Tuesday, March 6, 2012

From "Melancholia" - the Birth of Electroconvulsive Therapy

Upon seeing the facilities in Ugo Cerletti's Roman laboratory, German histopathologist Franz Nissl reportedly broke into tears and said "Impossible! Why don't you come work with us?" His multilingual former student had studied with some of Europe's finest medical luminaries, including Emil Krepelin (who was the first to describe manic depression) and dementia specialist Alois Alzheimer. But despite offers to work in better conditions, the brilliant neurologist stayed in his home country. His decision paid off. In 1935, after a series of promotions, Cerletti became professor of psychiatry and director of the Clinic for Nervous and Mental Diseases at the University of Rome.

There he continued his research on epilepsy, using electroshock to induce seizures in dogs and then examining their brains for signs of damage. As he read papers on Meduna's convulsive therapy, Cerletti wondered if it might not be possible to use electricity in place of PTZ. Having shocked many dogs, he knew that unconsciousness came almost instantly upon application of current, unlike the horrors of a PTZ seizure. But Cerletti was not sure of the duration and intensity of electricity required to induce a therapeutic seizure in a human patient. The only information available on the subject was less than helpful. The United States had for some time been using an "electric chair" for executions, but the current used was far above anything a doctor might find useful.

Nevertheless, Cerletti continued pondering the idea. When he presented a paper on the possible uses of electricity in convulsive therapy at a 1937 Milan conference, his ideas met little interest. Discouraged but not yet ready to give up, Cerletti and his assistants visited a nearby slaugherhouse which used electricity to kill pigs for butchering. They hoped to determine what it took to kill a pig. But when they saw the electrodes applied to the pig's ears and the switch thrown, they realized that the pig was not dead but merely stunned. When the butcher was delayed in cutting the throat, the pig exhibited all the signs of a grand mal seizure: left alone for a few minutes, it would get up and rejoin its porcine companions.

There was no shortage of pigs at the abattoir, and so Cerletti and his colleague Lucio Bini experimented with exactly how much electricity it would take to kill a pig. In Cerletti's words:
It turned out that the more serious results (prolonged apnea sometimes lasting many minutes and, exceptionally, death) appeared when the current crossed the chest; that this application was not mortal for durations of some tenths of a second; and, finally, that passage of the current across the head, even for long durations, did not have serious consequences. It was found that pigs, even when treated in this last way several times, 'came to' gradually, after a fairly long interval (five to six minutes), then started moving, next made various attempts to get shakily to their feet, and finally ran rapidly to mix with their mates in the pen.
These clear proofs, certain and oft repeated, caused all my doubts to vanish, and without more ado I gave instructions in the clinic to undertake, next day, the experiment upon man.
On April 11, 1938 Cerletti and several assistants attached electrodes to the head of a 39 year-old man. The patient had been arrested at the Rome railway station for boarding the train from Milan without a ticket. When he arrived at the hospital he spoke only in neologisms and incoherent gibberish, making it impossible to determine his identity. Cerletti and his assistants first shocked him for 0.2 seconds with a 70 volt charge: he tensed and began singing but did not convulse. Cerletti ordered a second shock of 110 volts for 0.5 seconds. At this the patient said suddenly, in a low voice, "Not a second. Deadly!" The observers urged Cerletti to reconsider, but he went ahead with the second shock.
The immediate, very brief cramping of all the muscles was again seen; after a slight pause, the most typical epileptic fit began to take place. True it is that all had their hearts in their mouths and were truly oppressed during the tonic phase with apnea, ashy paleness, and cadaverous facial cyanosis - an apnea which, if it be awe-inspiring in a spontaneous epileptic fit, now seemed painfully never-ending - until at the first deep, stertorous inhalation, and first clonic shudders, the blood ran more freely in the bystanders' veins as well; and, lastly, to the immense relief of all concerned, was witnessed a characteristic, gradual awakening 'by steps'. The patient sat up of his own accord, looked about him calmly with a vague smile, as though asking what was expected of him. I asked him: 'What has been happening to you?' He answered, with no more gibberish: 'I don't know; perhaps I have been asleep.'
Medical Experiments Then and Now

The Tuskegee Syphilis Study– where hundreds of poor blacks were given placebos without their knowledge so that doctors could chart the course of untreated syphilitic infection from 1932 to 1972 – have become one of the most infamous and shameful chapters in the history of American medicine. But medical experimentation on human subjects, with and without informed consent, is still being practiced today. No medication can be put on the market without clinical trials to ascertain its efficacy and its safety. Finding test subjects remains a challenge for researchers, and one which they have met in many different – if not always entirely ethical – ways.

From the 1940s through the 1970s, American doctors regularly performed medical experiments on prison inmates. Prisoners were infected with diseases like cholera, syphilis, malaria, ringworm and typhoid fever, then given unproven treatments. By 1972 the American pharmaceutical industry was doing more than 90% of its testing on prisoners. The majority of these plaintiffs were black men who were paid between $2 and $3 a day for "volunteering" for these tests.

Since 1978, Title 45 (the "Protection of Human Subjects" Act) has strictly regulated research on prisoners. But despite this experimentation continues. Between 2006 and 2008, a drug company called Hythian contracted with jurisdictions in at least five different states including Indiana, Washington, Texas, Louisiana, and Georgia to enroll criminal defendants in an experimental drug addiction treatment program. As part of this program, state judges “divert” drug court participants, who have been found in possession of drugs, into an experimental treatment program. called Prometa. The program involves thirty days of treatment with three different drugs, none of which has been approved for use in addiction treatment by the FDA.

Meanwhile, pharmaceutical companies have begun outsourcing their research to foreign facilities. According to the United States Department of Health and Human Services, roughly 80 percent of drug approvals in 2008 were based in part on data from outside the U.S: 8% of drugs approved for use in the U.S. were only tested using subjects in foreign nations. In 1997 a series of experiments in 15 African countries tested the effectiveness of the drug AZT in preventing transmission of HIV from a pregnant mother to her child. In this experiment, a "control group" of women were given placebos and the rates of infant infection were compared to those women given AZT. In a highly critical editorial in the New England Journal of Medicine, Dr. Marcia Angell charged "The fact remains that many studies are done in the Third World that simply could not be done in the countries sponsoring the work. It seems as if we have not come very far from Tuskegee after all."