An illustration of a brain

 

This article is all you will need to navigate through the winding and confusing path of antidepressants, but only for now. Medical research and Pharmaceutical pioneers will make sure there is something new to add to the subject from time to time, and those time intervals are getting shorter, always.

 

In the beginning…

Of course, back in the “olden days,” mid-last century, there was nothing for depression except walking it off. But this advice never really worked well, especially when it came to the suicide rate among depressed people. We have come to learn that not treating depression, because of the risk of suicide, is much more dangerous than the side effects patients new to antidepressants get into a panic over. This is selective panic over the wrong thing. The real fear is that the depression could get worse without treatment.

The psychiatrists and psychologists of the time did their best, but there was no way any insight, self-epiphany, change in attitude, or walking it off was going to change the chemicals in someone’s brain enough to fix them completely. Even the electroshock therapy used for depression back then offered only temporary and mixed results.

 

Help at last

In the 1950s, two drugs were introduced for the first time for depression. One of them was a tuberculosis (TB) drug and the other was straight-on new chemistry. A tuberculosis drug, iproniazid, was found to produce joy in patients with TB, a disease which didn’t exactly foster joy. This drug was found to inhibit an enzyme (monoamine oxidase), and as such, the iproniazid was called a monoamine oxidase inhibitors, or MAO. The enzyme it inhibited broke down serotonin and dopamine, two neurotransmitters important in mood stability (more on this below).

As promising as this drug was, the MAOs were eventually discontinued worldwide because they mixed horribly with almost everything—drugs, notably, but even many foods, including cheese. People suffering the “cheese effect” became hypertension emergencies. For example iproniazid was withdrawn from Canada in the 60s. But the good that came out of the iproniazid debacle was recognition of the importance of neurotransmitters in the brain.

 

We are all bags of chemicals and electricity

Neurotransmitters are how our nerves work, making it possible to send signals along the nerves to endpoints where thoughts and actions result.The end of each nerve cell (neuron) puts out little packets of chemicals—neurotransmitters—that can be recognized by the beginning part of the next neuron in line. Once the transfer from nerve end to nerve beginning happens, the cell membrane of the next neuron opens up to things like sodium and other things that bored you to death in chemistry class. The net result, however, is that the electrical charge of the neurons change, making the end of this next neuron do the same—put out more packets for even the next neuron. And so it goes—voila! nerve conduction.

The question that naturally pops up is that if nerves conduct their signals at up to 100 meters/second (hundreds of miles/hour), how can a chemical reaction be so quick between neurons all down the line, and the sum of the times it takes for all of them to fall like dominoes, explain this speed? The answer lies in the miraculous speed of the chemical reaction between each two neurons. The whole reaction, unlike waiting in the high school science lab for a reagent to turn red, takes just a couple of microseconds (2 thousandths of a second).

That’s how.

 

So what’s in this bags of chemicals?

There are almost countless numbers of different neurotransmitters, which makes sense when you consider what we as human beings do and feel and are. Three of them in particular, serotonin, dopamine, and norepinephrine, figure prominently in our moods. These neurotransmitters accumulate to do their thing, then get reabsorbed to get recycled for the next round of play. What the iproniazid did was show the importance of manipulating neurotransmitters, especially these three, and the race was on to get something that didn’t have the problems the TB drug had.

 

Tricyclic Antidepressants

So soon after iproniazid, the chemical family of tricyclics were developed, so called because of their three rings of atoms, and in the case of tetracyclics, four rings. What they do is inhibit the reabsorption of serotonin and norepinephrine, so more hangs around, keeping your mood up. The downside, besides dry mouth and affecting your sex life, is they can cause heartbeat abnormalities if too much is taken. They are still used, and they are safe when monitored by a doctor.

 

SSRIs Antidepressants

The next class of antidepressants to be developed, in the 1980s, were the “selective” reuptake inhibitors. Same thing, but more selective in their actions to avoid adverse reactions. Here things get more complicated, but what it boils down to is that there are types of neurotransmitter receptors on cells, and these new “selective” drugs affect not all of them, like a sledgehammer, but just the ones needed to do the job. The first ones out were the SSRIs (selective serotonin reuptake inhibitors), led by fluoxetine (Prozac) and followed by sertraline (Zoloft), which affected just serotonin.

