  One caveat to this promising conclusion is that given the high dropout rate in this study, these data apply only to the patients who were able to stay in treatment and complete comprehensive assessments for 52 weeks, a group that comprised only 20% of the original sample.” [emphasis added]

MEASURES OF EFFECTIVENESS

As mentioned earlier, the outcome criteria that were highlighted in the conclusions sections of the two papers were:  rate of treatment discontinuation and improvements in neurocognition.

However, various other items were assessed during CAFÉ that might usefully have been included in the papers’ conclusions.  In fact, the authors stated:

“Efficacy was measured in two domains:  1) psychopathology and 2) social and occupational functioning.  Psychopathology was assessed by the PANSS, the CGI, and the Calgary Depression Scale for Schizophrenia….  Social and occupational functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale….” (p 1053)

Measurements on these scales were taken before the study began, and at 12 and 52 weeks.  The results are presented in Table 2 (p 1052).    (Click on the image below to see the full-size table.)  This is a rather complex table, and comparisons across the three drugs are not easy.  For this reason, I restructured and graphed the data below.

Table 2 from CAFE Study

 

 

 

 

In Table 2, an improvement in some of the scales is indicated by a negative number, in other scales by a positive number.  For ease of comparison, I eliminated the signs and focused only on the magnitude of change from the baseline value.  In each graph the direction upwards on the page indicates more improvement from baseline.  As can be readily seen, the level of improvement with quetiapine is lower (at both 12 and 52 weeks) than with olanzapine or risperidone in 6 of the 7 scales.  This difference is marginal in the CGI Severity Scale, and only reached statistical significance with the PANSS positive symptoms scores (and this was mentioned in the abstract), but the fact that quetiapine fared worse on 6 of the 7 variables seems noteworthy.

This is especially true in that the six scales addressed here are precisely the measures that would be of particular interest in the assessment of treatment effectiveness for psychotic thoughts/behaviors.  In fact, CATIE used the PANSS positive and negative scales to assess effectiveness.  Since the entire purpose of the study was to compare the relative effectiveness  of these drugs, it’s difficult to find a valid reason for not presenting the relative effectiveness data more clearly

[visualizer id=”3797″]

[visualizer id=”3792″]

[visualizer id=”3800″]

[visualizer id=”3801″]

[visualizer id=”3802″]

[visualizer id=”3803″]

[visualizer id=”3804″]

DISCUSSION

The big question is:  was CAFÉ a piece of genuine scientific research; or was it a marketing exercise bought and paid for by AstraZeneca in an attempt to rehabilitate their drug quetiapine (Seroquel)?  Obviously arguments can be made on both sides, but here are two factors that may have some bearing.

1.  AstraZeneca funded the study.

2.  There were a total of twelve authors listed on the two write-ups.  All but three declared a history of financial ties to AstraZeneca.  Of these three, Dr. Lieberman acknowledged that he had worked for AstraZeneca as an unremunerated consultant.  Dr. Sweeney declared only the funding for the present study (he was lead investigator), and Dr. Gu declared no ties.  Two of the authors, Dr. Lazarus and Dr. Sweitzer were employees of AstraZeneca, and both held stock options. (p 1059 and 1070)

The importance of these kinds of funding issues was highlighted in a study of head-to-head comparisons of second generation neuroleptics by Heres et al (Amer Jour Psych 2006).  These researchers found:

“In 90.0% of the studies, the reported overall outcome was in favor of the sponsor’s drug….Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings.”

DAN MARKINGSON

There were two completed suicides in the study, both in the quetiapine group.  One of these was Dan Markingson.  Dan’s inclusion in the study has been the subject of considerable controversy.  His mother, Mary Weiss, stated that she saw his condition deteriorate markedly during the period in question, and that she made repeated attempts to have him removed from the study and taken off the drug.  It is also reported that she alerted the study coordinator to the danger of homicide or suicide.  Her protests were not heeded.  Recently, thanks largely to the persistent efforts of Carl Elliott, the Faculty Senate of the University of Minnesota has voted to commission an independent inquiry into the circumstances of Dan’s death.  However, on December 11, Eric Kaler, President of the university stated in a press interview that the inquiry will only be looking into the university’s review procedures and that it will not be a review of Dan Markingson’s death.  This announcement, predictably, has re-opened the controversy (subsequent letter from University of Toronto).

