Aging Begins at 30

Treatments For Mentally Ill Have Endured

Prolonged narcosis was introduced in the 1920s. I know about it as I was treated for a depression that way in 1945. One is kept asleep most of the day for several days by a combination of barbiturates. With me it was a failure. Later insulin coma was introduced with glucose resuscitation. In 1938 electroconvulsive therapy (ECT) was first used, in Italy. Most of those early treatments were abandoned but ECT was refined with muscle relaxants and remains useful.

In 1949 Dr. Henri Laborit was studying shock of various types in Tunisia. He theorized that infection shock or post operative shock might damage cells and release histamine better known for its role in hay fever. He tried various antagonists to histamine including one called promethazine (now phenergan). They produced drowsiness and in some, "euphoric quietude" or tranquillity without loss of consciousness. Because of this Dr. Paul Charpentier of the Rhone-Poulenc drug company made many variants of promethazine. Chlorpromazine (Thorazine) worked best in rats. Drs. Delay and Deniker, psychiatrists in Paris, tried it on a seriously ill schizophrenic patient they called Giovanni A. In three weeks he was normal and was discharged home. Larger successful studies were done in Birmingham, England, and in Montreal. These results led to the closure of many mental hospitals.

Dr. Roland Kuhn in Switzerland obtained one of the chlorpromazine variants from Geigy called imipramime (later Tofranil). To his disappointment it made schizophrenic patients worse because it overenergized them. He gave it to depressed withdrawn patients in 1955 with great success. With three benzene rings it was the first of the tricyclic antidepressants. It was only two atoms different from chlorpromazine.

Yet another variant formula found in the screening program was Prozac (fluoxetine) with a different mode of action and fewer side effects.

Maybe you remember the V2 rockets the Germans sent over London. I do. I was there. They were fueled by hydrazine, and after the war it was available cheaply. But it was poisonous, explosive, flammable, and caustic! First they made Isoniazid and then Iproniazid found on routine testing to be effective against tuberculosis. Drug companies often screen drugs looking for unexpected benefits. Some of the patients were euphoric (well-being in Greek) and overenergized so it was tried in depression. This led to the anti-depressant marsilid and variants that inhibited monamine oxidase, one of the brain’s messengers.

Minor tranquilizers, (milder than tranquilizers of the chlorpromazine family), were developed from the same molecule that had changed somewhat after long storage. This led to Valium or diazepam and related drugs (Librium, Ativan, Serax), which were better than barbiturates because they were not sleep inducing, toxic, or habit forming. They interfered with another brain messenger GABA. This family of drugs are called benzodiazepines.

In another column we have discussed lithium, a treatment for mania discovered in 1949 when trying to dissolve uric acid from the urine of mentally ill patients.

In 1754 Horace Walpole wrote a fairy tale of the Three Princes of Serendip (now Sri Lanka) who had the faculty of making unexpected happy discoveries by accident. That’s why many of the psychiatrically active drugs are called serendipitous!

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