A fellow blogger asked this question recently, and it’s taken me a while to pull this post together because there just isn’t a simple answer as to why psych medications stop working out of the blue sometimes. There are various possibilities, but there’s also a hefty dose of science just doesn’t know yet.
How the illness works
Part of the issue is that there’s still limited understanding of the biological processes in mental illness and what’s driving them. In schizophrenia, for example, it’s known there’s a strong biological element. There’s more to it than that, though. There isn’t a simple gene=>illness relationship. It’s known that there are abnormalities in dopamine transmission; okay, so there are meds that can do something about that, but what’s making the dopamine system wonky in the first place? That’s still a big question mark.
One of the criticisms of psych meds is that they treat the symptoms, not the root of the problem. That’s true, but it’s also the best we’ve got right now. No one knows what the root of the problem is, much less how to get to it, and popping vitamins or other alternative treatments don’t get at that unknown root any more than meds do. By treating symptoms, we’re always chasing the illness to some extent. But it’s all we got at the moment, so we do what we can with what we’ve got.
How the meds work
While science has figured out what medications do in the body, it’s still not known how that produces the therapeutic effect. If we know what drugs do but not why/how that matters in terms of getting people to feel better, it’s hard to come up with solid explanations for why those drugs may continue to do pretty much the same thing, but feeling better is no longer the end result.
To have an idea of why meds stop working, we have to have some idea of how they start working. Psychiatric medications affect things that happen at synapses, which are the connections between neurons. One side of that connection is the neuron sending a signal (the presynaptic neuron). The other side is the neuron receiving the signal (the postsynaptic neuron). The synaptic cleft is the space between the two neurons.
A lot of antidepressants block reuptake pumps on the presynaptic side. After the neurotransmitter has been released into the synaptic cleft and it does its thing, the reuptake pumps will suck back up leftover neurotransmitter molecules so they can be recycled. Blocking pumps like dopamine transporters (DAT) or serotonin transporters (SERT) means more neurotransmitter hanging around in the synaptic cleft. Those neurotransmitters can then attach to receptors on the postsynaptic nerve.
Postsynaptic receptors are other potential targets for psych meds; for example, antipsychotics attach to D2 dopamine receptors, and prevent dopamine from being able to attach onto those receptors. That means that the signal the dopamine is sending doesn’t get passed on to the next neuron down the line. Long-term medication can lead to changes in these various receptors.
Possible reasons meds might stop working
Sometimes, the body doesn’t stop responding to a drug altogether, it just stops responding to a particular dose. Certain drugs, because of the way they interact with receptors in the body, are more likely to produce tolerance. When tolerance occurs, the dose has to be increased to get the same effect that was previously had at the lower dose, but the drug will start working again if you bump up the dose. This is often seen in drugs with addictive potential, such as opioids or benzodiazepines. It may be related, but it’s not necessarily the same kind of process that’s happening when drugs conk out entirely.
Pharmacokinetic tolerance occurs when there are changes in the way the body moves the drug around and gets rid of it, changing how available the drug is at the site of action. When that happens, you’re still taking the same dose, but it’s now less available
Antipsychotics
One possible contributor to antipsychotics‘ loss of efficacy is changes that might occur in dopamine reuptake pumps (DAT) with long-term antipsychotic use. Antipsychotics don’t directly affect DAT; they attach to D2 receptors on the postsynaptic side. However, the changes in dopamine signalling over time may lead to changes in the number of DAT pumps and/or how they work. Those changes might contribute to increased psychotic symptoms even though the antipsychotic is still doing what it’s supposed to do on those D2 receptors.
Dopamine supersensitivity
Another possibility is something called dopamine supersensitivity. To understand that, first we have to look closer at what antipsychotics do, which is blocking D2-type dopamine receptors. They don’t block every D2 receptor that you’ve got, and that’s where we start to talk about receptor occupancy. Ideal receptor occupancy for antipsychotics is 70-80%; that means that for every 100 D2 receptors in a particular part of the brain, 70-80 of them have a drug molecule attached to them at a given point in time. If dopamine comes swimming along to a receptor with a drug molecule blocking it, the dopamine can’t do anything. At the other 20-30 D2 receptors with no drug attached, dopamine can hop on board and do its thing.