THE BIG QUESTIONS

Why did the research team at the University of Minnesota’s Department of Psychiatry not take protective action in response to Mary Weiss’s warnings concerning her son Dan?

Did they discuss these concerns, and, if so, is there a record of these discussions?

Was an assessment made of Dan’s suicide potential in response to Mary’s expressions of concern?  If so, what was the result of that assessment?

On which site(s) did the other suicide and the three suicide attempts occur?

Was the decision-making concerning Dan influenced by the desire to portray quetiapine in as favorable a light as possible?  In particular, was the decision not to hospitalize Dan influenced by the fact that quetiapine had fared so poorly in CATIE on the hospitalization measure?

With regards to this last point, there is, I suggest, a pressing need to separate and publish CAFÉ’s relative hospitalization rates for the three drugs.  This information was not published in the study write-up, but presumably would still be available in the research files.

It is also important to investigate the question of informed consent.  In the study write-up, the authors state that:

“…written informed consent was obtained from the patients or their legally authorized representatives.” (p 1051)

It has been suggested that Dan Markingson was incapable of providing informed consent at the time of his enrollment.  Carl Elliott has written:

“When Mary found out that Dan had been recruited into the CAFE study, she was stunned. “I do not want him in a clinical study,” she told Olson [Stephen C. Olson, MD, one of the researchers]. Just a few days earlier, Olson indicated in a petition to the court that Dan was both dangerous and mentally incapable of consenting to antipsychotic medication. How could he now be capable of consenting to a research study with the very same antipsychotics—especially when the alternative was commitment to a state mental institution?”

A complicating factor here is that AstraZeneca paid the University of Minnesota $15,648 for each person they enrolled in CAFÉ, and it has been suggested that this financial incentive might have clouded the researchers’ judgment with regards to the ability to provide informed consent.

At the very least there are unanswered questions.  Was Dan capable of giving informed consent?  Was his “consent” coerced in any way?

It is now over nine years since Dan’s death.  It is high time that these questions were addressed in a serious and impartial manner.

 

Neuroleptics for Children: Harvard’s Shame

In December 2012, Mark Olfson, MD, et al, published an article in the Archives of General Psychiatry.  The title is National Trends in the Office-Based Treatment of Children, Adolescents, and Adults with AntipsychoticsThe authors collected data from the National Ambulatory Medical Care Surveys for the period 1993-2009, and looked for trends in antipsychotic prescribing for children, adolescents, and adults in outpatient visits.  Here are the results:

Age Increase in no. of antipsychotic prescriptions per 100 population (1993-2009)
0-13 0.24-1.83 (almost 8-fold)
14-20 0.78-3.76 (almost 5-fold)
21+ 3.25-6.18 (almost 2-fold)

 

The authors provide a breakdown of the diagnoses assigned to the children and adolescents during the antipsychotic visits.

Diagnosis Visits %
Children
(0-13)
Adolescents
(14-20)
Schrizophrenia 6.0 8.1
Bipolar 12.2 28.8
Depression 11.2 20.9
Anxiety 15.9 14.4
Dev Disorders 13.1 5.0
Disruptive Behavior Disorders 63.0 33.7
Other Dx’s 18.0 16.8

 

Percentages do not total 100, because some individuals were assigned more than one diagnosis.

It is clear that disruptive behavior disorders are the most common diagnoses used in antipsychotic visits for both children and adolescents.

Thirty years ago, the prescription of neuroleptic drugs to children under 14 years of age was almost unheard of.  It was rare in adolescents, and even in adults was largely confined to individuals who had been given the label schizophrenic or bipolar.

By 1993, the first year of the Olfson et al study, about a quarter of 1% of the national childhood population were receiving antipsychotic prescriptions during office visits.  The percentage for adolescents was about three quarters of 1%.  By 2009, these figures had increased to 1.83% and 3.76% respectively.

The devastating effects of these neurotoxic drugs are well known, and it is natural to wonder what forces might be driving this trend.  The authors suggest that:

“Increasing clinical acceptance of antipsychotics for problematic aggression in disruptive behavior disorders may have increased the number of children and adolescents (especially male youths and ethnic/racial minorities) being prescribed antipsychotics.  The increase in the number of clinical diagnoses of bipolar disorder and autistic spectrum disorders among children and adolescents may have further increased antipsychotic use by youths, particularly by boys.”

