Let Them Eat Prozac

The Unhealthy Relationship Between the Pharmaceutical Industry and Depression

David Healy

• Publisher: NYU Press
• Year: 2004
• ISBN:
  9780814773000
• Topic: Psicologia
• Subtopic: Storia e teoria della psicologia

Prozac. Paxil. Zoloft. Turn on your television and you are likely to see a commercial for one of the many selective serotonin reuptake inhibitors (SSRIs) on the market. We hear a lot about them, but do we really understand how these drugs work and what risks are involved for anyone who uses them?

Let Them Eat Prozac explores the history of SSRIs—from their early development to their latest marketing campaigns—and the controversies that surround them. Initially, they seemed like wonder drugs for those with mild to moderate depression. When Prozac was released in the late 1980s, David Healy was among the psychiatrists who prescribed it. But he soon observed that some of these patients became agitated and even attempted suicide. Could the new wonder drug actually be making patients worse?

Healy draws on his own research and expertise to demonstrate the potential hazards associated with these drugs. He intersperses case histories with insider accounts of the research leading to the development and approval of SSRIs as a treatment for depression. Let Them Eat Prozac clearly demonstrates that the problems go much deeper than a side-effect of a particular drug. The pharmaceutical industry would like us to believe that SSRIs can safely treat depression, anxiety, and a host of other mental problems. But, as Let Them Eat Prozac reveals, this “cure” may be worse than the disease.

1

Take One

TONY L, one of the first patients I put on Prozac, was turning 50. He had a successful professional life and an attractive family. But both were being torn apart by a combination of stresses at work and home and by his nervous disorder.

When Tony first came to see me, he appeared depressed or obsessive-compulsive or both. Either way, taking the edge off his OCD or his depression might help.¹ My preference was to use behavior therapy, but I told Tony there was a new group of antidepressants acting on the serotonin system that might possibly be useful for both depression and OCD, enabling us to cover two problems with one drug. He took a prescription for 20 mg Prozac.

Several days later, having overcome his indecision about taking pills, he started treatment. On the third day, he felt “wonderful” but found it difficult to sleep, complaining that his mind was frighteningly “like a video on fast forward.”² The next day he felt “miserable and helpless.” Although it was increasingly difficult to focus on things, he could not stop thinking, with no particular content to these out-of-control thoughts.

Tony suspected the Prozac had caused the problem and discontinued treatment, only to find the symptoms continued. I took phone calls from him and reassured him that while his problem might have been drug-induced, it should clear up. I saw him five days after he’d stopped the pills. At that point he was better, although still unwell.

I assured him there were other drugs we could try. One was Luvox, which I had no reason to think would cause serious trouble. Uncertain, Tony delayed a month before starting this new drug.

After the first dose of Luvox, Tony felt agitated and nauseated. Feeling better the next day, he took a second dose but was unable to sleep that night. He seemed to be in a rerun of his Prozac experience. In both instances he felt “dangerous.” After the second dose of Luvox he wanted, for example, to “get into my car and drive a long distance at high speed whilst sorting out the problems of Western civilization as I went.” Again his mind felt “like a video on fast forward.” He had “a distinct feeling of my brain and my body being separated with my mind set to hurt and my brain overactive.”

The following morning he felt dreadful and unable to do anything—“helpless, ill, mentally restless, beyond despair, and suicidal.” He halted the pills immediately, but this reaction lasted for a week. During the week, he noticed finding it difficult to “gauge the passage of time … I looked at the clock frequently that night and it appeared repeatedly to show the same time.”

Tony’s reactions were a puzzle. I got hold of his old medical notes. While a student at university, he had briefly been seen for a nervous reaction. At the time, he had been prescribed the tricyclic antidepressant imipramine, which also inhibits serotonin reuptake. This appeared to cause an unusual fuguelike state. It began to seem this man had a peculiar reaction to drugs acting on the serotonin system,³ but I had no idea why.

His preference for pills over behavior therapy showed he was not antipills. One possibility was that Tony had a general problem with all psychiatric drugs, either some physiological sensitivity or a neurotic reaction. After his disastrous response to SSRIs, we put him on a monoamine oxidase inhibitor (MAOI), which has the opposite effect on the serotonin system, and this worked quite well for him.

Unfortunately, Tony did not get the benefits that taking SSRIs can offer in OCD, which might have made a difference to his future. It is now clear that if he’d been coprescribed a benzodiazepine, trazodone or propranolol, these drugs might have minimized his adverse reactions. Treatment might have been able to continue until his body had adjusted to the SSRI. Alternatively, if a lower, 5 mg dose of Prozac had been available, he might have found the reactions disturbing but tolerable until they wore off.