Dopamine supersensitivity may happen when the receptors that don’t have a drug molecule attached decide that it’s party time whenever dopamine shows up. A dopamine party can get psychotic symptoms going again. The antipsychotic could be working, in the sense that it’s blocking the 70-80% of receptors that it’s supposed to block, but the effects of that could get offset by supersensitivity. This is referred to as dopamine supersensitivity psychosis.
While researchers know this happens in rats, it’s still not clear that it’s also an issue in humans.
Some researchers (including one who was my superstar psychopharmacology prof when I was in pharmacy school) have suggested that aripiprazole could hypothetically reduce the possibility of developing dopamine sensitivity psychosis. This is because, as a D2 partial agonist, it does something slightly different at D2 receptors compared to other antipsychotics. However, that’s still very much a hypothetical possibility rather than something that’s actually been demonstrated in clinical populations.
Antidepressants
The term antidepressant tachyphylaxis is sometimes used to describe the phenomenon of responding to an antidepressant, but then having it stop working down the road. Tachyphylaxis is generally used to describe a sudden loss of effectiveness, so some researchers prefer to describe it as tolerance. Others use the term poop-out, which is certainly the most fun of the bunch; I’ll stick with it because it’s the least confusing.
Poop-out hasn’t just been observed with newer antidepressants; it was noticed with MAOIs back in the 1980s before SSRIs came along. People who experience this don’t tend to respond as well to future antidepressant trials compared to how they responded pre-poop-out. If changing to a different antidepressant, picking one with a different mechanism of action from the current drug may be most likely to be successful. Increasing the dose of the antidepressant sometimes helps, but sometimes it doesn’t, so something is going on other than simple tolerance like one sees with opioids.
There are various proposed mechanisms by which the brain essentially decides it’s going to find a way to work around the drug. These possibilities include changes in the sensitivity of different types of serotonin receptors. Certain genetic variations may increase the likelihood of developing poop-out.
One strategy that’s been suggested to reduce the chances of poop-out happening in the first place is lowering the dose or taking a drug holiday in an attempt to give receptors a chance to desensitize. A drug holiday comes with its own potential set of problems, though. There’s also some indication that lowering the dose can help to regain responsiveness.
The HPA axis
The hypothalamic-pituitary-adrenal (HPA) axis may also be involved. The HPA axis connects the brain and the adrenal glands and is involved in regulating the stress hormone cortisol. Long-term use of antidepressants that affect serotonin can possibly activate the HPA axis, which is bad for depression.
Illness progression
Certain illnesses have a tendency to get worse over time. With a mood disorder, the more mood episodes you have, the more likely you are to have another one. Primary psychotic illnesses like schizophrenia, and to a somewhat lesser extent schizoaffective disorder, tend to have a natural course of worsening level of functioning over time. So it’s possible that a return of symptoms may be less about a failure of the medication and more a progression of the illness that the medication can no longer keep up with.
Another possibility when it comes to depression is that a degree of bipolarity had been bubbling away beneath the surface and became more prominent over time. That’s relevant because antidepressants just don’t work very well in bipolar. In that case, the antidepressant didn’t really crap out; the illness evolved itself into something that isn’t very anti-responsive in general.
Other possibilities
Another possible explanation is that the psych med didn’t stop working because they were never actually working in the first place. Maybe there was an element of placebo response that wore off. Mood episodes can resolve on their own, and the medication may have just ridden along on the coattails. Perhaps another form of treatment, like psychotherapy, was actually responsible for effects that had been attributed to the medication.
Life circumstances may also play a role. Medication may have been enough to keep the illness contained with a higher level of support and lower level of stress, but if support decreases and stress increases, the medication might no longer be enough. There may also be some element of illness-related loss in the effectiveness with which our brains can handle stress.
