David Healy (psychiatrist)


 * For other David Healys see David Healy (disambiguation).

David Healy is an Irish psychiatrist who is currently a professor in Psychological Medicine at Cardiff University College of Medicine, Wales.He is also the director of North Wales School of Psychological Medicine. He became the centre of controversy concerning the influence of the pharmaceutical industry on medicine and academia. For most of his career Healy has held the view that Prozac and SSRIs (selective serotonin re-uptake inhibitors) can lead to suicide and has been critical of the amount of ghost writing in the current scientific literature. Healy's views led to what has been termed “The Toronto Affair” which at its core was a debate about academic freedom.

Background and research
Healy was born in Raheny, Dublin. He completed an MD in neuroscience and studied psychiatry during a clinical research fellowship at Cambridge University Clinical School. In 1990, Healy became a Senior Lecturer in Psychological Medicine at North Wales and in 1996 became a Reader in Psychological Medicine. He became a Professor a couple of years ago. His current research interests at Cardiff University include: cognitive functioning in affective disorders and psychoses as well as circadian rhythms in affective disorders, recovery in psychoses and physical health of people with mental illness.

He also heads the psychiatric inpatient unit in Bangor, North Wales, where treatment consists of electroconvulsive therapy (ECT) and psychotropic medication, amongst other things. Healy has authored a number of books and is an expert on the history and development of psychopharmacology. He is currently working on a book, History of Convulsive Therapy with Edward Shorter and Max Fink.

SSRIs
SSRIs are selective serotonin re-uptake inhibitors which are used to treat clinical depression. At one time it was thought that depression was due to low levels of serotonin in the brain. Today serotonin levels can be measured by 5-HT imaging with Positron emission tomography (PET) imaging as well as measuring tryptophan plasma levels. Prozac is a well known SSRI. In the 1970’s Bryan Molloy at Eli Lilly and Company created a phenoxyphenyl-propylamines termed LY-94949 but it could not be easily dissolved so David Wong reformulated it as a chloride salt and it was renamed LY-110140. Then on September 1, 1975 it was first called fluoxetine and then later marketed under the name Prozac. Prozac was launched in the United States and Canada in 1988 and in the United Kingdom in 1989.

Soon after its launch there was a large debate on whether or not Prozac was related to suicide.

Does Prozac Cause Suicide?
The debate was started by Martin Teicher from Harvard when they published an article in the American Journal of Psychiatry in 1990. The article outlined six individual cases of people who had become preoccupied with thoughts of suicide after going on Prozac.

Eli Lilly was quick to respond with a contradictory article by Charles Beasley and colleagues from Eli Lilly that examined evidence from 3,065 patients of which 1,700 had been put on Prozac. The authors concluded that there was no evidence for individuals taking Prozac to have a higher rate of suicide than those taking placebo. In his book, “Let Them Eat Prozac”, Healy points out several flaws in the Beasley experiment. In Healy’s view the entire experimental analysis rested on one question from the Hamilton Depression Rating Scale which is too insensitive to accurately measure suicidality.

The question reads: “This past week, have you had any thoughts that life is not worth living, or that you’d be better off dead? What about thoughts of hurting or even killing yourself?”

There are four choices from which the patient can choose: 1) has made a serious suicide attempt, 2) has clear suicidal ideas or gestures, 3) wished he were dead or any thoughts of possible death, 4) feels life is not worth living or absent. The problem that Healy has with this that the “Raters rate in a global way. If a patient is improving raters whiz through an interview, often completing the scale afterward in a manner that indicates a general improvement in the overall score. If some aspects of the patient’s condition are improving – which they might even when the patient is becoming suicidal – raters often won’t bother asking the suicide question.”

A second problem with that rating system is that if a significant number of people improve, their scores will drown out the noise being produced by patients who have worsened.

The debate centered around the question of which was more important, a handful of individual cases or a large randomized control trial. Healy believes that Prozac induces suicide. His comments in 1994 in CNS Drugs are often misquoted. Healy wrote that “data from several thousand patients must on any scientific scale outweigh the dubious evidence of a handful of case reports.” However, according to Healy this was a “piece of irony” and the “article came down firmly on the side of saying that Prozac did cause suicide”  In addition Healy believes that the problem could be managed with proper warnings.