These are not insignificant points. This man’s professional and family life were later torn apart irrevocably. His “instability” on the drugs may well have colored the reactions of his colleagues or his family to him. It may even have colored his own assessment of himself, leading him to give up on many things when he should not have done so. At the time, the idea that the injuries caused by a drug like Prozac might be both direct and indirect escaped me completely. It was a problem that was to revisit with a vengeance nearly ten years later.

TEICHER, GLOD, AND COLE

When I saw Tony, I was unaware that Prozac had already been reported to make people suicidal. I was in the process of moving jobs from a university post in Cambridge to one in Wales when the first paper by Martin Teicher, Carol Glod, and Jonathan Cole from Harvard appeared in the American Journal of Psychiatry in February 1990.⁴ This outlined the cases of six individuals who had become obsessively preoccupied with thoughts of suicide and in some cases had made suicide attempts after going on Prozac. The authors fingered the Prozac these patients had been given.

I first became aware of the article that summer, when visiting the Department of Pharmacology in Galway. Brian Leonard, my former head of department, asked me what I made of it. I suspected he had been asked by Lilly to give them a reaction. For both of us, the primary interest in the Teicher report lay in the fact that drugs supposed to increase serotonin levels were not supposed to lead to suicide.

A series of articles by Herman van Praag during the 1970s and 1980s put forward the idea that individuals with low levels of serotonin metabolites in their cerebrospinal fluid were liable to impulsive acts.⁵ On this basis Prozac might even be better than other drugs for patients who were suicidal. Although I was skeptical of van Praag’s proposal,⁶ it was difficult to know where the Teicher phenomenon might fit into this story.

Teicher was a biologically oriented psychiatrist with a background in preclinical research, testing out hypotheses by giving drugs to animals. He had done significant work on circadian rhythms and had a general interest in psychopharmacology. Glod was a nurse tutor who later went on to an academic position. Cole, a professor of psychiatry at McLean Hospital, had been responsible in the early 1950s for the first randomized controlled trials on chlorpromazine and had considerable experience in assessing and managing the problem of antipsychotic-induced side effects such as tardive dyskinesia. This was a man who knew all about the hazards of scare stories about drugs in the public domain—a man to whom the American Psychiatric Association turned to contain public hysteria. Their article described six patients who came to their attention during 1988.⁷

• First was a 62-year-old woman, Mrs. A, a patient of Cole’s, with a 17-year prior history of depression, who had been put on Prozac as part of a clinical trial for Lilly. On the eleventh day of treatment with a 60 mg dose of Prozac, she had “forced obsessional suicidal thoughts consisting of intense and obsessive wishes to kill herself and described by Mrs. A as ‘uniquely bad’ … she felt ‘death would be welcome.’ She also felt like jumping out of her skin, but had no signs of motor restlessness.” Her Prozac was stopped and she improved considerably after three days. As Cole later put it, he’d seen patients who were suicidal before but never anything quite like this.⁸

• Second was a 39-year-old man with a long history of depressions. He had previously done well on an MAOI; after a relapse, he was switched to Prozac. After three weeks on a 20 mg dose he appeared to be more depressed and preoccupied with “violent self-destructive fantasies.” After Prozac was discontinued, imipramine and doxepin (both serotonin reuptake inhibitors) were tried but did not appear to help. According to Teicher, this man’s suicidal thoughts persisted until the MAOI was restarted, and he developed similar suicidal thinking again when reexposed to Prozac a year later. Just what happened this patient was less than completely clear, as I was later to find out.

• The third case described was a 19-year-old student who seemed partly phobic and partly psychotic, with hints of an eating disorder as well as depression. She had previously had a variety of medications and occasional suicidal thoughts. Over the course of two weeks on a mixture of Prozac and the antipsychotic perphenazine, she became paranoid, depressed, irritable, and developed “disturbing self-destructive thoughts.” Her Prozac was increased and her perphenazine reduced because she showed signs of akathisia, but she became more depressed and preoccupied with thoughts of death. When her Prozac was increased further, she became actively suicidal. After a further increase in Prozac to 80 mg per day, she became violent and self-mutilating. When Prozac was finally discontinued, her self-destructive urges eased and she subsequently improved markedly.

• Fourth was a 39-year-old woman described as having a borderline personality disorder. Her depressed moods responded to an MAOI but she suffered side effects. She had a previous history of suicide attempts that appeared to be cries for help. Two weeks after being put on 20 mg of Prozac per day, she became significantly more depressed, with persistent thoughts of suicide. Although she herself began to blame the drug, she wished to continue taking it, apparently because other people had responded to it. After she began to drink alcohol some weeks later, while on an 80 mg daily dose of Prozac, her Prozac was stopped. Two weeks later she made a suicide attempt that did not appear to be a call for help. When interviewed after the suicide attempt, she made it clear that she had been having persistent severe suicidal ruminations, that she felt unreal, and that she had a belief she could neither fight nor control her suicidal impulses. The suicidal thoughts diminished over three weeks, and when she went back on the MAOI, she got much better.