What does all of this mean?
So, back to the title question, why do psych medications stop working in some cases? There are various possibilities as to why drugs might crap out, but also a whole lot of unknowns. Our brains are amazing things, but damn, they really suck sometimes.
References
- Amato, D., Canneva, F., Cumming, P., Maschauer, S., Groos, D., Dahlmanns, J. K., … & Müller, C. P. (2020). A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: The role of the dopamine transporter. Molecular Psychiatry, 25(9), 2101-2118.
- El Hage, C., Bédard, A. M., & Samaha, A. N. (2015). Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function. Neuropharmacology, 99, 715-725.
- Fornaro, M., Anastasia, A., Novello, S., Fusco, A., Pariano, R., De Berardis, D., … & Carvalho, A. F. (2019). The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications. Pharmacological Research, 139, 494-502.
- Nord, M., & Farde, L. (2011). Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neuroscience & Therapeutics, 17(2), 97-103.
- Samaha, A. N., Seeman, P., Stewart, J., Rajabi, H., & Kapur, S. (2007). “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. Journal of Neuroscience, 27(11), 2979-2986.
- Targum, S. D. (2014). Identification and treatment of antidepressant tachyphylaxis. Innovations in Clinical Neuroscience, 11(3-4), 24.
- Yin, J., Barr, A., Ramos-Miguel, A., & Procyshyn, R. (2017). Antipsychotic induced dopamine supersensitivity psychosis: A comprehensive review. Current Neuropharmacology, 15(1), 174-183.
Want to know more about psych meds and how they work? Psych Meds Made Simple is everything you didn’t realize you wanted to know about medications.
It’s available on Amazon and Google Play.
Ashley L. Peterson
BScPharm BSN MPN
Ashley is a former mental health nurse and pharmacist and the author of four books.
I’ve taken antipsychotics for 7 1/2 years (Olanzopine for bipolar). I know my comment is a little unrelated to your post, but I’m happy to report that I’ve slowly reduced the medicine since last May. I am 13 days now not taking the medicine. My only issues is not sleeping that well at night, and I have a lot stress in my neck and shoulders. I was wondering if you’d be interested in researching people who get off their meds and potential problems they might face. On the flip side, I have a lot more energy more day and I can actually experience a wide range of emotions.
I hope going off of it works out well. It’s the kind of thing you never really know until you try it. I think that for a lot of people there are pros and cons to being on meds as well as being off of them, and it’s so individual where the right balance will be.
Thanks for being understanding. I opened up this fact about myself because I know you do a lot of research on mental health, and I wanted to get your reaction. I appreciate your perspective.
I’m actually not a researcher, but thank you for sharing.
Thanks for letting me share my experience.
I take aripiprazole and I am very comfortable with it. It works and has really, truly been a godsend.
Awhile back, when I was going through a major life change, the drug became less effective for the stress I was under.
My doctor added a second antipsychotic, and I did my absolute best to get through my stressful situation.
At one point when things were beginning to wind down stress-wise, we removed the second antipsychotic and rolled the dice at simply keeping aripriprazole as the main medication.
It worked! But man, I can tell you it was damn tough for a number of months!
I am so glad I stuck with aripiprazole though!
Have you heard anything similar with stress and antipsychotics?
I’m glad it worked out well! I think it can be the case with any psych med that when stress increases, topping up with a higher dose or an extra medication can be necessary to keep symptoms manageable. What works for maintenance may not be enough to manage acute flare-ups.
No and I agree. I was commenting on aripiprazole specifically because you had, but it absolutely affects any psych med.
Your experience certainly makes a good example that having a return of symptoms doesn’t always mean that the person is no longer responding to the medication. The most appropriate course of action if the source of the worsening symptoms is increased stress may be quite different than the best course of action if the med has stopped working period. And even if it turns out that aripiprazole might be better at reducing risk of dopamine supersensitivity psychosis, that becomes irrelevant if the source of a specific individual’s problem is unmanageable stressors rather than supersensitivity.
