Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (38 page)

Before the introduction of the psychotropic drugs, there were about 380 to 400 patients per 100,000 population in mental hospitals in the United States, a figure that had remained constant for almost a hundred years. After their introduction in the mid-1950s, this figure steadily and dramatically decreased, causing many state hospitals to close down for lack of patients. The number of mental patients in U.S. hospitals declined from 558,922 in 1955 to 61,772 in 1996. In the first decade of the twenty-first century, it is estimated that there are about 2.2 million American adults with schizophrenia.

35

Your Town, My Town, Miltown!

A humorous scene from a 1960s Hollywood film illustrates the public's embrace of tranquilizers. In a department store, a crowd of about thirty people gather around a woman who is having an anxiety attack. A man who has bent down to help her turns to the onlookers and shouts, “Anybody have a tranquilizer?” Twenty people promptly reach into their pockets and purses.

Anxiety is a universal human response to stress. The reaction may occur in either the presence or the absence of a definable threat, and its magnitude may be out of proportion to the threat perceived. Subjectively, it is experienced as a state of tension or vulnerability accompanied by feelings of dread. This psychological state is accompanied by various symptoms, including dilated pupils, muscular tension, a racing heart, hyperventilation, excessive perspiration, nausea, and flushing.

“M
UCH TO
M
Y
S
URPRISE
…”

As miraculous as penicillin is in fighting infections, it does not work against certain bacteria, particularly gram-negative organisms (those that do not react to the microscopic staining technique). In 1945 Frank Berger, a Czechoslovakian pharmacologist working at British Drug Houses Ltd. in London, was trying to find antibiotics that would work against these other organisms.

At the time, there was a commercial disinfectant that was effective against gram-negative organisms. Berger hoped to devise some form of it that would be safe in the human body. He made chemical analogs of the disinfectant and began conducting toxicity tests on mice.

The results were totally unexpected. “Much to my surprise,” these compounds produced paralysis of their limbs “unlike that I had ever seen before.”
¹
Depending on the size of the dose, complete recovery occurred within an hour. Notably, with doses too small to induce muscle impairment, the marked “quieting effect on the demeanor of the animals” remained evident, and this was described as “tranquilization.” Many more compounds were synthesized, one of which had superior activity in acting directly on muscles rather than at the neuromuscular junction.

The new tranquilizer was brought to doctors under the name mephenesin (Myanesin) as an agent to produce muscular relaxation during light anesthesia, but its very short duration of action and lack of consistency were major drawbacks. A structural analog, Robaxin, was introduced later for the relief of muscle spasm by the AH Robins Company. Reports began to appear that mephenesin could ease symptoms of anxiety without clouding consciousness, bringing about a relaxed feeling in tense patients.

In 1947 Berger moved to New Jersey to work at Wallace Laboratories, where he eventually became president. Seeking a longer-acting central muscle relaxant with more reliable absorption than mephenesin, he and his chemist, Bernard Ludwig, synthesized and screened more than 1,200 compounds before developing one that was effective for about eight times longer than mephenesin. It was given the generic name meprobamate. Almost eleven years elapsed between the discovery of mephenesin and the availability of meprobamate as a prescription drug in April 1955. Marketed as both Miltown and Equanil, it was found to dispel anxiety with less sedation than barbiturates, along with promoting general muscle relaxation.
²

The drug quickly grew in popularity, and within two years it was widely prescribed. The demand for it was unprecedented.
³
It was not surprising to see signs in pharmacy windows that read “Out of Mil-town” or “Miltown available tomorrow.” By 1956 one American in
twenty was taking tranquilizers within a given month.
⁴
In the late fifties, it became the most popular among all psychotropic agents, especially in the United States, and remained unchallenged until the development of Librium and other benzodiazepines, which caused less drowsiness, almost a decade later.

36

Conquering the “Beast” of Depression

Depressions are a group of disorders universally marked by low energy and a mood often described by the person as sad, “blue,” discouraged, or “down in the dumps.” Depressive syndromes are characterized by a wide array of symptoms. There is always a persistent change in behavior, with loss of interest or pleasure in nearly all activities, and this may be accompanied by feelings of worthlessness, hopelessness, and helplessness. Often depressions are marked by a pervasive sense of emptiness and deprivation, as well as anxiety. The individual may have an impaired ability to think, concentrate, or make decisions, and in severe cases there may be thoughts of death, suicide, or suicide attempts.
¹

Depression is the most common mood disorder that comes to the attention of physicians. In 2005, about 10 million Americans had a major depressive disorder.

Throughout history, fanciful terms were adopted in the description of different complaints we now call clinical depression. “Neurasthenia” bespoke “nervous exhaustion.” From before the time of Hippocrates and up until the middle of the nineteenth century, physicians believed that health depended upon a balance between various body fluids, or humors. “Melancholia” was attributed to an excess of black bile (from the Greek
melan-,
meaning black, and
cholē,
bile). The humors theory finally crumbled with the advance of cellular
pathology by Rudolf Virchow in the middle of the nineteenth century, but it lingers in the terms “ill humor” and “good humor.”

Treatments toward the end of the nineteenth century and extending well into the twentieth century included electrotherapy, hydrotherapy, rest, diet, and massage.
²

MAO I
NHIBITORS

The breakthrough in discovering antidepressants and ultimately understanding the chemical basis of depression arose from an interlocking series of chance experiences. First among these was the accidental discovery of what became known as MAO inhibitors.

On a spring Sunday in 1953, Nathan Kline, a psychiatrist who was director of the Rockland State Hospital in Orangeburg, N.Y., read an interesting news item from Bombay in the
New York Times.
At a provincial medical conference, “a special prize was awarded to Dr. R. A. Hakim for his paper on ‘Indigenous drugs in the treatment of mental diseases.’” The indigenous drugs were from the plant
Rauwolfia serpentina,
and the special prize was a gold medal for treating more than seven hundred schizophrenics.