They also note that:

“The trend in the prescribing of antipsychotics to youths occurred within the context of a dramatic increase in the clinical diagnoses of bipolar disorder among young people.”

The notion that the increase in the prescription of neuroleptics for children is driven by increased use of the bipolar diagnosis is supported by another study:  Most Frequent Conditions in U.S. Hospitals, 2010,  by Plunter et al, January 2013, published by the Agency for Healthcare Research and Quality (a division of the US Department of Health and Human Services).  This study, which analyzed hospital admission data from 1997 to 2010, found that mood disorder, which in 1997 had been in the fourth place (behind asthma, pneumonia, and appendicitis) was by 2010 the most common diagnosis for children aged 1-17.  In the 13-year period admissions for mood disorders had increased 80%, while admissions for asthma and pneumonia had decreased by 30% and 16% respectively.

Most of the increase in mood disorder frequency was for bipolar disorder.  In the period studied, admissions for children for depression rose 12%, but admissions for bipolar disorder rose 434% (from 1.5 per 100,000 population to 8.2).  For children in the age group 5-9, the increase was 696%! – a seven-fold increase.

So, over the last decade or two, we’ve seen a huge increase in the number of children being hospitalized for bipolar disorder and in the number of children being prescribed neuroleptics in office visits.

HOW DID THIS HAPPEN?

Neuroleptics are probably the most damaging drugs used in psychiatry.  The adverse effects, including permanent and extensive brain damage, are devastating, and occur in virtually all of cases where use is prolonged (Breggin, 2011, p 197).  In former decades, their use was confined mainly to adults who had been labeled schizophrenic or bipolar.  It was routinely claimed by psychiatrists that their benefits outweighed the risks, though this contention is not standing up to the increasing scrutiny that has occurred in the past decade or so.

The increase in the prescription of neuroleptic drugs for children is a direct consequence of the increased use of the bipolar label in that population.  And most of the responsibility for that increase can, in my view, be laid at the door of one person:  Joseph Biederman, MD, of Harvard Medical School and Massachusetts General Hospital.  Dr. Biederman will go down in history as the inventor of pediatric bipolar disorder.

DSM-III-R was published in 1987.  It makes no reference to the existence of childhood bipolar disorder.  The total entry under Prevalence is:

“It is estimated that 0.4% to 1.2% of the adult population have had bipolar disorder.” [emphasis added]

DSM-IV, published in 1994, greatly expanded the concept of bipolar disorder, essentially by removing the requirement of a manic episode or a mixed (manic-depressive) episode.  References to age are vague – e.g.:

“Approximately 10%-15% of adolescents with recurrent Major Depressive Episodes will go on to develop Bipolar I disorder.”

It is not clear whether this “development” might occur in late adolescence or in adulthood. There is no suggestion that bipolar disorder can occur in a pre-adolescent child.

By 1996, however, Dr. Biederman and his colleagues at Harvard were promoting childhood bipolar disorder as an accepted psychiatric diagnosis that needed to be treated with pharmaceutical products, including neuroleptics.  This was accomplished primarily by selling the notion that childhood temper tantrums could legitimately be regarded as symptoms of mania.  This blatant distortion of the traditional concept of mania was facilitated by the “not otherwise specified” (NOS) qualifier which has been a component of almost all diagnostic categories since DSM-III.  The purpose of the NOS diagnoses is to enable psychiatrists to assign the diagnosis in question to an individual even though he doesn’t actually meet the criteria.  The fact that this renders the criteria somewhat pointless is generally lost on psychiatrists, but that’s a different story.

What the Bipolar Disorder NOS diagnosis enabled Dr. Biederman and his colleagues to say was essentially this:

We know that temper tantrums aren’t really an integral component of bipolar disorder as it is traditionally conceived.  But we believe that that’s how bipolar disorder presents itself in young children, and so that’s what we’re going to call it.

This is on a par with dermatologists deciding that pattern baldness is a symptom of psoriasis!  In real medicine, this isn’t how it’s done, but in psychiatry it’s the norm.  The “diagnoses” are fictitious.  They can be created, modified, and eliminated with strokes of a pen.  This is what Dr. Biederman and his Harvard colleagues did, and American psychiatry followed.  The neuroleptics-for-children spigot was opened, and is running freely to this day.

