Shrinks (25 page)

Kuhn rejected the standard psychoanalytic explanation that depressed individuals were suffering from buried anger toward their parents, so he didn’t believe depression should be treated with psychotherapy. On the contrary: he shared the assumption of biological psychiatrists that depression resulted from some unidentifiable neural dysfunction. Nevertheless, Kuhn disliked the prevailing “biological” treatment for depression, sleep therapy; he felt it failed to target the symptoms of depression, instead relying on crude chemical force to bludgeon the patient’s entire consciousness. Kuhn wrote to a colleague, “How often I thought we should improve the opium treatment. But how?”

Without telling Geigy, Kuhn administered G 22355 to three patients suffering from severe depression. After a few days, the patients showed no signs of improvement. This stood in sharp contrast to sedatives like morphine or chloral or even chlorpromazine itself, which produced often drastic effects within hours or even minutes of administration. For reasons known only to Kuhn, he continued administering G 22355 to his patients anyway. On the morning of the sixth day of treatment, January 18, 1956, a patient named Paula woke up feeling quite changed.

The nurses reported that Paula exhibited more energy and was uncharacteristically talkative and sociable. When Kuhn examined her, her melancholy was remarkably improved, and for the first time she expressed optimism for her future. This was just as astonishing as Laborit’s first patient, Jacques L., playing a full game of bridge. Some days after Paula, the other two patients also began to manifest thrilling signs of recovery. Kuhn enthusiastically wrote to Geigy about his unauthorized experiment, “The patients feel less tired, the sensation of weight decreases, the inhibitions become less pronounced, and the mood improves.”

Incredibly, Geigy expressed no interest in Kuhn’s discovery. The company was fixated on finding an antipsychotic to compete with chlorpromazine, not exploring some radical and unknown treatment for melancholia. Ignoring Kuhn completely, Geigy hurriedly sent G 22355 to other psychiatrists and ordered them to test the compound exclusively on schizophrenics, never mentioning its potential effects on depression. Geigy executives snubbed Kuhn again the next year, when he attended a psychopharmacology conference in Rome and repeated his request to pursue G 22355 as a depression-fighting drug. Kuhn’s lonesome discovery seemed destined for the scrap heap of medical history.

He tried to interest other academics, but they, too, collectively shrugged their shoulders. When Kuhn presented a paper on G 22355 at a scientific meeting in Berlin, only a dozen people showed up. After he finished his talk—in which he described the world’s first effective pharmacological treatment for depression—none of the attendees asked a single question. One person in the audience was Frank Ayd, an American psychiatrist and devout Catholic, who told me years later, “Kuhn’s words, like those of Jesus, were not appreciated by those in positions of authority. I don’t know if anybody in that room appreciated we were hearing the announcement of a drug that would revolutionize the treatment of mood disorders.”

But as with Laborit’s drug, fate—or blind luck—intervened once again. An influential Geigy stockholder and business partner named Robert Boehringer knew of Kuhn’s expertise in mood disorders and asked if he could suggest anything for his wife, who was suffering from depression. Without hesitation, Kuhn recommended G 22355—and made sure to point out that the stockholder’s company was refusing to develop the drug. After taking the experimental compound for a week, Mrs. Boehringer’s depression lifted. Delighted, Boehringer began lobbying Geigy executives to develop the drug as an antidepressant. Under pressure from such an influential partner (Boehringer also owned his own pharmaceutical enterprise), Geigy changed course and began formal human trials of G 22355 on depressed patients and finally bestowed the compound with its own name:
imipramine
.

In 1958, Geigy released imipramine to the public. It was the first of a new class of drugs known as tricyclic antidepressants—so named because the compounds’ molecular structure is composed of three joined molecular rings. (When a drug is named after its chemical structure rather than its physiological mechanism, it’s a sure sign that nobody knows how it works. Another class of antidepressants are known as selective serotonin reuptake inhibitors, or SSRIs; needless to say, scientists have since learned they produce their effects by inhibiting neurons’ reuptake of the neurotransmitter serotonin.) Unlike chlorpromazine, imipramine was an instant global success, equally embraced by psychiatrists in Europe and America. Other pharmaceutical companies soon released a flood of tricyclic antidepressants, all knock-offs of imipramine.