The drugs were derived from the snakelike roots of a small bush that is native to India. Its powdered extract had long been used in folk medicine to quiet babies and to treat insomnia. Indian holy men, including Mahatma Gandhi, were habitual users, as they found it helped them attain states of introspection and meditation.
³

At around this time, the Swiss pharmaceutical firm Ciba isolated the active ingredient from the plant, an alkaloid called reserpine, to treat people with high blood pressure. Each purified crystal was equivalent in activity to more than 10,000 times its weight in the crude drug. A few months after Kline read the
New York Times
announcement, Ciba marketed the drug as Serpasil for high blood pressure.

Kline was a bold, energetic, and often controversial innovator in psychiatric research. He tested the drug on many of his psychiatric patients. The results were highly variable. Several showed dramatic improvement, and most became sedated to varying degrees and indifferent to events around them. He went on to transform Rockland
State Hospital from a regular state mental institution into a leading research center. Kline became an evangelist in promoting the drug to treat schizophrenics. For his pioneer efforts in introducing the use of tranquilizers to the practice of psychiatry in the United States, he received the prestigious Albert Lasker Medical Research Award in 1957.

On the recommendation of the commissioner of mental health in New York State, reserpine was routinely administered to all 94,000 patients in the state psychiatric hospitals. The drug, however, had serious side effects, particularly permanent movement disorders, and its use was discontinued in the early 1960s.

But it was the drug's effect on mood in nonpsychiatric patients that threw a spotlight on the chemical mix at the brain synapses. As millions of patients in the U.S. with high blood pressure were now taking Ciba's Serpasil, it soon became apparent that reserpine precipitated a severe depression in many people, with some even committing suicide. Investigations into reserpine showed by 1955 that it reduces the level of the three major monoamines—serotonin, dopamine, and noradrenaline (now called norepinephrine)—in the brain.
⁴
This was a major illumination. And the investigators were able to figure out how it happened: Reserpine causes these amines to leak out from little storage pouches (called synaptic vesicles) at the terminal endings of neurons at the synapse, and they are broken down by the enzyme monoamine oxidase (MAO). The resultant deficiency causes the depression. For an antidepressant to be uncovered, the key was to find a way to inhibit this MAO enzyme.

In the early 1950s, clinical studies were being done in Europe to test how effective a new drug called iproniazid would be in treating tuberculosis.
⁵
Scientists discovered that the drug was extremely effective, but they also noticed a surprising side effect. The patients taking it experienced euphoria.
⁶
Kline, upon learning about the odd side effect, saw the potential, and conducted a clinical trial to test iproniazid, a known MAO inhibitor, as an antidepressant. The patient response was astonishing. In April 1957 Kline's team reported the results of their experiments with twenty-six patients that revealed iproniazid to be the first drug of value in treating depression.

It is difficult today—in this era of institutional review boards,
informed consent, and governmental regulation—not to marvel at the directness, simplicity, and lack of restraint possible at that time. Ethics, responsibility, and competence were matters that were, for better or worse, completely up to the clinician who undertook the trial.

Who Gets the Credit?

The pride of authorship and the credit for discovery are powerful dynamics among researchers. The circumstances surrounding the press announcements and the presentation at the regional meeting of the American Psychiatric Association in Syracuse, New York, of the evident value of iproniazid led to a long and bitter conflict between the participants.

Harry Loomer, the physician in charge of the clinical unit involved at Rockland State Hospital, read the paper at the meeting,
⁷
but the
New York Times
incorrectly credited the presentation to Kline. At a press conference in New York a few days earlier, details of the success of the trial had been provided principally by Kline. Loomer was infuriated, and the
New York Times
printed a retraction. Another member of the team, John Saunders, a physician and clinical pharmacologist who supervised the project and had correctly attributed the mode of action of iproniazid to monoamine oxidase activity, also felt exploited. The following year, under his single authorship, Kline published a paper on the clinical experience with iproniazid.
⁸
The spark of discontent burst into flame in 1964 when Kline, for work with iproniazid, became the single recipient of a second Lasker Award. (The accompanying citation said: “Literally hundreds of thousands of people are leading productive, normal lives who—but for Dr. Kline's work—would be leading lives of fruitless despair and frustration.”) Loomer and Saunders objected, saying they had made the discovery, but the awards committee was unrelenting. Seventeen years of litigation followed. A jury ruled for Loomer and Saunders, and the State Court of Appeals upheld that ruling and finally laid the case to rest in 1981.

Because iproniazid (Marsalid) had already been marketed since 1952 as an antitubercular drug, psychiatrists were able to obtain supplies as soon as they heard of its antidepressant properties. Within one year of Kline's report, more than 400,000 patients had received the drug for treatment of depression. A gratified Kline observed that “probably no drug in history was so widely used so soon after announcement of its application in the treatment of a specific disease.”
⁹

The report of a small number of cases of jaundice—most likely a coincidental epidemic of infectious hepatitis—led to the withdrawal of iproniazid from the American market by the manufacturer, Hoffman–La Roche, in 1961. It was then replaced by more potent MAO inhibitors, such as Nardil and Parnate.

MAO inhibitors (MAOIs) increase brain levels of norepinephrine, serotonin, and dopamine. Iproniazid's antidepressant effect is due to this mechanism. The discovery that depression can be lifted by agents that inhibit the enzyme MAO was a major breakthrough in the recognition of depression as a common disease. Moreover, MAO inhibitors had an important impact on the development of modern biological psychiatry.