SNRIs Antidepressants

Then ones that affected both serotonin and norepinephrine came out, the SNRIs (selective serotonin-norepinephrine reuptake inhibitors). Then, newer ones that involved the third neurotransmitter mentioned above, dopamine.

 

Why is Dopaine so important?

Dopamine is an interesting neurotransmitter. It is the “reward” neurotransmitter. It’s what explains the high you get from recreational drugs, cigarettes, even love. A deficiency in dopamine, of course, will do the opposite—bum you out terribly. But having large levels of it is the driving force behind addiction—you begin to crave its effects, subliminally, that is, when it’s constantly elevated by drug abuse. This is the rationale behind the drug varenicline (Chantrix), which is a selective dopamine reuptake inhibitor, for its use in quitting smoking. It keeps the dopamine levels up while you weather doing without the thing you’re trying to quit.

 

Antidepressants and Pain

Another interesting thing in this history of antidepressants is in pain. When you bang your thumb with a hammer, it hurts like hell. You immediately grab your thumb and squeeze. It feels less painful, but why? It’s certainly not because your thumb is any less injured than a moment ago, right? The reason this happens is that, besides nerves carrying the pain signals up to our brains, there is a response signal that goes back down to the area of injury to make it hurt less. The pain signal is dampened.

This is an evolution thing with survival benefits. Imagine the caveman getting mauled by a tiger. His body wants to send a clear message to him—that being in an “incident” with a tiger is bad, that tigers are to be avoided. So that message comes to him with severe pain to get his attention. Of course, once he “gets it” that mixing with hungry tigers is bad, his body wants him to be functional enough to be able to run away so the mauling won’t continue to its inevitable conclusion. So evolution, in its wisdom, devised an inhibitory signal to decrease his pain so he could run away. This signal uses three main neurotransmitters relevant here…our friends serotonin and norepinephrine, and another, GABA (gamma-Aminobutyric acid). There is an antidepressant class that inhibits reuptake of two of these—the serotonin and the norepinephrine, called SNRIs (selective serotonin and norepinephrine reuptake inhibitors). As you might guess, these antidepressants are also used to treat chronic pain by stimulating the pain inhibitory pathway, hence commercials on TV of chronic pain sufferers dancing on the beach because they take them. They do help, but probably short of beach dancing.

 

Types Of Antidepressants - Brief Timeline

In summary, in the 1950s, the MAOs came out first (the TB drugs), followed by the TCAs (tricyclics and tetracyclics). Next came the selective reuptake inhibitors—the SSRIs and SNRIs, in the 1980s. Currently, research is aiming to fine tune the selectivity of these to lessen the side effects (a whole ‘nother article—stay tuned), and to come up with new combinations of neurotransmitter manipulation. Things aren’t perfect, but they’re getting better and safer, which is a far cry from the electroshock therapy of yesteryear.

Cheer up. If you can’t, ask your doctor.

 

List of Common Antidepressants

 

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Resources

  1. Lopez-Munoz, Francisco; Alamo, Cecilio. (May, 2009) Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today. Current Pharmaceutical Design, Volume 15, Number 14, pp. 1563-1586(24).
  2. F López-Muñoz and C Alamo. (2009) Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des. 15(14): 1563-86.
  3. H L Fields, M M Heinricher, and P Mason. (1991) Neurotransmitters in Nociceptive Modulatory Circuits. Annual Review of Neuroscience 1991 14:1, 219-245.

 

For more information:

  • https://biology.stackexchange.com/questions/40522/what-is-the-speed-of-neurotransmitter-release-and-receptor-binding-in-a-neuronal
  • https://www.nps.org.au/medical-info/consumer-info/antidepressant-medicines-explained?c=types-of-antidepressants-cd5eacfd


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