The idea for this post came from Angela of I Am My Own Island, and others have also expressed interest in her suggestion. 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 relationships. 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 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 so it 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 the 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
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 onto 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.
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.
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 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 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.
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.
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 sucks sometimes.
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