Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (34 page)

The mechanism of aspirin's action was not understood until a historic 1971 report by the British biochemist John Vane, who was
awarded the Nobel Prize in 1982. Prostaglandins are chemicals released by the body in response to injury. They help blood to clot. Aspirin counteracts prostaglandin's effect of making platelets stick together, thereby “thinning” the blood.
⁸

Today one baby aspirin (81 mg) a day is widely recommended for the prevention of heart attack and stroke.

Just as the three princes of Serendip classically came upon things they were “not in quest of,” researchers came upon unexpected discoveries enabling a series of cardiovascular breakthroughs. Concentration on one problem may direct thinking, but this may obscure the big picture. Being too focused may exclude a peripheral observation that could reveal the solution to a problem not even originally conceived.

The British geneticist J. B. S. Haldane once commented, “The world is not only stranger than we imagine, it is stranger that we can imagine.” This famous quote is often used to support the notion that the mysteries of the universe are beyond our understanding. Here is another way to interpret his insight: Because so much is out there that is beyond our imagination, it is likely that we will discover new truths only when we accidentally stumble upon them. Development can then proceed apace.

Part IV

The Flaw Lies in the Chemistry,
Not the Character:
Mood-Stabilizing Drugs,
Antidepressants, and Other
Psychotropics

If we were to eliminate from science all the great discoveries that had come about as the result of mistaken hypotheses or fluky experimental data, we would be lacking half of what we now know (or think we know).

—N
ATHAN
K
LINE
, A
MERICAN PSYCHIATRIST

30

It Began with a Dream

In the United States today, doctors write a total of 3 billion prescriptions each year. An astonishing 10 to 15 percent are for medications intended to affect mental processes: to sedate, stimulate, or otherwise change mood, thinking, or behavior. The term “psychotropic” is used for a chemical substance with such effects.

Psychotropics are generally in four categories: antipsychotic, antianxiety-sedative, antidepressant (mood-elevating agents), and antimanic (mood-stabilizing drugs). Their introduction and subsequent widespread use created a medical and cultural revolution. Thorazine, the first major tranquilizer, appeared in 1954 and immeasurably changed the institutionalization of psychotics. The sedative Miltown was marketed a year later, to be followed within a few years by the antianxiety agents Librium and Valium, and two new classes of antidepressants, iproniazid and imipramine. Lithium, the mainstay in the treatment of manic-depressive disorder, was unexpectedly discovered in 1949 but not marketed in the United States until 1970. LSD, the powerful mind-altering chemical, was discovered in 1943, but only in the first decade of the twenty-first century is it being put to legitimate therapeutic use.

These psychotropic drugs have brought about the era of psycho-pharmacology, not only changing the clinical practice of psychiatry but also stimulating advances in biochemistry and the neurosciences. Particularly since the 1970s, the psychoanalytically oriented psychiatrists
have increasingly yielded to the biological group. The pervasive use of psychotropics has generated revolutionary changes in the understanding and treatments of mental illness. A profound shift has occurred, away from psychiatry centered on providing custody and care of “lunatics” (asylums, locked doors, straitjackets, and solitary confinement) to a much broader conception of mental illnesses and individualized treatment options.

In 2005 a survey by the government's National Institute of Mental Health revealed the high prevalence of mental illness.
¹
More than half of Americans (55 percent) will develop a mental illness at some point in their lives, often beginning in childhood or adolescence. The study found that the most common problems experienced are depression, affecting about 17 percent of the population with varying degrees of severity, and alcohol abuse, affecting 13 percent. Phobias are also common.