• Fifth was a 39-year-old woman whose past depression had been successfully treated with MAOIs. She had had persistent suicidal thoughts before but no suicide attempts. After starting on 20 mg Prozac per day, her dose was increased to 40 mg per day, at which point she began to have suicidal thoughts for the first time in years—fantasizing about purchasing a gun, something she’d never done before. On 80 mg of Prozac per day, she complained of out-of-body and other symptoms. When her Prozac was stopped, the suicidal thoughts cleared up. She later said that while on Prozac she had embraced thoughts of suicide in a way she had never done before. There was something different about this kind of suicidality.

• The key case in the series was a 30-year-old woman with a history of bipolar and multiple personality disorder, who had first been suicidal at the age of 17. MAOIs seemed to help her; tricyclic antidepressants did not. Teicher put her on a combination of medications, but she remained anxious, depressed, suicidal, and withdrawn. When Prozac was added to the mix, she appeared to get worse, with increased feelings of anxiety and splitting. She began to self-mutilate, planned lethal overdoses, and put a loaded gun to her head. One of her internal personalities began to shout at her to commit suicide. At this point her Prozac was discontinued, but it took a month for her suicidality to clear up.

Subsequently, it became clear that Teicher and his colleagues had other cases. These included a 15-year-old boy with OCD who had actually committed suicide after two weeks on Prozac.⁹

This was a complex group of patients on a range of medications other than Prozac, and with a range of diagnoses in addition to depression. Some had been suicidal before. Why implicate Prozac? These senior investigators, who had seen depressed and suicidal patients before, believed they had never seen anything quite like this. However much suicidality there had been in the background of some of these patients, something new seemed to emerge with treatment. All appeared to be reporting a recognition that “Gee, I’ve been suicidal before but never anything quite like this. This was ridiculous.”¹⁰

Publication of the Teicher article prompted a firestorm of criticism. These were cases being treated in a specialized center for suicidal and complex patients. There might be no implications for normal clinical practice. The alternative possibility—that the problem might be even worse in normal clinical practice, that less severely ill patients might have been at even greater risk—was apparently never contemplated by either Teicher or his critics. Another complaint was that these patients were on multiple other medications: How, therefore, could Prozac be blamed? Again, the alternative—that these other medications might have been protective—was never considered. Nobody knew that Lilly had put patients in its clinical trials on some of these other medications to minimize Prozac-induced problems.¹¹

THE PUZZLE DEEPENS¹²

I filed the Teicher article for further reference. A few weeks later, a community worker brought a patient with a peculiar story into the hospital. He had been a senior manager in a public utility company. After his retirement, 63-year-old Alan L. had moved with his wife to Wales. He was a very English stiff-upper-lip type, of the friendly rather than severe variety. Alan had a history of depression, which did not include suicidal thoughts. Thirty years before, he had been prescribed a combination of an MAOI and benzodiazepines and remained on them after recovery. During the 1980s benzodiazepine fuss, he reduced and discontinued these without much difficulty, continuing with the MAOI. When he retired to Wales, his mood slipped and he sought help. But his new primary-care physicians and psychiatrists didn’t know him.

A decision to change his medication was taken, and things began to slip out of control. He had to be admitted to the hospital. He was subsequently seen regularly in an outpatient clinic, where his antidepressant was changed frequently. During 1988 and 1989, he was given flupenthixol, Parstelin, alprazolam, thioridazine, viloxazine, and maprotiline,¹³ along with Valium. Nothing seemed to work very well, but he had no suicidal ideas during this period. Then, in January 1990, he went on dothiepin, which, unlike the other drugs with which he had been treated, has some serotonin reuptake-inhibiting properties. A week after this, he took a minor overdose of sleeping pills.

He developed a classic melancholic depression with early morning waking, mood variation so that he was worse in the morning and improved in the evening, poor concentration, loss of appetite, and loss of interest. In the hospital, he responded to electroconvulsive therapy. He was discharged on amoxapine and tranquilizers and did well at home for four months. But in August, he began to wake again early in the morning and found his mood swinging. His concentration slipped and he became apathetic. His amoxapine was changed to trazodone, with little effect.

Then he was put on 20 mg of Prozac. According to his wife, his spirits lightened during the subsequent week. He became more active but also tenser and more restless. Sixteen days after starting Prozac, he got out of bed at 5:00 a.m. and went walking in the rain. He came back five hours later with sand in his shoes, seemingly unable to give an account of where he had been. Detailed questioning later at the hospital revealed that, intensely preoccupied by suicidal thoughts, he had set off determined to kill himself by throwing himself into one of the many quarries around the area. He later told us that the only thing that had prevented this happening was his inability to find a suitable locale.

Five days later, he again woke early and walked into the sea fully clothed. The coastline where he lived is very shallow and he had to wal...