Psychiatry as a field is still attempting to determine why some people develop depression and others don't.
However, for over 50 years, scientists have been following a trail of clues.
By the 1950s, chlorpromazine had shown its efficacy in treating psychosis, and inspired the search for different psychoactive medications.
Building on the knowledge that chlorpromazine was an effective antipsychotic, a medication named imipramine was synthesized as a related compound in 1951. While it failed as an antipsychotic in clinical testing, case reports were showing that it helped with depression. As a result, the class of tricyclic antidepressants (TCAs) were invented.
In a very similar story, a medication named iproniazid was originally developed for the treatment of tuberculosis in 1952, but later was found to have mood elevating effects. A related compound isoniazid (which is still used today for tuberculosis treatment) was also found to have mood elevating effects. These medications led to the development of monoamine oxidase inhibitors (MAOIs), another class of antidepressants.
By the late 1960s, anatomical and physiologic research was showing that there were differences in key neurochemicals between patients with depression and patients without depression. For instance, patients who completed suicide had lower levels of serotonin or serotonin-related compounds in both their spinal fluid as well as their hind brains.
By the 1970s, TCAs and MAOIs were the major classes of antidepressants available clinically, but it was unclear how they were treating depression. Studies showed that both TCAs and MAOIs affect multiple neurochemical signals that are processed when neurons signal to each other. Because multiple signals were being affected at once by the available medications, it was difficult to study depression in a more precise way.
Clinically, psychiatry was navigating significant medication side effects. TCAs could cause drowsiness, constipation, difficulty urinating, lowered heart rate, and dizziness. Additionally, MAOIs forced patients to take on considerable dietary restrictions to prevent having possible lethal periods of high blood pressure.
Pharmaceutical companies began creating libraries of compounds that appeared on paper to be similar to known psychoactive medications, hoping they would discover the next novel treatment for depression or psychosis. A company named Eli Lilly created libraries of compounds related to a medication class called antihistamines, attempting to recreate conditions similar to the discovery of antipsychotics and TCAs.
In 1974, a researcher for Lilly Laboratories, Dr. David Wong, published a paper arguing that one compound he had studied was novel in that, unlike TCAs and MAOIs, it was selective and only affected how neurons interacted with a particular neurotransmitter named serotonin.
This new compound, he went on to write, could help us understand the role of serotonin in depression.
"We believe that the discovery of specific inhibitors of 5HT [serotonin] reuptake like 110140 will help in elucidating the function of 5HT in brain and the importance of reuptake as an inactivating mechanism in 5HT neurotransmission. In addition, such an agent may find clinical use as a therapeutic agent."
"In addition, 110140 may be an important tool to study the involvement of 5HT in sleep, in sexual behavior, in the regulation of hypophyseal [pituitary] function, and in other possible physiological functions of the central nervous system ."
Dr. Wong's compound went on to be known as fluoxetine, which was later branded as the antidepressant Prozac. In addition to revealing a new class of antidepressants, fluoxetine ushered in an era of developing more specifically targeted psychiatric medications.
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