The creation and promotion of pediatric bipolar disorder has been described and critiqued by several writers.  Joanna Moncrieff, a British psychiatrist, provides an excellent account in her book The Bitterest Pills (2013 , p 200-205).  Here are some quotes:

“Although it is the adult market that accounts for the bulk of sales of atypical antipsychotics, it is the use of these drugs in children alongside the emergence of the diagnosis of paediatric bipolar disorder that best illustrated the way in which a severe mental disorder can be morphed into a label for common or garden difficulties, as well as the role that money plays in this process.”

“Moreover, by locating the problem in the brain of the child, it seemingly detaches it from the situation within the family.”

“Academic psychiatry fuelled this craze, with added financial incentive from the pharmaceutical industry…”

“In the 1990s, a group led by child psychiatrist Joseph Biederman, who was based at Massachusetts General Hospital and the prestigious Harvard Medical School, started to suggest that children could manifest ‘mania’ or bipolar disorder, but that it was frequently missed because it was often co-existent with other childhood problems like ADHD and ‘antisocial’ behaviour…  In a paper published in 1996 the group suggested that 21% of children attending their clinics with ADHD also exhibited ‘mania’, which was diagnosed on the basis of symptoms such as over-activity, irritability and sleep difficulties…  A year later the group were referring to bipolar disorder in children as if it were a regular, undisputed condition, and emphasized the need for ‘an aggressive medication regime’ for children with the diagnosis…”

“Neither Harvard nor Massachusetts General Hospital nor any other psychiatric or medical institution has commented on the fact that prominent academics were found to be enriching themselves to the tune of millions of dollars through researching and promoting the use of dangerous and unlicensed drugs in children and young people.  Although some individual psychiatrists have expressed misgivings…academic papers continue to discuss the diagnosis, treatment and outcome of bipolar disorder in children as if no controversy existed, with more than 100 papers on the subject published in Medline-listed journals between 2010 and 2012.  Notwithstanding…the disgrace of Joseph Biederman, the practice of diagnosing children with bipolar disorder and treating them with antipsychotics remains alive and kicking.”

The spurious creation of childhood bipolar disorder has been critiqued also by Mickey Nardo, MD, a retired psychiatrist who blogs under the name 1 Boring Old Man (which, incidentally, he isn’t).  On July 2, 2011, he published a post called bipolar kids: an all too familiar lingo…  Here are some quotes:

“What happened in that second half of the 1990s is that they created a new diagnosis – Pediatric Bipolar Disorder. Looking at these articles…or at the COBY Study [started right around this time], Bipolar Disorder in children was becoming a common diagnostic term, but the diagnostic criteria bore little resemblance to the familiar symptom complexes from the Manic Depressive Illness of old. It was something new masquerading as something old [or vice versa]. These kids weren’t euphoric, they were irritable.”

“…the Biederman-led movement to broaden the category to call all kinds of difficult and disruptive children Bipolar had little to no scientific basis. It felt like a rationalization to use the new atypical antipsychotics to control difficult behavior-disordered kids – a trick.”

“And even without knowing what we know today about what happened, at the turn of the last century there was plenty of reason to smell a rat [named pharma]. The articles had all the tell-tale phrases – “urgent public health problem” “emerging new treatments” “need for more research” – an all too familiar lingo that pointed down a well-traveled yellow brick road. And this time it didn’t lead to Oz, it lead to Harvard University. And the guy behind the curtain was Joseph Biederman …”

Ultimately Dr. Biederman was disgraced – not for the spurious expansion of a diagnostic category.  Diagnostic expansion has been psychiatry’s primary agenda for the past 60 years.  A small minority of psychiatrists might have had reservations concerning Dr. Biederman’s work, but the mainstream psychiatry-pharma alliance embraced the new development with their customary zeal and self-serving enthusiasm.

