Explain the physiological aspects of my anti-depressant withdrawal

September 26, 2014 8:32 AM

What is happening inside me as my body adjusts to an unexpected lack of anti-depressant medication?

I've been taking a 60mg daily dose of the anti-depressant Duloxetine for the last 15 months. I recently decided that I wanted to see how I go without anti-depressant medication. My doctor was supportive, and prescribed a 30mg daily dose for two weeks, after which I could stop altogether.

I had no negative reaction during the fortnight on the reduced dose, which finished yesterday. Today has been my first drug-free day.

Late-afternoon, though, I began to experience withdrawal symptoms - a fuzzy, nauseating sensation in my face and hands. The nausea has continued through the evening and into the night.

I'm feeling pretty lousy, but I'm trying to stay positive and remind myself that it will pass.

But I'm curious: what is happening inside my body that is causing this nausea? I assume that key parts of my insides are adjusting to the unexpected lack of the usual chemical input; can you explain the details?

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Also, feel free to send me an encouraging MeMail. I could use a lot of cheering up.

posted by paleyellowwithorange to Health & Fitness (9 answers total)

Best answer: Duloxetine works by increasing the amount of norepinephrine and serotonin in your brain, which it does by inhibiting the reuptake of those transmitters. Reuptake is a process that occurs in the transmission of neurotransmitters between neurons. Here's basically what happens:

-One neuron sends a serotonin and/or norepinephrine signal to another neuron. The neurons don't actually touch each other, they just come close. There is a little space between them, called a cleft. The neurotransmitters are sent into this space.
-The receiving neuron only has so many receptor sites to receive the neurotransmitters. So it takes what it can, and little transporters then take whatever neurotransmitter is left in the cleft and 'reuptake' it back into the source neuron.
-A reuptake inhibitor like duloxetine basically binds to these reuptake transporters so they can't reuptake the neurotransmitters. The serotonin and norepinephrine get left in the cleft.
-The receiving neuron will then over time develop new receptor sites to accommodate for this increase in neurotransmitter. This is why it takes some weeks for reuptake inhibitors to really start showing an effect.

So when you cease taking them, what happens is that that inhibitor is no longer going to bind to the reuptake transporters, and your neurotransmitters will start getting reuptaken again, and so less overall serotonin and norepinephrine are going to be being sent between your neurons. Again, your brain will have to adjust for this, but you will feel the effects much quicker than the onset of the drug because you aren't developing new receptor sites - you're just rather rapidly decreasing the amount of serotonin and norepineprhine that's flowing through your brain.

As to why exactly this withdraw manifests in the exact way it does for you: the answer is nobody knows. Neurotransmitters are really funny things. We don't actually understand them all that well. We have vague ideas about serotonin and calmness and dopamine and happiness and such, but then again dopamine is also the primary transmitter of movement signals. So they are very complex things that don't control just one aspect of our mood or neurology. While you adjust to lower levels of them, you will experience everything from grogginess to depression to all sorts of weird and unexplainable things (like the so-called brain zaps). There is no very good and specific reason why we can say a sudden decrease in serotonin causes this feeling, etc.

As for going off them - just be careful, and good luck.
posted by Lutoslawski at 9:09 AM on September 26, 2014 [11 favorites]

This does not answer your question as written, but what about a slower taper, like going to 15 mg for two weeks?
posted by fiercecupcake at 9:26 AM on September 26, 2014 [1 favorite]

IANAD, though I've taken various SNRI- and SSRI-class drugs over the years and have experienced withdrawal. (SSRIs are in many ways similar to SNRIs and if you ask me the withdrawal is similar as well.) I am currently in the process of stopping escitalopram, an SSRI. Six days to go.

Lutoslawski's answer is pretty much spot on as far as I know. Your brain has gotten used to having more serotonin and norepinephrine hanging around, since the duloxetine is stopping them from getting reabsorbed by the transmitter cell, as would normally happen to any neurotransmitters left floating around after a discharge. When you stop taking the duloxetine, your neurotransmitters start scavenging serotonin/norepinephrine again at their normal rate, and so your serum levels (your standing concentrations) of those transmitters drop fairly quickly. It sometimes takes a few days for this to happen because the half life of SNRIs in the blood is fairly long, but once they get below a certain level (which varies) you start to notice pretty fast.