Through the end of 2004, there were fourteen potential new drugs for depression, eighteen for anxiety disorders, and fifteen for schizophrenia. Overall, there were 109 medications being developed for all mental illnesses.
²

It was not until the latter decades of the nineteenth century that the complex anatomy of the central nervous system began to be understood. The Spanish neuroanatomist Santiago Ramón y Cajal showed that the direction of the nervous impulse in the brain and spinal cord is from the small end branches (dendrites) of a nerve (neuron) to the cell body of another. However, the mechanism by which nerves transmit their impulses from one to another evoked considerable controversy. How is the stimulus transmitted from one nerve cell (axon) to another across the space of their microscopic junction (synapse) or, in the case of the peripheral or autonomic nerve system, to the end organ? Is it by a chemical messenger or an electric discharge? Arguments raged in the “soup vs. sparks” debates.

The breakthrough in understanding that transmission occurs via a chemical produced by the nerve endings themselves occurred through an almost mystical experience.

Otto Loewi, chairman of pharmacology at the University of Graz in Austria, was a man of many interests. In his early school years he
had studied the classics, training that he believed “widened horizons and encouraged independent thought.” Throughout his life, he was an ardent music lover. He spent a postgraduate year studying art history but was persuaded by his parents to pursue medicine instead. He found research more challenging than clinical practice, and in 1909 he began his long tenure of the pharmacology chair in Graz.

Loewi had long been interested in the problem of neurotransmission and believed that the agent was likely a chemical substance and not an electrical impulse, as previously thought, but he was unable to find a way to test the idea. It lay dormant in his mind for seventeen years. In a dream in 1921, on the night before Easter Sunday, he envisioned an experiment to prove this. Loewi awoke from the dream and, by his own account, “jotted down a few notes on a tiny slip of thin paper.” Upon awakening in the morning, he was terribly distressed: “I was unable to decipher the scrawl.”

The next night, at three o'clock, the idea returned. This time he got up, dressed, and started a laboratory experiment. He set up in separate baths of nutrient fluid two frog hearts connected to each other by tiny glass tubes through the blood vessels that supply and drain the hearts. He left the nerve supply of one heart intact and removed the nerves from the other. Stimulation of the vagus nerves—which regulate the body's internal organs—to the first heart produced the well-known effect of slowing the heartbeat. Loewi then drained the fluid from the first heart's bath and transferred it to the second, nerveless heart. Loewi was euphoric to see that it produced the same effect of slowing the heartbeat. Clearly, a chemical substance had been secreted from the nerve ending of the vagus. Loewi named this neurotransmitter
Vagusstoff
(vagus stuff). It was identified chemically by others some years later as acetylcholine.
³

Loewi won the Nobel Prize in 1936, but events soon overtook him. In March 1938 the Nazis marched into Austria and assumed power. Stormtroopers arrested the rotund, avuncular-looking scientist at gunpoint and jailed him along with hundreds of other Jewish males. Fearful that he would be killed, Loewi was desperate to record the results of his current research. He had just completed the very last of a series of experiments begun almost twenty years earlier to show that
nerves taking messages to the brain secrete a different chemical than do those coming from the brain. He persuaded a prison guard to mail a hastily written postcard summarizing his findings to the journal
Die Naturwissenschaft,
and felt “indescribable relief” that his results would not be lost.

After transferring his Nobel Prize monies to a Nazi-controlled bank, the sixty-five-year-old Loewi was allowed to leave Austria. He was given refuge by friends and colleagues in England. In a short time he was offered a research professorship at New York University School of Medicine. In applying for an American visa, Loewi encountered a farcical situation. The U.S. consul in London required formal proof of his experience as a teacher. Loewi suggested that the consul contact Sir Henry Dale, but the consul had no idea of Dale's eminence. Perhaps the consul should consult Dale's entry in
Who's Who,
Loewi suggested. The volume was duly obtained and approval given. With visa finally in hand, Loewi politely inquired of the consul if he knew who had written the entry on Dale in
Who's Who.
Loewi then informed him that it was he himself.

To add insult to injury, as he was passing through immigration in New York, Loewi glimpsed the medical certificate from London. It read: “Senile, not able to earn his living.” A wise immigration officer ignored this observation, and Loewi went on to an active career at NYU for the next fifteen years.

