Sunday, November 2, 2008

A Short Medical History of Antidepressants


The first antidepressant to gain attention was chlorpromazine. In 1939 the Pasteur Institute found that dimethylamines were powerful and less toxic antihistamines. During world war II they began to be marketed as phenbenzamine (Antergan), and diphenhydramine (benadryl). It was found that the antihistamines had an effect on brain chemistry, prompting a sedated state. This led to the marketing of promethazine (phenergan), common today for travel sickness, and diethazine, found useful for physical and mental symptoms of Parkinson’s Disease, as well as its analgesic properties. In 1950, Rhone-Poulec, a leading French laboratory, desired a clearer understanding of antihistamines and possible benefits. Pierre Koetschet, who headed the project, began with behavioral tests in animals. Additionally, phenothiazines were developed, including chlorpromazine, known as RP4560. This particular phenothiazine showed very little secondary effects. Simon Courvoisier, who headed the behavior tests, found that chlorpromazine had peculiar effects. Rats trained to climb a rope to a platform with food when administered chlorpromazine, showed little interest in climbing. Courvoisier attributed this simply to a lack of interest instead of a possible lack or coordination of severe sedation.


Between April and August of 1951, chlorpromazine was given to leading French and international physicians. What they found was a number of central effects including drop of body temperature, analgesia, and mild sedation. Initially they pondered its helpfulness addressing medical stress, serious burns, and cardiovascular disturbances, such as Raynaud’s Disease.
Jean Delay, a leader in French psychiatry, administered the drug to patients in the Hospital Sainte-Anne. Delay’s findings were published and chlorpromazine gained notable attention as a psychiatric breakthrough. Delay organized a conference in Paris in 1955 to address leading European psychiatrists, many excited about an option for those affected by mental illness. The drug mainly gained popularity in American asylums, favored by doctors and nurses, hoping to calm those with various forms of mania. The large pharmaceutical companies quickly responded. The relationships between drug manufacturers, clinical investigators, and psychiatrists led to the formation of the Collegium Internationale Neuropsychopharmacologium (CINP).


As with chlorpromazine, imipramine developed also from a fascination with antihistamines. One drug company, Geigy, found phenothiazine worthy of more research, finding imipramine through the tricyclic anti-depressant-iminodibenzyl. This compound had originally been synthesized in 1898 by Thiele and Holzinger, being described chemically, yet without any idea of possible uses for it. When this compound was reexamined by Geigy in the late 1940’s, animal testing suggested it might be used for anesthesia. It was in 1950 that Geigy supplied the iminodibenzyl closest to the chlorpromazine structure to schizophrenic and mentally ill patients. Imipramine was given to 300 patients, many of whom had been chlorpromazine users. When one patient escaped from the hospital and rode a bicycle into town, singing joyfully at the top of his lungs, wearing only a nightshirt, Geigy discontinued the study.


In 1955, a second study was set up, this time for people who considered themselves depressed. Of the 40 participants, most responded very positively, attributing arousal of interest and activity to the drug. The promising results were presented at a poorly attended World Congress of Psychiatry in Zurich, as well as Galesberg State Hospital in Illinois. Imipramine was carefully called an anti-depressant, yet not a euphoriant. Treatment with the drug was found to restore interest in general activities, while easing anxiety. Sleep was found not to be effected like the common hypnotic drugs. Despite what appeared to be a hopeful option for those with depression, the drug was not pushed for a number of years. There was uncertainty whether there truly was a market. Depression was not seen as a disease or being treatable like other disorders. While imipramine was still being debated by Geigy and those in the field, another antidepressant did enter the market, Iproniazid. During World War II German engineers depended on using the compound hydrazine to power their rockets. When the war ended large quantities of hydrazine were bought up by chemical companies who had an interest in pharmaceutical production. Hydrazine was formulated into certain derivatives, one being iproniazid at a laboratory in Nutley, New Jersey. As a monoamine oxidase inhibitor (MAOI) it was used for Tuberculosis. Iproniazid was withdrawn not long after its use due to reports of jaundice.


In 1958 drug company, Merck, began to look at amitriptyline, exhibiting a three-ringed central structure which looked similar to imipramine. Amitriptyline began its life on the market in 1961. Drug companies Roche and Luncbeck followed in production. Merck sought to begin marketing the drug by promoting the idea that depression was not confined to simply the asylum. Merck was intrigued by the book, Recognizing the Depressed Patient, by Frank Ayd, published the same year of amitriptylines introduction to the market. The text is simple, forthright, and written for the non-psychiatrist. Merck bought 50,000 copies of Ayd’s book, distributing it worldwide. The book matched Merck’s goal of marking amitriptyline a more relevant drug for more people. The idea caught on and it sold considerably, also leading to larger sales of imipramine. In 1966, Psychiatric Illness in General Practice was published, suggesting that primary care physicians rather than psychiatrists might be seeing that majority of nervous disorders, which in turn indicates depression.