Lilly’s Knowledge of Prozac and Suicide
In “Let them Eat Prozac” Healy presents evidence that Eli Lilly already knew in 1986 that patients on Prozac attempted more suicides than patients on other anti-depressants and placebo. A memo from Barbara von Keitz, who was working in Germany for Eli Lilly, was sent to Joachim Wernicke at Eli Lilly Headquarters in Indianapolis. A result of a clinical trial showed that patients on Prozac had rate of suicide attempts of 10 per 1000 but those patients randomized to other anti-depressants (imipramine, amitripyline, doxepin or mainserin) had a rate of only 1.5/1000. Placebo patients had a varying rate or 6, 4.3 or 1 per 1000. The varying placebo rate is due to suicide attempts during the washout period being placed in the placebo groups. Healy sees this experimental method as “highly inappropriate”. There are two appropriate ways to respond. One is to count only the five suicide attempts in the placebo group which would give a rate of 4.3/1000. The second is to count all the patients that went into clinical trials as placebo which would give a rate of 1.0/1000.

The signs of violence and suicidality were there since Prozac (fluoxetine) was tested in premarketing trials.

In May 1984, Germany’s regulatory agency (GBA) rejected Prozac as “totally unsuitable for treating depression.” In July 1985, Eli Lilly’s own data analysis—from a pool of 1,427 patients—showed high incidence of adverse drug effects and evidence of drug-induced violence in some patients. In May 1985, FDA’s (then) chief safety investigator, Dr. Richard Kapit, wrote: “Unlike traditional tricyclic antidepressants fluoxetine’s profile of adverse side effects more closely resembles that of a stimulant drug than one that causes sedation.” He warned “It is fluoxetine’s particular profile of adverse side-effects which may perhaps, in the future give rise to the greatest clinical liabilities in the use of this medication to treat depression.”

Dr. Kapit’s safety review described the clinical trial data from 46 trials with a total of 1,427 patients. He noted under the section, “Catastrophic and Serious Events,” 52 cases of “egregiously abnormal laboratory reports which were the reason for early termination,” and “additional adverse event reports not reported by the company [which] were revealed on microfiche.” Dr. Kapit reported: “In most cases, these adverse events involved the onset of an unreported psychotic episode.” There were 10 reports of psychotic episodes; 2 reports of completed suicides; 13 attempted suicides; 4 seizures—including a healthy volunteer; and 4 reports of movement disorders.

In 1985 Dr. Kapit recommended “labeling warning [for] the physician that such signs and symptoms of depression may be exacerbated by this drug". No such warning was issued until 2004.

In 2005, an internal document purportedly from Eli Lilly and Co. made public showed that the drug maker had data more than 15 years old showing that patients on its antidepressant Prozac were far more likely to attempt suicide and show hostility than were patients on other antidepressants and that the company attempted to minimize public awareness of the side effects. The 1988 document indicated that 3.7 percent of patients attempted suicide while on the blockbuster drug, a rate more than 12 times that cited for any of four other commonly used antidepressants. The document, which cited clinical trials of 14,198 patients on fluoxetine also stated that 2.3 percent of users suffered psychotic depression while on the drug, more than double the next-highest rate of patients using another antidepressant.

The document was provided to CNN by the office of Rep. Maurice Hinchey, D-New York, who called for tightening FDA regulations on drug safety. "The case demonstrates the need for Congress to mandate the complete disclosure of all clinical studies for FDA-approved drugs so that patients and their doctors, not the drug companies, decide whether the benefits of taking a certain medicine outweigh the risks," Rep. Hinchey said.

Tobin vs. SmithKline; SSRIs in Court
In February of 1998, Donald Schell, a 60-year old, went to see his doctor complaining of difficulty sleeping. He was diagnosed with an anxiety state and placed on Paxil, an SSRI. Within forty-eight hours of being put on Paxil Schell killed his wife, daughter, infant grand-daughter, and himself. Tim Tobin, Schell’s son-in-law took legal action against SmithKline. Healy was retained as an expert witness in the case.