It was not until twenty-four years after receiving the Nobel Prize that Loewi, at age eighty-seven, revealed that the solution had come to him in a dream. He wrote that the process of his discovery “shows that an idea may sleep for decades in the unconscious mind and then suddenly return. Further, it indicates that we should sometimes trust a sudden intuition without too much skepticism.”
⁴

Within a few decades, some mental states of mood, thinking, or behavior came to be recognized as arising through an error in synthesis, storage, metabolism, or release of neurotransmitters in the brain. Chief among these chemicals identified were serotonin, dopamine, and noradrenaline. Released by a nerve cell at its junction with another, such a chemical transmitter is picked up by receptors, or binding sites, on the latter, initiating a series of chemical changes inside the
cell with specific effects on mood, behavior, or thought. The entire system of release of a neurotransmitter into the synaptic junction and re-absorption by the neuron is mediated by a series of enzymes. It is these neurotransmitters that may be modified by the action of drugs. These brain neuroreceptors and transmitters came to be seen as factors constituting and influencing the basis of mind.

Thorazine, for example, blocks the dopamine-binding receptors in the forebrain. The antidepressant drug imipramine blocks reabsorption of noradrenaline and serotonin, prolonging the time they spend in the synapse. The longer they act on the neuron's receptors, the less depressed a patient is.

One dominant fact courses through this revolutionary development, recognized by psychiatrists, pharmacologists, and archivists alike. Serendipity, not deductive reasoning, has been the force behind the discovery of virtually all the psychotropics: Chlorpromazine (Thorazine) was unearthed in a hunt for antihistamines. The first antianxiety drug meprobamate (Miltown) was chanced upon in a search for an antibiotic. Valium was found by a scientist tidying up a lab bench. Antidepressants were uncovered as a side effect in the treatment of tuberculosis or stumbled upon in the quest for a tranquilizer. LSD was a surprising result in experiments for an ergot-derived stimulant. Lithium was happened upon through a misguided theory regarding a metabolic defect in manic states.

It's as if the muse of serendipity set the stage, inspired the main actors, and found an accepting audience.

31

Mental Straitjackets

Shocking Approaches

To fully appreciate the explosive advances in psychiatric treatment brought about by pharmacotherapy (psychotropics) since its advent in 1949, one must put them in the context of how little was known about diseases of the mind in the first half of the twentieth century. The radical nature of the treatments used for mental illness in earlier times is reflected in the title of Elliot Valenstein's chronicle of this era,
Great and Desperate Cures.
¹
These cures were often based on serendipitous clinical observations made in mental hospitals in Europe.

F
EVER
T
HERAPY

Psychotic symptoms of advanced neurosyphilis accounted for a large proportion of mental hospital admissions in the nineteenth and early twentieth centuries. The first successful treatment for any mental illness originated in the observation that certain psychotic patients improved dramatically when suffering from acute fevers caused by various diseases.
²
In 1917, on this association, Julius Wagner von Jauregg, the director of the psychiatric division of the Vienna General Hospital, introduced the malaria treatment. One of his patients, a soldier sent back from the Macedonian front with shell shock, had malaria. His blood, which contained malaria parasites, was injected
intramuscularly into nine patients suffering from insanity caused by advanced syphilitic infection. Multiple episodes of high fever, intended to destroy the spirochetes (the syphilis microbes) that had invaded the brain, were controlled with quinine.

Several of the patients demonstrated impressive remissions, some of which lasted ten years. Wagner von Jauregg approached psychiatry as an experimental biologist.
³
This therapy was directed against an underlying brain disease expressing itself in psychiatric manifestations. This approach for neurosyphilitic psychosis was path-breaking in that it ended the nihilism of earlier generations who had not experimented with treatments at all. If the neurosyphilitic psychoses could be halted, perhaps psychotic illness from other causes was treatable as well.
⁴