What Even Are SSRIs?

SSRI’M OK

In this episode, we briefly discuss what a selective serotonin reuptake inhibitor (SSRI) is since the name of our podcast is “SSRI’M OK” and some people don’t understand the reference and that’s okay. That’s what we get for trying to be creative. We also briefly discuss the history of the discovery of some antidepressant medications like SSRIs and monoamine oxidase inhibitors (MAOIs.)

Key Points:

• Your brain is made of cells. The two main types of cells in the brain are neurons, and glial cells, also known as neuroglia.
• Neurons communicate with each other using neurotransmitters like serotonin, norepinephrine, and dopamine.
• The space between the neurons where neurotransmitters are released is called the synapse.
• The neuron (let’s call it neuron A) that drops off neurotransmitters to another neuron (neuron B) has reuptake channels that take back the neurotransmitters that neuron A released. The reuptake channels are named after the specific neurotransmitter they reuptake (serotonin reuptake transporters reuptake serotonin, norepinephrine reuptake transporters reuptake norepinephrine, etc.)
• SSRI are “selective serotonin reuptake inhibitors,” meaning they block the reuptake transporters for serotonin. This leaves more serotonin in the synapse which can lead to downstream changes that are theorized to help treat depression.
• The discovery of antidepressant medications and the belief that “low serotonin leads to depression” was started when studying an anti-tuberculosis medication called “Isoniazid.”
• While investigating different formulations of isoniazid, they developed a similar medication called Iproniazid which is slightly different to Isoniazid molecularly.
• When they were giving Iproniazid to patients in their research trials, they found that anyone who got the drug, regardless of whether or not they had tuberculosis, had “mood elevating” effects. Patients showed improved sleep, sociability, and appetite. A psychiatrist, Max Lurie, coined the term “antidepressant” in reference to the mood effects that iproniazid had on people. [1]
• It turned out that Iiproniazid stops the activity of an enzyme in our brains that breaks down specific neurotransmitters like serotonin, dopamine, and norepinephrine. The enzyme is called MAO, short for monoamine oxidase.
• The pharmaceutical company Eli Lilly began developing molecules that would selectively inhibit the reuptake of serotonin at serotonin transporters to increase serotonin in the synapse, which led to the first report on an SSRI called fluoxetine being published [2].
• Fluoxetine was approved by the FDA in December of 1987 and was launched to the market in January 1988 under the trade name Prozac.
• SSRI examples: Prozac (fluoxetine), Zoloft (sertraline), Celexa (citalopram), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine)
  • Brand names capitalize, generic names are in parentheses. They are the same medications.
• Some SSRIs don’t selectively bind to the serotonin reuptake transporter. For example, fluoxetine also binds to the norepinephrine reuptake transporter. It is sometimes referred to as an “activating” SSRI because norepinephrine is a neurotransmitter linked to alertness and arousal. However, the clinical relevance of this norepinephrine effect is not clear. Fluoxetine is an antagonist at 5HT2C receptors; this has been proposed as a potential mechanism for its activating properties. [3]

Resources Mentioned:

• Van Der Walt, M., & Keddy, K. H. (2021). The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future. Frontiers in psychiatry, 12, 617751. https://doi.org/10.3389/fpsyt.2021.617751
• Wong, D. T., Horng, J. S., Bymaster, F. P., Hauser, K. L., & Molloy, B. B. (1974). A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life sciences, 15(3), 471–479. https://doi.org/10.1016/0024-3205(74)90345-2
• Ni, Y. G., & Miledi, R. (1997). Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac). Proceedings of the National Academy of Sciences, 94(5), 2036-2040.

Also mentioned in today’s episode is “The Body Keeps the Score” by Bessel van der Kolk.

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Art by Zoe Zakson.

Music is “As I Figure” by Kevin MacLeod.

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