Nor was Dr. Biederman disgraced because he had deliberately encouraged the exposure of thousands of children to neurotoxic chemicals.  Again, that’s just business as usual.  And in fact, he received awards and accolades for drawing attention to the plight of these tragically “underserved” children.  Here are some of the awards and honors he has received since his ground-breaking work on childhood bipolar disorder:

  • NAMI Exemplary Psychiatrist Award
  • NARSAD Senior Investigator Award
  • ADHD Chair of World Psychiatric Association
  • Outstanding Psychiatrist Award, Massachusetts Psychiatric Society
  • Excellence in Research Award, New England Council of Child and Adolescent Psychiatry
  • Mentorship Award, Psychiatry Department, Massachusetts General Hospital
  • William A. Schonfeld Award for outstanding achievement and dedication
  • Distinguished Service Award, MGH/McLean Child and Adolescent Psychiatry Residency

He was disgraced for under-reporting to his employers at MGH and Harvard the amount of money he was receiving from the pharmaceutical industry for conducting research that was used to promote their products.  Here again, there was nothing particularly unusual in this.  The so-called Key Opinion Leaders (KOL’s) in psychiatry have been awash in pharma money for decades.  But Dr. Biederman’s take ($1.6 million) was on the high side, and came to light at a time when the corrupt psychiatry-pharma alliance was being exposed nationally, largely through the efforts of Iowa Senator Charles Grassley.

Dr. Biederman was also criticized for promising Johnson & Johnson a positive result for their neuroleptic drug risperidone in pre-school children before he had actually conducted the research.  Obviously this makes a mockery of the research, but psychiatric research was hijacked by pharma marketing decades ago.  It has long since ceased to be a source of genuine scientific information, and much of it instead is little more than marketing material bought and paid for by the pharmaceutical industry.  Dr. Biederman’s error in this area was that he committed his promises to writing (in the form of slides that he presented to Johnson & Johnson executives), and these slides and other correspondence came to light during lawsuits against Johnson & Johnson for fraudulent marketing of their products.  These are the same lawsuits that Johnson & Johnson recently settled for $2.2 billion.

The great irony with regard to Dr. Biederman’s premature promise of a positive result for Johnson & Johnson is that he was absolutely correct!  If you give a neuroleptic drug to a misbehaved child, the incidence of misbehavior will indeed decrease.  If you give him enough, he’ll go to sleep and won’t misbehave at all!  That’s why these drugs used to be called major tranquilizers.  Dr. Biederman could accurately predict this result in advance because that’s what major tranquilizers do.  If you conduct a study to see if alcohol will make people drunk you’ll get a positive result.  If you conduct a study to see if major tranquilizers subdue childhood temper tantrums, you’ll get a positive result.  Dr. Biederman couldn’t use this defense, however, because he, like psychiatrists in general, has to play along with the big fiction:  that childhood temper tantrums are a symptom of an illness, and that the drugs are medicines targeting specific faults in neural circuitry or chemical imbalances or whatever.  Dr. Biederman’s proposed study would have produced a positive results for Risperdal in the same way that most industry-sponsored studies obtain positive results:  by limiting outcome criteria to the known effects of the drug, by keeping follow-up times short, and by ignoring adverse effects.

Dr. Biederman’s ethical lapses were thoroughly investigated (for three years) by his bosses at MGH and Harvard, and in 2011 they gave him and two of his colleagues (Thomas Spencer – total take:  $1.0 M, and Timothy Wilens – total take:  $1.6 M) very, very severe slaps on the wrists.  The Boston Globe covered this story.  Here’s a quote:

“The three psychiatrists apologized in their letter for the ‘unfavorable attention that this matter has brought to these two institutions.’  They called their mistakes ‘honest ones’ but said they ‘now recognize that we should have devoted more time and attention to the detailed requirements of these policies and to their underlying objectives.’

They said the institutions imposed remedial actions, requiring them to refrain from all paid industry-sponsored outside activities for one year, with an additional two-year monitoring period during which they must obtain approval before engaging in paid activities. They were also required to undergo unspecified additional training and suffer ‘a delay of consideration for promotion or advancement.'”

The notion that the ethical lapses of these three psychiatrists were “honest mistakes” is a little hard to credit, given that the total dollar amount was more than $4 M!

Today Dr. Biederman is fully rehabilitated and is back in business. He’s receiving research funding from ElMindA, Janssen, McNeil, and Shire, and is once again churning out research papers on topics such as ADHD and, guess what? – pediatric bipolar disorder.

THE BIG QUESTIONS

The two big questions in all of this are:

1.  Why do Harvard and Massachusetts General Hospital stand for this kind of blatant corruption and deception in the upper echelons of their psychiatry department?

2.  Why does the APA not take a stand against the medicalization and drugging of childhood temper tantrums – a problem that parents of previous generations simply took in their stride as an integral part of normal childrearing?

