101. Unlocking the Science of Antidepressant Withdrawal
How SERT Occupancy Plays a Key Role
Welcome to Science Corner by Happiness Is A Skill, where I take a few minutes to teach you about the relevant neuroscience of antidepressants and antidepressant withdrawal. No more half assed assumptions without evidentiary support, like the whole chemical imbalance theory of mental illness. The idea that “too little” serotonin causes depression? Or that “too little” dopamine causes ADHD? Obsolete, oversimplified, hogwash conveniently packaged by marketing departments of pharmaceutical companies in order to convince you to “talk to your doctor about Zoloft, because when you know more about what’s wrong, you can help make it right.”
That’s the actual tagline for Zoloft by the way, from 2001. Brilliant, isn’t it? Here’s a very simple explanation for your distress. It has nothing to do with your life or your choices or the bad things that happened to you, but instead has to do with some chemicals in your brain you can’t control. So take this pill and the sun will shine and flowers will bloom and scary thoughts will go away and we’ll all be content. Right? Right?
If one could die of bullshit overload, I would long be gone.
Instead, let’s talk serotonin transporter (SERT) occupancy, something researchers have actually measured and analyzed in labs.
Let's start with some background information. The serotonin transporter is a protein in the brain that helps regulate levels of serotonin. When someone takes an antidepressant, the drug binds to the SERT protein and blocks it from transporting serotonin out of the brain, disturbing the brain’s longstanding homeostasis by increasing the amount of serotonin available. When early test subjects reported an elevated mood after taking antidepressants in clinical trials, the assumption was that the increase in serotonin was responsible for this relief, therefore thus forming the basis of the serotonin theory of depression. If more serotonin = happier people, then less serotonin = sad people. And that’s how Prozac was born!
Too bad it was all a pipe dream.
Over time, the brain adapts to the presence of the drug and learns to produce less serotonin on its own. The body is always trying to get back to homeostasis, remember. The pharmaceutical industry spends billions of dollars trying to convince you that they can override hundreds of thousands of years of evolutionary physiology, but the bottom line is the body has to remain in equilibrium to stay alive. If you’re hot, you sweat to cool down. If you’re cold, you shiver to warm up. If either of those systems don’t work like they should, you die.
So let’s say you’ve been on 20mg Prozac (fluoxetine) for ten years and you decide it’s time to come off. Your doctor drops you to 10mg for a few weeks and you tolerate it. Maybe you’re a little emotional and antsy but you can handle it. Your doctor has heard about all this withdrawal stuff so he thinks he’s got it all figured out and tells you not to drop from 10mg to 0, but to instead cut the capsule in half and take 5mg for a week or two. You don’t feel great and wonder if it’s the depression coming back. But you figure you’ll drop to zero and give it a few weeks to know for sure. After all, 5mg is miniscule. Smaller than the smallest dose on the market! They give 5mg of Prozac to six year olds!
You drop to zero and all hell breaks loose—akathisia, huge emotional swings, paranoia, brain fog, gut issues. Back to the doctor you go, because clearly you’re sick and how stupid you were to think that you could operate without the Prozac. So you go back on 20mg. Hell, make it 40mg this time. Clearly, you need it. Your doctor suggests an antipsychotic as well because the paranoia suggests an emergence of Bipolar Disorder. Life, now, is all about managing symptoms.
Where did everyone go wrong? A fundamental misunderstanding of SERT occupancy.
Let’s look at the following graphs, courtesy of researcher Mark Horowitz:
The black curve is the measure of SERT occupancy as determined through brain-imaging techniques called PET scans that allow researchers to see the biological workings of the body. As you can see, at 25mg of fluoxetine, 80% of the serotonin transporters are occupied.
Figure (a) is a representative of the conventional line of thinking for linear tapering of antidepressants. Rather, the idea of lowering dosages by equal, measured steps—5mg, in the case of this graph. The problem is that if you lower the dose of Prozac from 20mg to 5mg—a 75% reduction—SERT occupancy only reduces by 20%. This means that not only are there fewer operating receptors, there is also less serotonin in the brain because the body long ago lowered its production. It is likely that withdrawal occurs at least in part because of this chemical imbalance created through linear tapering. And yes, it is ironic that this time, a true chemical imbalance is responsible.
Due to the hyperbolic nature of SERT occupancy, this dissonance is even more extreme at lower dosages, as seen in Figure (b). At 2.5mg of Prozac—20% of the lowest dose available on the market—SERT occupancy is 40%, just half of what it is at a robust dose of 25mg. This explains why it can be more difficult for people taper as they get closer and closer to zero.
Though SERT occupancy occurs with all antidepressants, the levels of SERT occupancy vary from drug to drug, as shown by this systematic analysis of 10 different psychiatric drugs, done by Anders Sorenson, et al.
The reason why you need to know about this is because it’s likely your prescriber is completely unaware. More understanding of SERT occupancy, as well as more robust research (especially when multiple drugs are involved), would lead to better de-prescribing practices that will likely lessen or eliminate severe withdrawal effects.
In the fictional example I gave above, our now “bipolar” patient needed a much slower taper that followed the hyperbolic curve and was adjusted only once she stabilized from the previous dose reduction. Had she tolerated a 10% reduction—from 10mg to 9mg to 8.1mg to 7.29mg and so on to 0—her brain likely would have had much more time to fire up dormant receptors and naturally ramp up serotonin production, leading to a more gentle, symptom-free re-introduction into a world without SSRIs.
Instead, when she was pulled off too quickly, her system went haywire because neurotransmitters are responsible for regulating the entire body. Instead of recognizing this as withdrawal, both she and her doctor assumed it was mental illness and plunked her back in the system with a shiny new diagnosis. This happens all the time. All. The. Time.
I hope you’ve enjoyed this Science Corner issue of Happiness Is A Skill. Please keep in mind that we are very much in the infancy of antidepressant withdrawal research, and that no single piece of information is the whole answer. But as they say on NBC, the more you know! Ding ding dong!
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