The Tobin case was heard in Cheyenne, Wyoming from May 21 to June 6, 2001. On the stand SmithKline representative Ian Hudson indicated that no matter how many physicians or clinicians reported to the company that they thought suicide was related to the Paxil, SmithKline would deny causation. The jury returned a guilty verdict against SmithKline and awarded Tobin eight million dollars. This was the first verdict returned guilty against a pharmaceutical company regarding adverse behavioral effects of a psychotropic drug.

Healy’s Healthy Volunteer Study
Healy designed an experiment to examine if disinhibition, which Healy believes can lead to suicide, is associated with SSRIs. He compared Zoloft (an SSRI) to reboxetine (a non-SSRI anti-depressant) in a group of healthy volunteers. The volunteers would be placed on Zoloft or reboxetine for two weeks, halt for two weeks and then take the other drug for two weeks. The experiment would test if the marketed “better than well” phenomenon for SSRI was true.

At the end of the study two-thirds of the participants rated themselves as “better than well”. However, the volunteers’ quality of life and social functioning decreased on Zoloft but remained the same on reboxetine. Approximately half the group reported emotional blunting on the drugs.

Two patients in the study became suicidal which Healy associated with disinhibition caused by Zoloft. One patient highlighted the trend of suicide by hanging which is a trend in SSRI suicides. Healy calculated the probability of two healthy volunteers without mental illness and no current interpersonal legal or financial problems becoming suicidal during a two week period on Zoloft as p = 0.0000005. In other words, the chance that Zoloft was unrelated to the two healthy volunteers' becoming suicidal during the trial period (that is, the chance that it was coincidental) is only 1 in 2000000.

Healy concluded that he had “accidentally demonstrated conclusively that the drugs could cause the problem”

The Toronto Affair
On August 17, 2000 Dr. David Goldbloom, the Physician-in-Chief at the Centre for Addiction and Mental Health (CAMH) and a Professor of Psychiatry and the University of Toronto, wrote to Healy to formally offer him “the position of Clinical Director, Mood and Anxiety Disorder Program, CAMH”.

The Lecture
On November 30, 2000 Healy was invited to a meeting at the University of Toronto entitled “Look Back. Looking Ahead – Psychiatry in the 21st Century: Mental Illness and Addiction”. Healy presented a talk with the title “Psychopharmacology and the Government of Self”. This talk gave an overview of the history of psychopharmacology and was critical of several aspects of the pharmaceutical industry.

Healy talked about the inadequacy of clinical trials stating that “clinical trials in psychiatry have never showed that anything worked”. His point was that clinical trials demonstrate treatment effects and not whether or not a drug works. Also critical of ghost-written scientific literature; he noted that the fact that unsuccessful clinical trials are suppressed and successful clinical trials are over reported was not science.

In addition, Healy made the direct comment that “Prozac and other SSRIs can lead to suicide" and that “these drugs may have been responsible for 1 death for everyday that Prozac has been on the market in North America”. Moreover, Healy criticized the industry by the fact that “since the controversy blew up, there has not been a single piece of research carried out to answer the question of whether ‘Prozac’ does cause suicide or not”.

The Aftermath
On December 7, 2000, shortly after Healy’s talk he received an email from Dr. Goldbloom, who was retracting his previously offered position at CAMH. The reason Goldbloom indicated was as follows: “Essentially, we believe that it is not a good fit between you and the role as leader of an academic program in mood and anxiety disorders at the Centre and in relation to the University. This view was solidified by your recent appearance at the Centre in the context of an academic lecture. While you are held in high regard as a scholar of the history of modern psychiatry, we do not feel your approach is compatible with the goals for development of the academic and clinical resource that we have.” However, Healy believes that his job offer was retracted because his critical views of the pharmaceutical industry and especially Eli Lilly. This has been denied by the President of the University of Toronto, Dr. Robert Birgeneau who stated in a letter to the Canadian Association of University Teachers (CAUT) that Healy’s contract was “not influenced in any way by Eli Lilly or by any other pharmaceutical company.”