With regards to the APA, it’s really not much of a question.  Their agenda has always been: more psychiatric drugs for more people, and the neuroleptics-for-children development is really just business as usual.  They have dulled their ethical sensibilities through decades of prescribing benzodiazepines, SSRI’s, methylphenidate, and various other neurotoxins for an ever-widening range of human problems, and prescribing a neuroleptic to a 1½ year old for temper tantrums is a short step.

The APA, however, did express some mild concern about the spurious extension of the bipolar label to children.  In DSM 5 (p 132) they state:

“In individuals with severe irritability, particularly children and adolescents, care must be taken to apply the diagnosis of bipolar disorder only to those who have had a clear episode of mania or hypomania – that is, a distinct time period, of the required duration, during which the irritability was clearly different from the individual’s baseline and was accompanied by the onset of Criterion B symptoms.”

But rather than risk losing the pediatric business, hard-won by Harvard’s psychiatrists, they created a new diagnosis:

“When a child’s irritability is persistent and particularly severe, the diagnosis of disruptive mood dysregulation disorder would be more appropriate.”

The effect of all this is that psychiatrists can go on prescribing drugs for childhood temper tantrums, but instead of calling them bipolar disorder, they should use the new label:  disruptive mood dysregulation disorder – but they can continue to use the bipolar diagnosis also, with a few caveats, couched in the APA’s characteristically vague language.

Harvard’s stance on the scandals is a little harder to fathom.  After all, Harvard is hallowed ground – America’s Oxbridge.  It has acquired an image as a center of learning where educational and research standards eclipse all other considerations.

And in fact, there are legal and medical ethicists at Harvard who clearly recognize the implications of the psychiatric scandals.

Earlier this year, the Journal of Law, Medicine & Ethics (Vol 41, Issue 3) published a symposium of 17 papers written by members of Harvard’s Edmond J. Safra Center for Ethics.  Here are some of the titles:

Here are some quotes:

“The pharmaceutical industry has corrupted the practice of medicine through its influence over what drugs are developed, how they are tested, and how medical knowledge is created.” (Light et al)

“In this article, we analyze how drug firms influence psychiatric taxonomy and treatment guidelines such that these resources may serve commercial rather than public health interests.” (Cosgrove and Wheeler)

“Pharmaceutical and medical device companies apply social psychology to influence physicians’ prescribing behavior and decision-making.” (Sah and Fugh-Berman)

Clearly these papers are addressing important and relevant topics.  But what’s particularly noteworthy, from the present perspective, is that they originated in Harvard – the same institution in which senior psychiatry faculty members were hand-in-glove with pharma in the production of fraudulent research and advertizing.  How are we to understand this contradiction?  How are we to understand the minimal response from Harvard’s management, and incidentally from the other academic departments, given that such a wealth of ethical resources was there on their own campus, presumably available and willing to be consulted on these kinds of matters.

BUSINESS ETHICS VS UNIVERSITY ETHICS

In America, it is becoming increasingly recognized, and even accepted, that big businesses are frequently amoral.  Considerations of right and wrong are routinely subordinated to bottom line accounting.  Many big pharmaceutical companies are perceived in this light.  Indeed, the recent $2.2 B  penalty levied against Johnson & Johnson was discussed in some media outlets quite simply as a “cost of doing business.”  The question of whether it is a good thing to promote the use of neuroleptics for children doesn’t even come on the radar.  The perverse calculus is reduced to the difference between the projected profits from the drugs sales, and the fines and lawsuit settlements that might ensue.

Has Harvard’s Psychiatry Department, in concert with their pharmaceutical allies, crossed this line?  Have they now, implicitly or explicitly, adopted the ethical standards of the business world?  Have they subordinated their sense of decency and shame to considerations of prestige and revenue?

And what of the MGH/Harvard leadership?  Do they actually believe that the sanctions imposed on Dr. Biederman and his colleagues are adequate?  Or do they reckon that the years of past and future pharma revenue are worth the cost?  Have they crossed the line into the shady realm of business ethics?

And as we ponder these thorny questions, let’s not forget that the Johnson & Johnson lawsuit listed psychiatric researchers at other renowned universities, including Johns Hopkins, Stanford, UCLA, University of Illinois at Chicago, University of Texas at Austin, Georgia Regents, University of Toronto, and Dalhousie University.