If you drop SNRIs "cold turkey", withdrawal is pretty much assured. Like Lutoslawski, I cannot shed any light on why it causes the specific symptoms that it does (and I am unsure if anybody can, though if we have any neurologists in the house maybe they'll take a crack at it) but what you're describing sounds fairly early stage to me; be prepared for it to get worse, possibly including the dreaded "brain zaps", and for it to last for maybe four or five days in total. I actually don't know how long it lasts, I've never been able to sit out the entire process and wait for it to get better.

If I were you, I would put another step in my SNRI taper. Rather than going from 60mg to 30mg to 0mg, I would go from 60mg to 30mg to 15mg to 0mg, with each step being about two weeks long. This is similar to what I'm doing with escitalopram right now, and it's similar to how I've done things every time I've successfully ceased to take an SNRI or SSRI. I generally go to a half dose for two weeks, a quarter dose for two weeks, and then stop. Going from a half to nothing always causes me withdrawal.

Note that the above is just what I would do if I were you. I'm not, and SNRIs are tricky drugs that affect everyone a little differently (and some people a lot differently). I can't say that what works for me would work for you. Even so, I would really recommend going back to your doctor (or just giving him/her a call) and saying, "Hey doc, I'm getting some 'SNRI discontinuation syndrome' [the precise medical term for what you are suffering] over here. Do you think you could prescribe me a month of 15mg pills, or another two weeks of 30mgs and I'll split them in half?"

Then what I would do is I'd take the 15mg dose for two weeks, try stopping, and if I got withdrawal again I'd start splitting it to a 7.5mg dose and take that for two weeks before stopping. I realize that that is not exactly what you were (hypothetically) implying to your doctor you would do, but I've sometimes found that trying to explain things like that often just confuses doctors. Again, that is what I would do. You should feel free to do whatever you feel most comfortable with, though I really do suggest you ask your doctor to put you back on a reduced dose of SNRIs for a while in some way, since SSRI/SNRI withdrawal blows goats.
posted by Cashmere Sock Handjob at 10:12 AM on September 26, 2014 [1 favorite]

This doesn't directly answer your question, but you might be interested in this article that was published in the NY Times a couple years ago. It looks at our evolving understanding of what the underlying mechanism is for how antidepressants work on the brain. It's focus is not on withdrawal, but I think it's worth a read for anyone who has taken psych meds or is interested in how they work. (Disclaimer: I'm not up on the latest research, and this stuff changes very rapidly, so some of this may be outdated.)
posted by litera scripta manet at 10:18 AM on September 26, 2014 [1 favorite]

Duloxetine is a serotonin reuptake inhibitor.

Serotonin is one of the most important neurotransmitters for that brain in your gut.

Serotonin is important for the functions of your brain and your mood, but it is crucial to the function of your digestive system. Your gut creates 95 percent of the serotonin in your body.


I have discussed this a lot with my older son, who knows a lot more science than I do. I often throw up because of my medical situation. When things improve, it usually moves from nausea and vomiting to diarrhea before it is all over with. My son determined that serotonin is part of that process, but I am having kind of a hard time finding supporting links that show this relationship and I have trouble explaining the science of it. If you google it, the Wikipedia page on vomiting talks about serotonin playing a not well understood role in vomiting. And several sites do explicitly say that serotonin can cause diarrhea (I think specifically that high levels can cause diarrhea).

I have gotten off of a long list of medication, both prescription and OTC, and my experience has been that there is a long adjustment period that is helped by slower tapers. It let's the body gear down instead of essentially dropping you off a cliff. I have also found that eating rice helps with the nausea. Sometimes, if my nausea is mild, eating rice will stop it and prevent me from throwing up. (For me, eating hot peppers makes my nausea worse and makes me more likely to vomit. I am not sure about how that might or might not relate to serotonin specifically, but it might be a thing to look out for.)

