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Tapering antipsychotic medication: practical considerations
Published online by Cambridge University Press: 20 September 2021
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References
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Antipsychotic medications are the gold-standard treatment for psychotic patients, and their efficacy is evident (Kahn et al., Reference Kahn, Winter van Rossum, Leucht, McGuire, Lewis, Leboyer and Sommer2018). Most guidelines recommend long-term, continuous treatment with antipsychotic medication to prevent relapse (Shimomura et al., Reference Shimomura, Kikuchi, Suzuki, Uchida, Mimura and Takeuchi2020). This is based on the increased relapse rates in patients who have their previous antipsychotic medication withdrawn, often abruptly or very rapidly, compared to those who remain on treatment (Moncrieff, Gupta, & Horowitz, Reference Moncrieff, Gupta and Horowitz2020). However, the extent of antipsychotics' relapse prevention properties is uncertain, because withdrawal problems (including withdrawal-induced relapse) with short-term follow-up might partly explain these results (Leucht et al., Reference Leucht, Tardy, Komossa, Heres, Kissling, Salanti and Davis2012; Moncrieff et al., Reference Moncrieff, Gupta and Horowitz2020).
Furthermore, many patients report aversive effects of taking long-term antipsychotics. In a meta-analysis of 41 qualitative articles, patients were largely positive about acute and short-term use, but were more ambivalent about long-term use, especially highlighting negative effects on functional and social recovery (Bjornestad et al., Reference Bjornestad, Lavik, Davidson, Hjeltnes, Moltu and Veseth2019). Patients perceived that long-term antipsychotic use disrupted their individual efforts to overcome their condition and undermined their sense of agency. They also expressed concern about irreparable bodily damage caused by the drugs (Bjornestad et al., Reference Bjornestad, Lavik, Davidson, Hjeltnes, Moltu and Veseth2019; Thompson et al., Reference Thompson, Stansfeld, Cooper, Morant, Crellin and Moncrieff2020). Others perceived long-term use more positively, and described adapting their use to minimize their side-effects. In one qualitative survey conducted online, most respondents (70%) had tried to stop taking antipsychotics at least once, mainly due to unpleasant side effects (64%) and worries about long-term physical health (52%), while 35% reported that their quality of life was improved by antipsychotics and 56% thought that the drugs reduced the problems that they were prescribed for (Read & Williams, Reference Read and Williams2019).
Many patients want to try to reduce or discontinue their antipsychotic medication. Moreover, 75% of respondents in a UK-based survey among 172 clinicians working with first episode patients (Thompson, Singh, & Birchwood, Reference Thompson, Singh and Birchwood2016), thought that early discontinuation of antipsychotic medication after remission was beneficial for most patients. Previous studies have demonstrated that some patients can stop their medications associated with an improvement in their functional capacity, while the majority restarted medication at the same or reduced dose (Wunderink, Nieboer, Wiersma, Sytema, & Nienhuis, Reference Wunderink, Nieboer, Wiersma, Sytema and Nienhuis2013). After decades of trying to identify people who are more likely to relapse following antipsychotic withdrawal, no consistent findings have emerged, and so it has been suggested that all patients should have the opportunity to try to discontinue medication if this is what they want and if risks allow (Sommer, Oomen, & Hasan, Reference Sommer, Oomen and Hasan2019; Wunderink, Reference Wunderink2018). Ongoing work to try to determine who may benefit and who may not, might contribute further clarity to this area. To fill the gap in understanding the benefits and disadvantages of antipsychotic reduction, several large-scale trials are currently being undertaken (Begemann et al., Reference Begemann, Thompson, Veling, Gangadin, Geraets, van ‘t Hag and Sommer2020; Moncrieff et al., Reference Moncrieff, Lewis, Freemantle, Johnson, Barnes, Morant and Priebe2019; Weller et al., Reference Weller, Gleeson, Alvarez-Jimenez, McGorry, Nelson, Allott and Killackey2019).
However, in the meantime, little guidance is available on how to best taper antipsychotic medication. Below, we discuss several considerations based on our experience in tapering medication in patients with first- and multi-episode psychosis from the HAMLETT (Begemann et al., Reference Begemann, Thompson, Veling, Gangadin, Geraets, van ‘t Hag and Sommer2020), and RADAR (Moncrieff et al., Reference Moncrieff, Lewis, Freemantle, Johnson, Barnes, Morant and Priebe2019) studies to assist clinicians in this task.
