for review…

Posted on Tuesday 31 August 2010

Like countless medical students before me, my first encounter with Schizophrenia was jarring and remains with me still. The woman was in her late thirties in a Memphis mental hospital. As she began to tell me of her delusional ideas, I felt myself disengaging [involuntarily]. Her ideas were bizarre, paranoid, and fantastic, yet they were delivered with almost no emotion. I had no idea what to say or think, but when I later heard that Psychiatrists were formerly called Alienists, I knew exactly why that term was chosen. It’s an overwhelming illness for the afflicted, their families, and those who attempt to treat it. In many ways, the history of its treatment is a testimonial to the magnitude of that illness we know as Schizophrenia:

… at a 1935 neurology conference in London that Egas Moniz attended, he noted the data presented by Jacobsen and Fulton showing that a leukotomy on two chimpanzees successfully reduced their aggressive behavior without untoward side effects. Learning of this likely prompted Moniz’s bold step to attempt the process, and in 1936, he published his first report of performing a prefrontal leukotomy on a human patient. Moniz refined his surgical methods by fashioning a "leucotome", a surgical instrument with a movable wire loop which he replaced with a steel band. He used this instrument to cut six holes in each of the brain’s two hemisphere’s white matter, severing the connections of the prefrontal cortex to the rest of the brain. Moriz judged the results acceptable in the first 40 or so patients he treated. However, he conceded that patients who had already deteriorated from the mental illness did not benefit much from the operation. Moniz concluded the following, "Prefrontal leukotomy is a simple operation, always safe, which may prove to be an effective surgical treatment in certain cases of mental disorder."Moniz did no long term follow up, and his evaluations of the success of the procedure were short term only. He believed deeply that the benefits of surgical lesions in the frontal lobes, even if some behavioral and personality deterioration occurred, were needed to treat the debilitating effects of severe mental illness. He was the first to write a scientific report of lobotomy as a psychosurgical treatment for severe mental disorders in 1936.

In 1939, Moniz was shot by a disaffected patient and as a result was confined to a wheelchair for the rest of his life. In 1949 he received the Nobel Prize, "for his discovery of the therapeutic value of leucotomy in certain psychoses."  This procedure consists of cutting the connections to and from the prefrontal cortex, the anterior part of the frontal lobes of the brain. The procedure immediately became popular, as at that time there was not an effective treatment for psychosis… Soon Dr. Walter Freeman developed a version of the procedure [the transorbital lobotomy] which was much easier to carry out. Due in part to this procedural ease, lobotomy was often prescribed injudiciously and without regard for modern medical ethics. Endorsed by such influential publications as The New England Journal of Medicine, lobotomy became so popular that, in the three years immediately following Moniz’s receipt of the Prize, some 5,000 lobotomies were performed in the United States alone, and many more throughout the world. Even Joseph Kennedy, father of U.S. President John F. Kennedy, had his daughter Rosemary lobotomized when she was in her twenties. Freeman performed at least 4,000 lobotomy operations during his career. Since the 1950s, this procedure has fallen into disrepute and is even prohibited in many countries.

Convulsive therapy was introduced in 1934 by Hungarian neuropsychiatrist Ladislas J. Meduna who, believing mistakenly that schizophrenia and epilepsy were antagonistic disorders, induced seizures with first camphor and then metrazol (cardiazol). Within three years metrazol convulsive therapy was being used worldwide.  In 1937, the first international meeting on convulsive therapy was held in Switzerland by the Swiss psychiatrist Muller. The proceedings were published in the American Journal of Psychiatry and, within three years, cardiazol convulsive therapy was being used worldwide.  Italian Professor of neuropsychiatry Ugo Cerletti, who had been using electric shocks to produce seizures in animal experiments, and his colleague Lucio Bini developed the idea of using electricity as a substitute for metrazol in convulsive therapy and, in 1937, experimented for the first time on a person. Sherwin B. Nuland, having discussed the matter with a first-hand observer in the 1970s, gave the following description of the results of the first use of ECT on a person:
    "They thought, ‘Well, we’ll try 55 volts, two-tenths of a second. That’s not going to do anything terrible to him.’ So they did that. […] This fellow — remember, he wasn’t even put to sleep — after this major grand mal convulsion, sat right up, looked at these three fellows and said, ‘What the fuck are you assholes trying to do?’ Well, they were happy as could be, because he hadn’t said a rational word in the weeks of observation."
ECT soon replaced metrazol therapy all over the world because it was cheaper, less frightening and more convenient.  Cerletti and Bini were nominated for a Nobel Prize but did not receive one. By 1940, the procedure was introduced to both England and the US. Through the 1940s and 1950s the use of ECT became widespread. ECT is the only form of shock treatment still performed by modern medicine.
Manfred Sakel [1900-1957]