In sort of generic, non-scientific (laymen's) terms, when you take a drug for a long time, you develop tolerance because cellular processes change such that the body can more efficiently dump what it often views as kind of a poison or bad thing, interfering with its functioning. So, depending on the substance, you see specific changes in specific parts of the cell which basically grow the processing mechanism for that substance. And when you suddenly stop taking it, it sort of reacts to that like you have a "deficiency" -- like there is not enough of it coming through to meet the expected demand, in some sense. And then the cells do weird things and you can develop cravings for it because your body is kind of going WTF?

This is why tapering helps: It leaves you with a smaller difference between what your body is expecting to deal with and what it is actually dealing with. It makes it easier to ramp down and reduces side effects where, suddenly, for example, your system is flooded with some excess of something that it was producing at high rates to counter some thingy and now that thingy isn't there anymore.
posted by Michele in California at 10:27 AM on September 26, 2014

Best answer: As far as I understand it, SNRIs & SSRIs affect all synapses in your nervous system, not just the brain (thought that is the highest concentration of nerve cells & synapses, so obviously the biggest effect lands there).

But your gut also has a very large concentration of nerves--it's been called a 2nd brain. Hands & face and the extensive system of muscles etc that control them are also pretty concentrated areas of nervous system activity.

So it is just possible that is one reason your feeling strange sensations involving your hands, face, and gut.
posted by flug at 10:28 AM on September 26, 2014 [1 favorite]

Best answer: As a note, duloxetine is a capsule, not a tablet, so it can't be split reliably, and 20mg is the smallest available dose.

On the encouraging side: I am not making recommendations for anyone else, but I found it extremely helpful when I was withdrawing from duloxetine to take a tyrosine supplement (which is supposed to help the body produce norepinephrine) and a B-vitamin supplement (which is supposed to help with stress in general) and to eat a lot of tyrosine-rich seaweed (dried snacks, seawood salads at sushi restaurants). I have read other recommendations to add a tryptophan supplement, but as that is supposed to increase serotonin and I was worried about too much serotonin, I skipped that one.
posted by jaguar at 10:45 AM on September 26, 2014 [1 favorite]

Best answer: Crazymeds.us has lots of info about duloxetine and SSRI/SNRI discontinuation. Your symptoms sound typical.

It has a short half-life (12h), so it should clear your body in 3-4 days. You could ask your doc to put you on 20mg for another week or two if the symptoms are too much.
posted by Johnny Wallflower at 11:55 AM on September 26, 2014

Best answer: Hey bud, sorry to hear about your situation. I only skimmed the responses above, but I see the key things mentioned already: this is a poorly understood part of SNRI therapy for which we don't fully have a mechanism sorted out, but nevertheless it's fairly common and duloxetine withdrawal syndrome is well-documented in the literature. A more gradual tapering is also recommended via case studies in the lit (like this one, if you have access). There's a possible genetic polymorphism component that predisposes some to the withdrawal syndrome by slowing pharmacological clearance and metabolism of the active ingredient (one paper points out East Indian / African descent). Tapering slowly (or more slowly, or more slowly still) are univerally recommended precautions against and treatments for many patients' experiences with withdrawal syndromes.

As to the proposed mechanisms behind these syndromes, some theories have a little bit more support than others. Serotonergic compounds and monoamine-oxidase inhibitors might be interacting to hyperactivate central 5-HT 1A receptors, causing all sorts of downstream effects: restlessness, hyperreflexia, sweating, etc. Sometimes researchers even wonder if the buzzing, nausea-type feelings might actually be better described as paresthesias brought on by the absence of the neurotransmitters that were until recently so present instead of a primary response to some new metabolic process going on in your body. I wish we knew better what to tell you, other than all indications suggest this is usually quite temporary.
posted by late afternoon dreaming hotel at 1:34 PM on September 26, 2014 [1 favorite]