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Where Do Antidepressants Come From? Part 1: MAO Inhibitors

How surplus rocket fuel led to the first modern medicines for depression.

In the years after World War II, there were no effective medicines for schizophrenia, bipolar disorder, or major depression. There were not even names for such things. The word ‘antipsychotic’ was first used at a medical meeting in 1956; ‘antidepressant’ was coined in 1952, and ‘tranquilizer’ in 1953, but they were slow to be accepted. Yet within the next two decades, all these types of medicines were developed. Most of these discoveries occurred inadvertently, often with a chance observation by a physician or scientist who was looking for something else.

The story of the first antidepressants goes back to World War II and the V2 rockets with which the Nazis terrorized London, by some accounts killing over 9,000 civilians. They were originally fueled by liquid oxygen and ethanol, but when shortages made this difficult, hydrazine, an unstable inorganic compound first synthesized in the 1880s, was developed as an alternative. It continues to be used to this day, having powered the maneuvering thrusters of the space shuttles and the descent engines of the Curiosity rover on Mars.

AElfwine / Wikimedia Commons Public Domain
V2 rocket in the museum in Peenemünde, Germany
Source: AElfwine / Wikimedia Commons Public Domain

As a consequence of its role in the V2 rocket program, when World War II ended, there were large stocks of hydrazine available, which were sold at reduced prices to chemical and pharmaceutical houses. One buyer was Hoffman-LaRoche, which at the time was engaged in a program of developing alternative uses for hydrazine derivatives as medicines. In 1951, chemists at its laboratory in Nutley, New Jersey, developed isoniazid as an antitubercular drug, which proved to be effective and is still available today, as well as a second related compound known as iproniazid. Chemical analysis determined that iproniazid blocked the action of the enzyme monoamine oxidase, leading to the name ‘monoamine oxidase inhibitor,’ or MAOI.

Early on in human testing, it was noted that, particularly with iproniazid, tuberculosis patients were less fatigued, had a better appetite, and gained weight. Their mood, sleep, and general manner improved, though it was not clear whether this was a direct result or a consequence of better nutrition. At higher doses, some developed confusional states or psychotic reactions. The mental changes were also inconsistent, and they were originally viewed as side effects. Some doctors thought that perhaps they might be of benefit in lower doses for weight gain and mood in debilitated patients.

A major study at Staten Island’s Sea View Hospital in 1952 captured the public’s imagination. Newspapers displayed photos of patients clearly enjoying themselves, and in one famous phrase, reported that ‘they were dancing in the halls tho’ there were holes in their lungs.’1 Nathan S. Kline (1916-1983), a psychiatrist at Rockland State Hospital, and others took the next step of giving iproniazid to depressed patients. He and others associated its clinical benefits with increases in the neurotransmitters serotonin and norepinephrine due to inhibition of MAO and promoted it as the first of a new type of 'psychic energizers.’

Iproniazid came onto the market in 1958. It was later withdrawn in the U.S. in 1961 due to liver toxicity, but it was replaced by a series of safer compounds, including phenelzine and tranylcypromine. The use of MAOIs was limited to some degree because they required a special diet to prevent the ‘cheese effect’ which involved the development of hypertension. Three of the original ones (phenelzine, isocarboxazid, and tranylcypromine) are still on the market. Selegiline (L-deprenyl) is given orally as adjunctive therapy in Parkinson’s disease and in 2006 was approved in the form of a skin patch (‘Emsam’) for depression.

In general, MAO inhibitors are less widely used now, and they are often reserved for patients who have not responded to other treatments. Nonetheless, their effects at the time were profound. The prevailing view at the time was that depression was best understood as the response to a loss, and it didn't seem to make sense that a medicine could replace a loss. Most of the medicines then available for psychiatric illness were sedatives and were relatively ineffective; now, the MAOIs and the tricyclic antidepressants, developed around the same time, were seen to improve a wide range of the symptoms of depression.

Although Kline and others attempted to reconcile this success with the prevailing psychoanalytic view of depression, it forced a kind of re-thinking about the nature of mental disorders. As he pointed out, the fact that persons with depression could benefit from medicines made them seem more like traditional patients and made it harder to maintain older widespread attitudes that implicitly suggested weakness in terms of strength or morals. In short, it was one step in the long, still unfinished, process of acceptance and respect for persons with mental disorders.

This blog was excerpted and adapted from The Curious History of Medicines in Psychiatry.


Note: This article is adapted from The Curious History of Medicines in Psychiatry by Wallace B. Mendelson MD.

1. Sandler, M: Monoamine oxidase inhibitors in depression: history and mythology. J. Psychopharmacol. 4: 136-139, 1990.

2. Swatowski, Natalie (3 August 2018). ""Understanding Antidepressants" – A Book Review"