Good points. I didn’t think I would be so fortunate, but I am quite grateful that I am. Thanks for your helpful words and have a great day!
Same to you!
Dang, I didn’t know dopamine supersensitivity psychosis is a thing. Curious how it’s treated.
I feel like psychiatrists in my country are polarised between
1) “give patients only a little” (like my experience and I suffered needless MDD episodes which affect my likelihood of yet more MDD)
2) And aren’t keen at allllllll on lowering meds even if the patient doesn’t have a psychotic illness, is doing better etc.
It’s still not known for sure if dopamine supersensitivity psychosis is a thing in humans, so things haven’t progressed as far as identifying treatment yet.
Sounds like a whole lot more listening to patients is needed…
I feel like compared to the West, my country is pretty far behind. C has had great psychiatrists but they all eventually retired. Her current one asks only 3 questions, doesn’t even listen, appointment lasts only 3 minutes… and refuses her request to transfer her case to the hospital she’s getting autoimmune treatment in. I did not know they could block transfers, and that psychiatrist is extra terrible considering C’s mobility/transport issues and how she’s going to need a wheelchair.
That’s really shitty.
Yeah, ugh. Psychiatrist refused telehealth too, so C has to hire a car there and back.
Yuck.
I may or may not write more about that psychiatrist but yeah, definitely fuming about the nonsense from various people C has to juggle around as her health deteriorates. Even getting that wheelchair is a freaking mess, and she has to do it alone. While fearing her abusive brother (released from another stint in prison) will come after her.
So unnecessarily difficult.
This is a really interesting one. The body building up a tolerance seems to go sometimes for pain meds too, or other drugs. But like you mention with psych conditions potentially getting worse, I also wonder how you’d be able to tell the difference in the condition getting worse (ie. experiencing more pain or worsened mental health) versus the medication losing effectiveness.
“Pharmacokinetic tolerance” is something I wasn’t aware of. So how the body moves the drug around and deals with it, affecting its availability. I always learn something new from you! xx
I know a whole lot less about chronic pain than I do about psych stuff, but I would guess that even though a specific kind of tolerance is a known phenomenon with opioids, there are probably multiple ways that the body can come up with to get around the effects of all kinds of different pain meds.
Thank you so much for this post it really helped me understand I was on abilify for years and I know it stopped working for me when things started going back to premed status quo. I am thankful I advocated for myself and now have a good combo but damn it I always have in the back of my head when is this going to end.
This is fascinating. I could only follow 40% because my brain can’t process complex facts unless I take forever over it!! I was interested to read about SSRIs … I am only on 10mg and have sunk into a good old period of depression in recent weeks with the only change being the intro of HRT! I wondered if that had reduced the effectiveness of the antidepressants. Difficult to know what to do now. Work has really caused me a mental health decline so I have to consider that as a factor too! So difficult to get this right isn’t it? Really great info as always x
Ugh, that sucks that work has been having that effect.
It’s 95 degrees where I live. I’m at the high school sitting in an un-air-conditioned car waiting for my kids, but I had to post to thank you for writing such a relevant, incredible post. I can only understand some of it. I think it’s because my brain has melted.
I’ve been on tranylcypromine (MAOI) for 8 yrs and it’s still working, and I just pray in my agnosticy way that there’s no poop-out for as long as possible!
Once again, great job! And even though you may not be a researcher at some houty toity university, I consider I consider you to be an awesome researcher all the same.
Ugh, that sounds rather grossly hot!
I’m very glad the tranylcypromine is still doing such a good job, and fingers crossed that there will be no poop-out!
I forgot to add I also take lithium and that’s going well, and my fingers are crossed for that one too!
🤞💕
I wonder if my years of being under-treated for depression in 2014 to late 2020 (felt like MDD episodes every year, which would take over 2 weeks and often months to recover from) contributes to my probably treatment resistant depression…