Insulin shock therapy or insulin coma therapy was a form of psychiatric treatment in which patients were repeatedly injected with large doses of insulin in order to produce daily comas over several weeks. It was introduced in 1933 by Polish-Austrian-American psychiatrist Manfred Sakel and used extensively in the 1940s and 1950s, mainly for schizophrenia, before falling out of favour and being replaced by neuroleptic drugs. Insulin coma therapy and the convulsive therapies were collectively known as shock therapy. Although insulin coma therapy had disappeared in the USA by the 1970s, it was still being used at that time in some countries such as China, and the former Soviet Union.

In 1927 Sakel, who had recently qualified as a doctor in Vienna and was working in a psychiatric clinic in Berlin, began to use low [sub-coma] doses of insulin to treat drug addicts and psychopaths. Having returned to Vienna, he treated schizophrenic patients with larger doses of insulin in order to produce coma and sometimes convulsions. Sakel made public his results in 1933 and his methods were soon taken up by other psychiatrists. Joseph Wortis, after seeing Sakel practice it in 1935, introduced it to the USA. British psychiatrists from the Board of Control visited Vienna in 1935 and 1936, and by 1938 thirty-one hospitals in England and Wales had insulin treatment units. In 1936 Sakel moved to New York and also introduced insulin coma treatment into American psychiatric hospitals. By the late 1940s the majority of psychiatric hospitals in the USA were using insulin coma treatment.
[Unlike the earlier treatments, the antipsychotics emerged from mainstream medicine and were not the product of any single scientist.]

In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs… The chemist Paul Charpentier produced a series of compounds and selected the one with the least peripheral activity, known as RP4560 or chlorpromazine, on 11 December 1950. Simone Courvoisier conducted behavioural tests and found chlorpromazine produced indifference to aversive stimuli in rats. Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the Val-de-Grâce military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients.and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards…

Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns, Reynaud’s Syndrome, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an intravenous dose to psychiatrist Cornelio Quarti who was acting as a volunteer. Quarti noted the indifference, but fainted upon getting up to go to the toilet, and so further testing was discontinued. Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on January 19 1952, it was administered [alongside pethidine, penthothal and ECT] to Jacques Lh. a 24 year old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.

Pierre Deniker had heard about Laborit’s work from his brother in law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Hôpital Sainte-Anne in Paris where he was Men’s Service Chief. Together with the Director of the hospital, Professor Jean Delay, they published first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents. The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour. They also found that doses higher than those used by Laborit were required, giving patients 75-100 mg daily.

Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the Verdun Protestant Hospital in Montreal trialled it in 70 patients and also noted its striking effects, with patients’ symptoms resolving after many years of unrelenting psychosis. By 1954, chlorpromazine was being used in the United States to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders… The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases. But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotics were developed…
While it’s hard to imagine now, each of these treatments was seen as a massive breakthrough in the treatment of an illness that can be devastating to the course of a human life. All of them have gone through a similar cycle of great promise, widespread usage, overutilization, and finally concern over unintended consequences. While modified versions of ECT are still used in selected cases of severe depression, the first three have no place in the modern treatment of Schizophrenia. The neuroleptics, once seen as magic are now known for their toxicity and the focus is on developing less toxic alternatives. As each treatment emerged, the phases are those of any paradigm shift – each new solution ultimately leading to new problems.

It’s easy to criticize a treatment for its failures. I’ve been critical of the newer atypical antipsychotics. But that criticism is not for the effort. The drugs were developed in an attempt to avoid some of the more difficult and sometimes permanent neurological side effects of the earlier neuroleptics, and they have generally moved towards that goal. The criticism is instead directed towards the minimization by the manufacturers of the unique toxicities of these drugs and overblowing their effectiveness. Even worse, the invasion of clinical medicine by market driven [often downright corrupt] strategies and the attempts to extend the use of these drugs inappropriately is a genuine tragedy for medical science.