Meanwhile the destructive prescribing continues, and Dr. Biederman is still at MGH, where he is Chief of the Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, and at Harvard, where he is a full Professor of Psychiatry, a position, which, by his own account, ranks just below God!

Psychiatry’s primary agenda for the past 60 years has been the expansion of their diagnostic net to embrace an increasing range of ordinary human problems, and the unscrupulous prescribing of more and more psycho-pharmaceutical products to more and more people.  In the final analysis, Dr. Biederman’s problem was that he was particularly good at this job.  He was, in effect, a Model Psychiatrist – the perfect embodiment of everything that the APA stands for.

CLARIFICATION OF TERMINOLOGY

My frequent use of the term bipolar disorder in this article should not be interpreted as an endorsement on my part of the ontological validity of this expression, much less its status as an illness or disease.  I use the term bipolar disorder (and the various other so-called diagnoses) for the sake of readability and linguistic convenience.  What I mean by “bipolar disorder” is:  the vaguely defined and loosely clustered behaviors, thoughts, and feelings that psychiatrists call bipolar disorder.

Neuroleptics in Nursing Homes

Earlier this year, The American Society of Consultant Pharmacists published a report on the use of neuroleptic drugs in nursing homes.  According to this report, 25% of nursing home residents receive neuroleptic drugs.

In general, the Centers for Medicare and Medicaid Services (CMS) consider these prescriptions appropriate only if the recipient is psychotic.  (Obviously we could discuss this at length, but let’s set that issue aside for now.)

What CMS considers entirely inappropriate, however, is prescribing these products to residents with dementia as a way of controlling “difficult” behaviors such as wandering, being abusive, or resisting care.

In January 2013, CMS produced a 43-page report on this topic titled: Improving Dementia Care and Reducing Unnecessary Use of Antipsychotic Medications in Nursing Homes.

Here’s a quote:

“High prevalence rates of antipsychotic medication use in nursing home residents have been reported in several studies; Much of the use is in residents with a diagnosis of dementia.

According to CMS’s Quality Measure/Quality Indicator report, between July and September 2010, 39.4% of nursing home residents nationwide who had cognitive impairment and behavioral issues but no diagnosis of psychosis or related conditions received antipsychotic medications.” [Emphasis added]

Antipsychotic, or more accurately, neuroleptic, drugs provide little or no treatment benefit for people with dementia.  The risks, however, are considerable, including tardive dyskinesia, akathisia, infections such as pneumonia, and reduced life expectancy.

In their report, the American Society of Consultant Pharmacists wrote:

“It is important to note that the Food and Drug Administration requires a ‘black box’ warning on all antipsychotics about an increased risk of mortality when used in older adults with dementia.”

In May of last year, CMS launched a program designed to reduce this off-label prescribing by a modest 15% by the end of 2012.  In fact, for all their efforts, the rate declined by only 8% nationally.  [Quoted in No restraint at drug-dosing New York nursing homes in The New York World.]

The problem may be lax enforcement.  Toby Edelman, senior policy attorney with the Center for Medicare Advocacy, is quoted as saying:

“The other piece of this is stronger enforcement…If they misuse the drugs and have to pay a $139 fine, what do they care? It’s the cost of doing business.”  [Quoted in High Use Of Antipsychotics In Nursing Homes Stirs Concerns, Reforms, by Lisa Chedekel.]

Why are neuroleptics, with all their well-established risks, being used so widely to control “difficult” behavior in nursing homes?  And why is CMS unable to put a stop to the practice?

Here’s a quote from Gwen Olsen’s 2009 book Confessions of an Rx Drug Pusher:

“It was the end of the third quarter, and I was behind in my sales quota for Haldol…So, I determined the best way to build my Haldol business would be to campaign for the institutionalized patient. These patients were not only encouraged to take the medication; they were actually given the drug. This completely eliminated the compliance issue.”

“I set about scheduling training in-services in the local nursing homes and mental health and mental retardation (MHMR) facilities. I increased my call frequency on physicians whom I knew to have nursing home relationships and directorship responsibilities.”

Ms. Olsen has been out of the business for several years now, but maybe things haven’t changed that much.  The pharmaceutical industry gave $234 million to politicians last year.  I guess they wouldn’t be doing that if it didn’t buy them something.