It’s not possible to overstate the prodigious impact of chlorpromazine and imipramine on the practice of psychiatry. Less than a decade after the release of Thorazine in the United States, the entire profession was utterly transmogrified. Two of its three flagship illnesses, schizophrenia and depression, were reclassified from “wholly untreatable” to “largely manageable.” Only manic-depressive illness, the final mental scourge of humanity, remained bereft of treatment and hope.

Serendipity Down Under

As these accidental discoveries of miracle medications were occurring in Europe, an unknown doctor in an obscure corner of the medical world was quietly pursuing his own professional hobbyhorse: a cure for mania. John Cade was initially trained as a psychiatrist, but during World War II he served as a surgeon in the Australian Army. In 1942, he was captured by the Japanese during their conquest of Singapore and locked up at Changi Prison, where he observed many of his fellow prisoners of war exhibiting the unhinged behavior that so often accompanied combat trauma. They trembled, they shrieked, they babbled mindlessly. Struck by what he perceived as the similarity between these war-induced symptoms and those produced by mania, Cade hypothesized that the prisoners’ quasi-manic behavior might be caused by a stress-induced toxin produced by the body. Perhaps such medical speculations helped him endure the sweltering nights in his dank, cramped cell.

Cade was eventually released, and after the war he pursued his toxin theory of mania at the Bundoora Repatriation Mental Hospital in Melbourne. His experiments were straightforward, if somewhat crude: He injected urine from manic patients into the abdomen of guinea pigs. Uric acid, found in urine, is a naturally occurring metabolite in humans. Excessive uric acid causes gout, and Cade guessed that uric acid might also cause mania if it accumulated in the brain. After the guinea pigs received a gut-full of human urine, Cade recorded that they exhibited “increased and erratic activity.” He interpreted these manic-like behaviors as confirmation of his toxin theory, though an alternative interpretation might be that any creature will exhibit erratic activity after getting a syringe of foreign urine in its belly.

The next step, Cade reasoned, was to find a compound that would neutralize uric acid, the putative mania-producing toxin. Since uric acid is not soluble in water (this is why it accumulates in gout victims), he decided to add a chemical to the manic-derived urine that would dissolve the uric acid and help the guinea pigs (and, presumably, manic patients) excrete it more easily, thereby reducing the guinea pigs’ mania.

Now, let’s pause just a moment to put Cade’s experiment into perspective. Henri Laborit, recall, was pursuing a (largely incorrect) theory of surgical shock when he stumbled upon the first antipsychotic drug entirely by accident. Roland Kuhn, for no logical reason, decided to find out if a psychosis-fighting compound might be better suited for lifting the spirits of the despondent, leading to the first antidepressant. From these examples it is clear that the process that led to such momentous discoveries was not a rational one, but rather, more guided by intuition and serendipity. And now, since metabolic toxins have absolutely nothing to do with mania, John Cade was pursuing the totally spurious hypothesis that mania could be eliminated by finding the right solvent to dissolve uric acid.

The solvent Cade selected was lithium carbonate, a compound known to dissolve uric acid. Cade first injected his guinea pigs with “manic urine,” then injected them with lithium carbonate. To his delight, the previously “manic” guinea pigs soon became calm. Cade took this as further confirmation of his toxin theory—after all, weren’t the guinea pigs quieting down because they were successfully excreting uric acid? Unfortunately for Cade, when he tested other uric acid solvents on the animals, they failed to produce any calming effects. Gradually, he realized that the guinea pigs’ placated behavior was not because uric acid was getting dissolved—there was something special about the lithium itself.