Today, in one of my volunteer jobs, I saw a 17 year old boy who I’ve seen for several months. The boy had been quietly psychotic, mostly staying in his room for several years ["he’s always been shy and quiet"]. In spite of constant attacking auditory hallucinations, paranoid feelings, and uncanny mystical ideas, he’d continued high school and graduated with his psychosis largely un-noticed. I initially tried an "atypical" [Resperidol] hoping to avoid side effects, but his symptoms persisted in spite of increasing the dose. I started him on an older drug [Haldol] and at 2mg/day, his symptoms abated. Predictably, today he and his father came to discuss a frightening dystonic reaction, so we spent our time talking about how to manage his EPS if it happened again.

As I was driving home, I was fretting about the long term management of this boy’s illness, wondering what his life would be like, worrying about neurological symptoms that might be in his future. Then I recalled that his father was quietly crying after his son left to use the restroom. He said that for the first time in years, his son was coming out of his room and interacting with the family, watching tv with them, playing with his younger sisters. They were tears of joy. Schizophrenia can still be a show stopping illness, particularly in patients like this young man where the onset is prolonged and unrelenting, but for the moment, we’re headed in the right direction. His fate is definitely going to be better than before any treatments were available at all. They’re far better than in the days of lobotomy or the shock therapies. And maybe we’ll be able to use a less toxic drug as things progress. No silver bullet yet, but a bullet nevertheless. I hope that the antipsychotic research continues in earnest, driven by this young man’s needs rather than by some corporate balance sheet…
    Ivan the Terrible
    August 31, 2010 | 10:55 PM

    We should not discount the achievements of the early drug developers. They did some very good things. They discovered lithium treatment for mania. They discovered the early antidepressant drugs. And they discovered the early antipsychotic drugs. There was room for improvement in all of these, but make no mistake – they were dramatic positive developments.

    Most of the work in the past 20 years, however, put marketing first. Humbug aside, the goal was not to improve the management of depression or mania or schizophrenia but to jump whatever bar the FDA was setting in order to get a product on the market. And for this, academic key opinion leaders were indispensible. Eventually, the tail began to wag the dog.

    August 31, 2010 | 10:55 PM

    I’ve seen that side also, and the one constant is how not one person responds the same to one treatment. I have witnessed 2 in a decade do a 360 on meds. I’ve seen a lot and of different magnitudes in several hospitals, some hard core places. It’s hard on parents to see their children come and go as transcient visitors to a place they once knew in themselves.

    September 1, 2010 | 6:43 AM

    “Most of the work in the past 20 years, however, put marketing first. “

    That time-frame seems about right to me. In my time in grade, most of my experience with Schizophrenia was during residency and time on the faculty training residents [1974 – 1987] . That was the pre-atypical-antipsychotic era as well as a time when the funding for mental health care was evaporating. Not long after I left academic medicine, Charlie Nemeroff arrived at Emory in that wave of biological psychiatry [in Atlanta, that was actually was code for drug research – often industry funded]. Candidly, I never paid much attention to him or his colleagues. They seemed like chemists rather than doctors. For a time, I referred people needing medication expertise in their direction thinking they might be able to help, but that didn’t happen – so the gulf widened. The new psychiatrists were mostly doing “med evals” and “med checks” and sent psychotherapy to other specialties. Somehow, psychotherapy and psychopharmacology became dichotomous rather than neighbors in a toolbox, along with a lot of other things. Except for the coming of the SSRI’s, most of what they talked about seemed superfluous – DSM this-or-that, new atypicals, everything “bipolar,” everything was “exciting new…” I recall once thinking that the old term for Psychiatrists – Alienists – which came from the idea that psychotic people were “aliens,” ought to be changed to Alienish. These new colleagues seemed like Aliens to me. I felt increasingly cynical, but questioned that feeling, like I was being defensive.

    When I agreed to volunteer in several public clinics here in the “country,” I thought I was going to have to do a lot of boning up on my psychopharmacology to catch up with all the changes since I had moved into a practice more oriented towards psychotherapy and analysis for the last twenty years. I did my homework, but there wasn’t that much to learn. And now that I’ve been at it for a while, I find I spend a lot of time getting people off of those drugs that are in the “ask your doctor” tv ads because of side effects, and prescribing much as I did over twenty years ago. I feel like Rip Van Winkle – except I woke up after twenty years and things hadn’t changed after all. And I often wonder what all of that was about. Yours is the best answer,

    “… the goal was not to improve the management of depression or mania or schizophrenia but to jump whatever bar the FDA was setting in order to get a product on the market.”