Eli Lilly was a significant contributor to the University of Toronto. It supported 52% of the budget for the Mood and Anxiety Disorder Clinic that Healy would have headed up. In addition it gave a 1.5 million dollar gift to CAMH to help its fundraising campaign. Furthermore, there was precedent for Eli Lilly removing its financial support in response to anti-Prozac comments or publications. In March of 2000, the Hasting Center published an article by Healy which indicated that Prozac induced suicide. Eli Lilly pulled their support of $25,000 per annum. The Hasting Center re-reviewed the article but stood behind its decision.

The Canadian Association of University Teachers (CAUT) fully supported Healy and lobbied the University of Toronto on his behalf. In one letter to President Birgeneau, in March of 2001 they stated “retraction of a job offer suggests a fundamental attack on academic freedom…what happened to Dr. Healy appears to be an affront to academic freedom in Canada.” The CAUT was concerned that CAMH and the University of Toronto were concerned about employing a widely recognized critic, who raises questions about corporate connections and how this might impact funding.

In September of 2001, Healy filed a lawsuit against the CAMH and the University of Toronto for 9.4 million dollars in damages and lost income. In a press conference Healy stated that his greatest concern was academic freedom and that with some of the damages awarded he would set up a fund to promote academic freedom. The lawsuit settled out of court and many of the terms of settlement remain undisclosed; but the settlement did result in Healy being offered a visiting professorship at the University of Toronto.

Ghost Writing
Medical ghost writing occurs when people with scientific backgrounds are paid to stay anonymous and produce favorable reports for drug companies then doctors are added to these studies for money, prestige or perks. Healy estimates that up to 50% of literature on drugs is ghost written. Ghost writers write on research given to them by drug companies, which want both positive results and positive research; therefore ghost writing is biased from the beginning.

Healy had an encounter with ghost writing gone wrong involving Wyeth’s SSRI Effexor. Healy attended a meeting promoting Effexor and was given the opportunity to have an article ghost written. When he received that first draft he left the main article intact but made two additions. One that contradicted Wyeth’s claim that Effexor got patients fully well compared to patients on other SSRIs and that SSRIs could make some individuals suicidal. The article went through more reviews and was already submitted to the Journal of Psychiatry and Neuroscience before Healy saw it again; both of Healy’s inserts had been removed. In response Healy removed his name from the article.

Healy believes that ghost writing is not all evil but insists that to be honest the raw data must be made available.

Solutions
In the preface of Let them Eat Prozac Healy describes the need for a “new contract between society and the pharmaceutical industry – a contract that will require access to the raw data”. Healy suggests a new division that can manage the hazards that only becomes visible after products are launched. This new division would be separate from the regulatory bodies and pharmaceutical companies.

Selected bibliography

 * The Psychopharmacologists Vol I (1996) ISBN 1-86036-008-4
 * The Antidepressant Era (1998) ISBN 0-674-03958-0
 * Psychiatric Drugs Explained (2001) ISBN 0-443-07018-0
 * The Creation of Psychopharmacology (2002) ISBN 0-674-00619-4
 * Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression (2004) ISBN 0-8147-3669-6

Resources
Ashcroft G. The receptor enters psychiatry. In Healy D. The Psychopharmacologists Vol 3 (London: Arnold, 2000), 189-200

Coyne J. Lessons in conflict of interest: The construction of the martyrdom of David Healy and the dilemma of bioethics. American Journal of Bioethics (2005) 5 (1): W3-W14.

Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. American Journal of Psychiatry 147 (1990), 207-210

Beasley CM, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH, Heiligenstein JH et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment of depression. British Medical Journal 3-3 (1991), 685-92

Healy D, The fluoxetine and suicide controversy. CNS Drugs 1 (1994), 252-4

Memo from B von Keitz and H Weber to J Wernicke: Fluoxetine suicides and suicide attempts, October 1986, Exhibit 19 in the deposition of Joachim Wernick in Fentress Vs. Eli Lilly

Tranter R, Healy H, Cattel D, Healy D. Functional variation in agents differentially selective to monoaminergic systems. Psychological Medicine 32, 517-24