To his credit as a scientist, Cade abandoned his toxin theory of mania, which his data simply didn’t support. Instead, he threw himself wholeheartedly behind the development of lithium carbonate as a treatment for mental illness, without having any clue why it pacified hyperactive animals. In 1949, Cade conducted a small-scale trial of lithium on patients diagnosed with mania, psychosis, and melancholia. The effect on the frenzied behavior of the manic patients was nothing short of extraordinary. The calming effect was so robust that Cade came up with a new hypothesis: mania was caused by a physiological deficiency of lithium.

While Cade’s second theory turned out to be as short-lived as his first, his treatment was not. Lithium proved to be a godsend, and today lithium is used around the world as a first-line drug to treat bipolar disorder. Left untreated—and before the discovery of lithium, bipolar disorder always went untreated—the illness is highly destructive to the brain and can sometimes be fatal, as illustrated by the untimely death of Philippe Pinel’s friend. Another casualty of bipolar disorder was Philip Graham, the celebrated publisher of the
Washington Post
. On August 3, 1963, while on a brief leave from the Chestnut Lodge psychiatric hospital, where he was receiving psychoanalytic treatment for his manic-depressive illness, he went to his country home and killed himself with one of his hunting rifles. His widow, Katherine Graham, never forgave the psychiatric profession for failing him. Sadly, lithium was already available at the time of his death, though it was not approved for use in the U.S. until 1970.

When given in the proper dosage, lithium levels out the wild mood swings of bipolar disorder, permitting those suffering from the illness to live normal lives. To this day, lithium remains the most effective mood stabilizer (the name given to the class of medication for treating bipolar disorder), though alternative mood stabilizing drugs are now available.

By 1960—after a century and a half of groping in the darkness—psychiatry possessed reliable treatments for all three types of severe mental illness. What made chlorpromazine, imipramine, and lithium so different from the sedatives and tranquilizers that came before was that they directly targeted psychiatric symptoms in a kind of lock-and-key relationship. Sedatives and tranquilizers produced the same broad mental changes in everyone, whether or not a person suffered from a mental disorder, whereas antipsychotics, antidepressants, and mood stabilizers reduced the symptoms of illness without producing much of an effect on healthy people. Even better, the new drugs were not addictive and did not produce euphoria, like barbiturates or opiates. This meant the drugs were not particularly appealing to the worried well and did not become habit-forming in those suffering from mental illness.

Unfortunately, the fact that these new classes of drugs were not habit-forming meant that many patients did not feel compelled to continue taking them once their symptoms subsided, especially since chlorpromazine, imipramine, and lithium each had various unpleasant side effects, particularly if the doses were not carefully regulated. But for most patients (and their families), the side effects of psychopharmaceuticals were far outweighed by the near-miraculous relief from chronic, distressing symptoms.

I have experienced firsthand the unique effects of each class of psychopharmaceuticals. During my pharmacology class in medical school, my instructor assigned us to imbibe a series of medications during the semester, one dose each week. Every Friday we were given a small cup of liquid to swallow. Our assignment was to describe the effects we experienced over the following hour and then guess which drug it was. While we knew the possible choices—which included alcohol, amphetamine, the sedative Seconal, Valium, Thorazine, the antidepressant Tofranil, and a placebo—the identity of each drug was not revealed until we had completed the entire series. The results shocked me. I had guessed wrong on every single drug except for Thorazine; the antipsychotic had made my mind feel fatigued and dull, thinking demanded painful effort, and I felt indifferent to everything around me. Later, as a resident, I sampled lithium but didn’t feel much of anything other than increased thirst and the paradoxical need to urinate.

The mind-boggling effectiveness of psychiatric drugs began to transform the fundamental nature of psychiatry—and elevate its professional status. The black sheep of medicine could rejoin the flock because it finally
had
medicine. President Kennedy, in his address to Congress in 1963, acknowledged the changing landscape of mental health: “The new drugs acquired and developed in recent years make it possible for most of the mentally ill to be successfully and quickly treated in their own communities and returned to a useful place in society. Such breakthroughs have rendered obsolete a prolonged or permanent confinement in huge, unhappy mental hospitals.”

Needless to say, the transformation of psychiatry also transformed the psychiatrist.