Monoamine hypothesis and the first antidepressants
It is the 1940s. People understand that depression is a very complex disease. Effective treatments for depression are that of talk therapy (Freud’s psychoanalytical alternative), physical therapies (e.g. electro-shock therapy, lobotomies), and indirect changes in lifestyle (e.g. healthier eating, exercise, relaxation).
Scientists clearly started to think that the origin of the disease can have a neurobiological basis. Depression seems to stem from the changes in the brain. However, the ways in which psychiatrists could investigate this claim in alive subjects in the 40s were rather limited. A breakthrough came through a serendipitous discovery involving a new tuberculosis drug.
Tuberculosis was one of the most devastating diseases in the 18th, 19th, and early 20th centuries. Often called the “white plague” tuberculosis was killing about 350 people per 100,000 US citizens. It is a bacterial disease characterized by chronic cough with blood-containing mucus, fever, night sweats and weight loss. The discovery that Tuberculosis is caused by a bacteria called Tubercle bacillus inspired clinical trials with newly created antibiotics like Streptocymin in 1944. The miraculous improvement in the conditions of even the sickest patients was overshadowed by the fact that patients would relapse in the long-term as the bacteria gained resistance to the antibiotic.
A new generation of antitubercular compounds was needed. Chemists at a drug company called Hoffmann-La Roche Ltd USA had developed a compound called isonicotinyl hydrazide (isoniazid). The drug was tremendously effective in reducing tuberculosis mortality rate only a year after it was rolled out for the public. Another group of chemists kept working on this drug by chemically modifying it to make it even more effective. In 1953, Fox and Gibas synthesized a drug called iproniazid which is a monoalkyl derivative of isoniazid (monoalkyl derivate means that it had a couple of chemical groups named alkyl added to the isoniazid molecule). (look figure 1 for illustration)
Clinical observations of the effects of iproniazid observed notable “side-effects”. Tuberculosis patients administered iproniazid showed euphoria, psychostimulation, increased appetite, and improved sleep. In other words, this drug was discovered to make people more happy, active, and motivated. Clinical trials carried out by Loomer, Saunders, and Kline (1958) have shown that depressed patients treated by iproniazid reported significant improvements in 70% of these cases. This was a fantastic and long-awaited news for the psychiatric community as the most commonly used alternative at the time was electro-shock therapy. Interestingly, the drug was still sold as an anti-tuberculosis drug, but doctors would prescribe iproniazid off-label. This means that iproniazid was not recognized as a pharmacological treatment for depression, but it was still prescribed by psychiatrists “under the table”.
Scientists soon figured out how Iproniazid produced its antidepressant effects - it inhibited an enzyme called monoamine oxidase (MAO). I will now explain what terms “enzyme”, “inhibit”, and “monoamine” mean which could help you understand the neuropsychopharmacological mechanism of action of iproniazid.
“Monoamines” are a class of molecules that share a common chemical structure (aromatic ring and two-carbon chains) and that are commonly “used” by our neurons to “communicate” with each other (they are what neuroscientists call “neurotransmitters”). Examples of monoamines include dopamine, serotonin, and norepinephrine. Modulation of the concentration of these monoamines has profound effects on individual’s brains. If an individual has too much serotonin, one can develop what’s could serotonin syndrome which leads to agitation and restlessness as well as potential for seizures. Sometimes our brains might have too much of these monoamines which can have negative effects (like the serotonin syndrome). For that reason, we need to be able to break them down. Enzymes are very important proteins in this process of breaking down monoamines. Enzymes are defined as proteins that act as biological catalysts that speed up various chemical reactions. In this case, these enzymes are called monoamine oxidases and they facilitate the breakdown of “surplus” monoamines which helps the brain restore to its “normal” state.
Sometimes we want to stop the breakdown of these monoamines. It turned out that the new antidepressant drug, iproniazid, was “inhibiting” the enzyme responsible for breaking down monoamines and that lead to a less depressive behavior of subjects. Consequently, that means that when you inhibit MOAs, you have more monoamines since they are not being broken down. We are getting at something very important here. The most often used neurobiological explanation of depression is that it is caused by a decrease in the “feel-good” monoamines like serotonin and dopamine. This explanation is called the monoamine hypothesis. The first antidepressant drugs, monoamine oxidase inhibitors, reinforced this theory and was a big argument used by the proponents of the monoamine hypothesis. Their reasoning would be that depression is caused by a decrease of monoamines (serotonin, dopamine, etc.) which can be fixed with monoamine oxidase inhibitors which inhibit the breakdown of these monoamines which leads to the accumulation of monoamines.
The first antidepressants were not perfect. The enzyme described previously, monoamine oxidase, is distributed all over the human body. The consequence of this is that the side-effects are also, then, very varied. The usual psychopharmacological side-effects like headache, fatigue or sleep disturbances also coincided with tremors and possible convulsions. An interesting side-effect was what is called the “cheese reaction”. In the late 50s, when the drug was rolled out legally, epidemiologists observed a peculiar coinciding of increased heart rate, hypertension and sweating with patients taking MAO inhibitors. It turned out that foods that contain high amounts of tyramine, such as cheese or dairy products, would not be broken down by MAOs that were inhibited by the newly rolled out antidepressant drug. MOA inhibitors were not silver bullets that solved all of our psychiatric problems.
The article was prepared by Matas Vitkauskas on behalf of INA