    That academic medicine and its key opinion leaders were part of that is just pathetic, just plain pathetic…

    September 1, 2010 | 7:00 AM


    I’ve particularly appreciated your comments and the comments from Mary Weiss on the various blogs. With the case in this post, the young man was cutting himself and had bought a large hunting knife. He described his suicide plans to a schoolmate who told a teacher. That’s how his illness came to our attention. His parents resisted hospitalization, but the boy requested it, so he went, but signed out AMA after three days because he was afraid of the other patients. He was headed in the Dan Markingson direction, so I had to be aggressive with medications. The alternative was likely fatal. On the other side of the coin, I’m older now. I’ve seen the problems caused by over-medication. So in spite of being glad to have some tools to address his illness, I’m much more aware of the possibility of unintended consequences than I was as a young resident doing what I was taught to do.

    Besides being appalled by some of the things that have happened in my specialty over the last number of years, returning to the treatment of the severely mentally ill after a long hiatus has been fascinating. I’m so much more aware of the constant double binds in every intervention, but that’s a lot easier to tolerate than it was long ago. I guess there’s something to be said for age and experience. Hearing examples of times when things have gone badly keeps all the possibilities fresh.

    September 1, 2010 | 8:21 AM

    I knew you’d never truly retire.

    September 1, 2010 | 1:14 PM

    A man named Fred Hassan runs Schering-Plough. His compensation in 2009 was $49,653,063. Perhaps incidentally, he laid off 16,000 people but sometimes a leader’s got to make tough choices yes? CEO compensation is it’s own can of worms in this topsy-turvy world of ours. At the same time, what possible justification could there be for the inheritors of Carter’s Little Liver Pills in any sense “earning” such remunerations?

    September 1, 2010 | 2:09 PM

    My daughter is a case of misdiagnosis based on antidepressant adverse reaction. Classic case for the last decade increase of childhood bipolar disorder brought to us by the KOL Joseph Biederman, who equates himself as “God”, in his deposition for a Risperdal trial. When asked his rank at Harvard he stated his rank and when asked what is above that, his replied, “God”. That’s the man who influenced psychiatrists back then, and now the fall out is, a steady course of dx of children younger and younger and being placed on these meds.

    Thanks for allowing my comments here. I’ve been reading yours throughout the blogosphere for a while now and always appreciate a professional speaking out to confirm what I’ve seen in person. I’ve had many speeches from doctors “I’m the doctor”, and been served a hefty dose of ego-driven arrogance to last me a lifetime as a result, leaving me skeptical and lacking in trust of doctors who blindly believe in medication efficacy and use without seeing RESULTS. There are doctors who believe in the medication paradigm with unwaivering and concrete stances….those are dangerous doctors who do not stop to see some of the dark side of what has happened to their patients.

    Exposing Nemeroff and others for what they are is a community service, frankly. So thanks for that.

    September 1, 2010 | 10:00 PM

    btw thanks again for allowing my comments. I’ve just checked at Carlat’s and as usual he screens and chooses what to approve (has always). I left a comment there asking about why the Seroquel XR would be allowed to be trialed currently at the UMN esp after the CAFE scandal, same Schulz, same AZ sponsored all up against a placebo for BPD. Some doctors do not like conversing with parents or patients. The road of a parent on this journey is not easy, we are up against the ppl such as the ones Mary Weiss was….thanks for the time here.

    February 5, 2011 | 11:33 AM

    […] In fact, Insel’s brand of Clinical Neuroscience itself comes from former Days of Wine and Roses [yet another synonym] – the discovery of the antipsychotic drugs. Psychiatry has grappled with two disease-like conditions since they were defined by Emil Kraeplin in 1893 – Dementia Praecox [Schizophrenia] and Manic-Depressive Illness [Bipolar Disorder]. The introduction of condition-specific medications in the 1950’s revolutionized Psychiatry and emptied the Mental Hospitals. But all was not so rosy, and we now deal with the plight of the Chronically Mentally Ill, the long term side effects of these drugs, and the perception of Psychiatrists as controlling people with toxic medications [see this week’s comments on Cartlat’s Psychiatry blog: Anatomy of an Epidemic: The Carlat Take, Part 2]. And there are other striking examples in our history [see for review…]. […]

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