Avrid Carlsson, a Swede and one of the first neuroscientists took the antihistamine chlorpheniramine and manipulated it coming up with zimelidine. Carlsson applied for a patent on zimelidine as a selective serotonin reuptake inhibitor in Sweden, Belgium, and Britain in 1971. In 1980, a revised diagnostic psychiatric manual was introduced, DSM-III. The DSM manual lumped all depressive disorders into one large category, major depressive disorder. Soon there was a national campaign, Depression Awareness, Recognition, and Treatment.


Prozac hit the United States and Canada in 1988. Prozac is a registered trademarked name for fluoxetine hydrochloride. The appeal was that Prozac could be taken once a day with little side effects. This drug and other new SSRI’s took off in America, with patients asking for them by name. Within three years of Prozac’s launch, annual sales neared $800 million. In the early 1990’s the idea grew that SSRI’s like Prozac could alter lives for the better, curing shyness, low self-esteem, and compulsiveness, in addition to depression.


There is overwhelming evidence that depressive disorders affect an overwhelming amount of people. In the United States, close to 9% suffer from some type of depressive disorder, while 3.7% suffer from bipolar disorder. Diagnosis of major depression is based on certain clinical criteria published in the American Psychiatric Association. The criteria includes at least two weeks of depressed mood, loss of interest, or loss of sense of pleasure in addition to four of the other seven features which would declare psychological impairment.


For those who suffer depression, physical symptoms are common. A recent study suggests a promising correlation between antidepressants and improvement in physical symptoms. Patients were randomized to receive three selective serotonin reuptake inhibitors and were periodically assessed for depressive and physical symptoms over nine months. Depressed patients were taken from 37 practices who were about to begin antidepressant therapy. They were randomized to receive either paroxetine, fluoxetine, or sertraline. Almost 600 patients followed through with the nine month study providing encouraging information. Of the 14 physical symptoms assessed, the most common ones were fatigue, sleep problems, headaches, nausea, and back pain. The periodical questionnaires found that all physical symptoms improved substantially in the first month with antidepressant use, with a plateau effect occurring during the remainder of the study. Depression continued to show gradual improvement over a nine month period. This was charted using the Hopkins System Checklist, which has shown to detect differences in depression severity between treatment options. A number of health related quality of life domains were evaluated within eight domains including physical functioning, social functioning, mental health, general health perception, and pain. The various HRQL domains, life physical symptoms, increased rapidly in the first month of treatment, however, improvement continued throughout the study.


Although awareness of healthy treatment for depression has risen largely in the last couple of decades there remains many in the health field who find depression under treated. A consensus conference, organized by the National Depressive and Manic Depressive Association on January 17-18, 1996, was put together in order to address such concerns. The audience included health policy makers, clinicians, patients and their families, and a general public. The consensus panel members pulled from each audience category listened to various presentations from experts in epidemiology, treatment services, and those involved in diagnosis studies. Panel members engaged in discussion with experts and concluded an "overwhelming evidence that individuals with depression are being seriously under treated." The panel attributed the under treatment to a lack of public education programs, failure of patients to recognize symptoms, reluctance to see mental health care specialists due to stigma, as well as lack of health insurance. The panel found health care providers as having limited training in interpersonal skills, inadequate time to evaluate depression, failure to consider psychotherapeutic approaches and inadequate doses of antidepressant medications. Incentives for positive identification of depressive disorders were also suggested in the conference official statement.


One especially encouraging argument for a stronger stance with antidepressant medication is the link to suicide. About 30,000 Americans commit suicide on a yearly basis, with about 60% occurring during a mood disorder, most being untreated. A study was done to examine the relationship between antidepressant medication prescriptions and suicide rates by analyzing associations at a country level in the United States. The study found that within classes of antidepressants, prescriptions for serotonin reuptake inhibitors and newer non-SSRIs, like nefazodone hydrochloride or mirtazapine were associated with lower suicide rates. Higher suicide rates were found in rural, lower income areas where tricyclic antidepressants were more often used. Therefore suicide rates are lower where SSRIs and newer non-SSRIs are more available due to better quality mental health care.


Antidepressant medications have successfully reduced the severity of panic symptoms for those who suffer from panic disorder. Those who suffer from this disorder experience intense fear and discomfort, palpitations, sweating, nausea, shortness of breath, and other dangerous symptoms. Those unpredictable symptoms can impair patient’s normal activities at home and work. Antidepressants have improved the lives for those suffering these potentially debilitating consequences. Selective serotonin reuptake inhibitors and tricyclic antidepressants have shown to be equally effective in reducing panic severity and the number of attacks.

1 comment:

  1. Research indicates when people become severely depressed, changes occur in chemicals in the brain. Antidepressant medication is designed to correct the imbalance of chemical messages between nerve cells (neurones) in the brain. Certain antidepressants are more suited to being taken when pregnant or breastfeeding. When the symptoms are directly due to depression, then they are likely to begin to improve following four to six weeks of effective therapy.
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    Bobwilliams
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