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Ready for a paradigm shift or at least a new twist on a common process?
Hi! Jim Phelps here for the Psychopharmacology Institute. In this Quick Take, we’ll look at a method for tapering medications that’s based on PET scan studies of receptor occupancy. You may know of an earlier paper by Horowitz and Taylor in which they suggest a hyperbolic taper of antidepressants, big steps at first, followed by multiple small steps at the end. Here’s an extension of their approach to antipsychotics. The idea is to reduce medication blockade of receptors linearly, which actually requires exponential reductions in dose. Imagine a typical graph of exponential decay with an asymptotic tail. That tail is a series of very small steps down. For many antidepressants and some antipsychotics, this means using liquid formulations or a lot of pill chopping into little bits.
The big difference in this new article about antipsychotics is the time frame. For antidepressants, Horowitz and Taylor recommend tapering over 3 to 6 months with a rate that is “titrated to patient tolerance.” For antipsychotics, the authors are clearly describing a process that takes many months, often years. Indeed, they wisely suggest reconceptualizing the whole endeavor. This is not “stopping your antipsychotic.” This is finding a new minimum effective dose. At each step down, one waits months to look for any signs of worsening. If there are none, then another step may be taken. Perhaps this will continue all the way to zero.
Now, this is what is new. Check out the dosages. For example, take risperidone going down from 4 mg daily. The first step in the author’s 10-step pharmacologically informed taper is to 2.5 mg, but the last 5 steps are all less than 1 mg—0.6, 0.4, 0.25, 0.1, and then 0. Obviously, this requires a liquid preparation and a pretty organized patient. This idea that one should asymptotically approach zero may be one of the most important things I’ve learned in 30 years of practice.
But I beg to differ with Horowitz and Taylor on 2 things. First, I think the first step down should be small, not large. Here’s why: For most patients who have been on an antidepressant or an antipsychotic for a long time, the first step down is likely to provoke some apprehension. Will my symptoms come back? That anticipated worsening could actually lead to worsening, a sort of nocebo effect, which could lead to a crucial false conclusion, which is, “Oh, I must need this medication.” They might even increase the medications on their own. Or you might reach that false conclusion and recommend that they go back up and stay on this medication, likely for years, possibly for a lifetime, all because of a nocebo effect.
Here is an additional concern. For years, some patients, prominent psychologists, and psychiatrists have suggested that too rapid a dose decrease can cause withdrawal effects that looks like relapse. For antidepressants, that’s not just nausea, dizziness and brain zaps, but also anxiety, irritability, and mood. For antipsychotics, that’s hallucinations, delusions, and agitation. In both cases, it’s very difficult to determine if these symptoms are a return of the patient’s illness or a withdrawal reaction. So, to avoid a nocebo effect or a withdrawal response that looks like relapse, it seems to me that the first steps should be small, not large. If all goes well, take another step. Make that first step so small that your patient has little or no apprehension. A 100 mg of sertraline down to 87.5—nah, that shouldn’t make any difference, right? At least not like going straight down to 50, as Horowitz and Taylor’s guide suggests.
My second point of difference with their guide is, who’s making the decision about this taper, whether and when to start, how fast to go, by what size steps? In my view, this is one of the most important moments for shared decision making. If you call the shots and your patient is not in full agreement, you’re just setting up noncompliance. Now, this is going to take some patient education, especially when they want to just stop. So, you negotiate a first small step, after which you can meet again and determine the next step. Maybe that next step will be bigger, maybe even faster than you’d advise, but jointly work out a plan better than the patient going off on their own and stopping their medication entirely.
To conclude, deprescribing requires the same care as prescribing—patient education, shared decision making, and monitoring. For antipsychotics, advice by Horowitz and Taylor, think of it as finding a new minimum effective dose. In their article, you’ll find tables of dosage decrements with estimated receptor occupancy for olanzapine, clozapine, haloperidol, and quetiapine. They are really eye-opening.
Abstract
A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse
Mark Abie Horowitz, Sameer Jauhar, Sridhar Natesan, Robin M Murray, David Taylor
The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication-from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D2 blockade “evenly”): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D2 blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3-6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D2 blockade when stopped. This proposal should be tested in randomized controlled trials.
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Reference
Horowitz, M. A., Jauhar, S., Natesan, S., Murray, R. M., & Taylor, D. (2021). A method for tapering antipsychotic treatment that may minimize the risk of relapse. Schizophrenia Bulletin, 47(4), 1116-1129.
Related References
Horowitz, M. A., & Taylor, D. (2019). Tapering of SSRI treatment to mitigate withdrawal symptoms. The Lancet Psychiatry, 6(6), 538-546.
