Antidepressants Enter the Picture

It took a great amount of time, energy, resourcefulness, and a not inconsiderable portion of luck to discover and develop the first antidepressants. There are now three main classes of medications for depression: selective serotonin reuptake inhibitors (SSRIs), tricyclics (TCAs), and monoamine oxidase inhibitors (MAOIs).

Introducing Lithium

Back in 1949, an Australian psychiatrist by the name of John Cade introduced lithium into the pharmacopeia as a treatment for bipolar disorder. He'd noticed the sedating effect that lithium had on guinea pigs in the lab and decided to become a guinea pig himself.

He self-administered lithium and then sat back and waited to see what would happen. Nothing happened. At least nothing bad. He didn't experience any ill effects from the drug, and so he began prescribing it for his patients with manic symptoms. Today, nearly 60 years later, lithium is still the drug of choice for the treatment of bipolar disorder.


Lithium was only one drug, but it opened the door and opened some minds. It so happened that a drug being used to treat tuberculosis (TB) — iproniazid — was found to significantly increase the energy levels of TB patients. This side effect led to its use in treating unipolar depression.

As researchers continued to study the drug they found it had the ability to block the activity of monoamine oxidase, the enzyme that destroys the monoamine neurotransmitters norepinephrine, serotonin, and dopamine. Iproniazid was the first of the monoamine oxidase inhibitors (MAOIs). However, a nasty side effect of iproniazid was jaundice, and the drug was withdrawn from the market.

MAO inhibitors (MAOIs) are now the most rarely prescribed type of medications for depression, because of their potentially serious side effects. Fortunately, these early setbacks didn't discourage the researchers, and the push was on. In 1952, chlorpromazine, the first generation drug for treating schizophrenia, came on the market.


The tricyclics came on the market in the 1960s. The first tricyclic antidepressant was imipramine, discovered in 1950 by researchers who were looking for a new class of antipsychotic drugs. Impramine didn't do much for schizophrenia, but it did have antidepressant qualities.

Researchers determined that the tricyclics increased the activity of the monoamine neurotransmitters norepinephrine and serotonin by inhibiting their reuptake into neurons. TCAs can cause side effects such as dry mouth, constipation, bladder problems, sexual dysfunction, blurred vision, dizziness, and drowsiness.

Because of their side effects, they have fallen out of favor and are not commonly prescribed. Elavil, Tofranil, and Anafranil are members of the tricyclic family of antidepressants.

SSRIs — The Breakthrough!

Finally, in 1971, a researcher at Eli Lilly began working on the neurochemistry angle. Previous drugs had affected more than one neurotransmitter, so his objective was to produce a drug that would specifically target a single neurotransmitter. He discovered that one compound, fluoxetine hydrochloride, blocked reuptake of serotonin but did not block other neurotransmitters.

Fluoxetine hydrochloride was approved as a treatment for depression and came on the market in 1987. Its trade name was Prozac, and soon the drug became a household word. Side effects for SSRIs include weight gain and sexual dysfunction. SSRIs are now the most commonly prescribed class of antidepressants.

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