Involve family
As with all major changes in treatment, it is important to consider the individual's circumstances when initiating antipsychotic reduction, including their social support and the attitudes of family and caregivers. It is crucial to involve key persons providing support, including family psychoeducation which has been shown to reduce the risk of relapse by 20% (Pitschel-Walz, Leucht, Bäuml, Kissling, & Engel, Reference Pitschel-Walz, Leucht, Bäuml, Kissling and Engel2001).
Add non-pharmacological interventions
Non-pharmacological interventions may be useful to enable people to manage emerging symptoms during the withdrawal process and to re-adapt to a ‘new normal’ following medication reduction/cessation, including more intense emotions. A recent systematic review has found that non-pharmacological interventions, like cognitive-behavioural therapy, Needs Adapted Treatment and Soteria have outcomes, including relapse, similar to usual care (Cooper, Laxhman, Crellin, Moncrieff, & Priebe, Reference Cooper, Laxhman, Crellin, Moncrieff and Priebe2019), with encouraging but inconsistent findings for other non-pharmacological interventions. These approached may therefore be useful to support patients, though they have not been formally evaluated in the withdrawal process.
The longer antipsychotics have been used, the longer tapering should take
Long-term antipsychotic use causes adaptations in the brain to the presence of the medication, including up-regulation of post-synaptic D 2 dopaminergic receptors (Horowitz, Murray, & Taylor, Reference Horowitz, Murray and Taylor2020). Indeed, one study found that longer duration of antipsychotics treatment produced a small increase in risk of relapse on antipsychotic discontinuation (Bowtell et al., Reference Bowtell, Eaton, Thien, Bardell-Williams, Downey, Ratheesh and O'Donoghue2018), consistent with the notion of increased adaptation to the drug over time. The rationale behind tapering is therefore to reduce the drug slowly enough to allow the brain to re-adapt incrementally to lowered levels of neurochemical effects (Horowitz, Jauhar, Natesan, Murray, & Taylor, Reference Horowitz, Jauhar, Natesan, Murray and Taylor2021). These adaptations may take years to normalize after long-term use and therefore tapering may also need to last a year or longer in these situations (Moncrieff et al., Reference Moncrieff, Lewis, Freemantle, Johnson, Barnes, Morant and Priebe2019). However, less prolonged tapering schedules may be tolerable for patients with shorter term use (Begemann et al., Reference Begemann, Thompson, Veling, Gangadin, Geraets, van ‘t Hag and Sommer2020). As higher doses take longer to taper, initial dose should be kept as low as possible, and reduction considered as soon as acute disturbance settles.
Motivate patients for gradual tapering
Patients may want to stop their antipsychotics rapidly, as initial reductions may make them feel more energized and motivated. However, abruptly stopping medication is most likely to cause relapse, as will be familiar to many patients and clinicians (Bogers, Hambarian, Michiels, Vermeulen, & de Haan, Reference Bogers, Hambarian, Michiels, Vermeulen and de Haan2020). Patients therefore should be encouraged to reduce more cautiously. Although prolonged tapering may be unappealing for many patients, the benefit of a slow rate, especially when down to lower doses, should be emphasized, as it may decrease their risk of relapse, need for future re-instatement and ongoing treatment (Bogers et al., Reference Bogers, Hambarian, Michiels, Vermeulen and de Haan2020).
Dose reduction following a hyperbolic pattern
Like many other pharmacological compounds, the relationship between dose of antipsychotic and its effect on target receptors is hyperbolic (Horowitz et al., Reference Horowitz, Jauhar, Natesan, Murray and Taylor2021); at low doses, there is a very steep relationship between drug-dose and receptor occupancy; at higher doses, this relationship flattens out. Tapering antipsychotics according to a hyperbolic pattern produces linear reductions of D 2 occupancy and other antipsychotic-induced changes. In other words, dose reductions should get smaller as total dose becomes lower (e.g. a pharmacologically informed haloperidol dose regimen would entail the following sequential reductions: 4, 3, 2, 1.5, 1, 0.75, 0.5, 0.375, 0.25, 0.1875, 0.125, 0.063, 0 mg) (Horowitz et al., Reference Horowitz, Jauhar, Natesan, Murray and Taylor2021). While these final doses may seem very small, it should be noted that 0.063 mg still causes 8% D 2 occupancy and so this final dose reduction represents the same reduction in D 2 occupancy as reducing from 10 to 4 mg of haloperidol. As tablets of most antipsychotic drugs do not enable this type of tapering, the use of liquid formulations is recommended, which are available for many antipsychotics.
An individual approach
Despite the overall patterns, there are large individual differences regarding dose occupancy, symptoms, self-management skills and people's social networks, which are reflected in variations in the tolerability of patients to different rates of tapering. A reasonable approach, therefore, is to start with a small decrease in dose, perhaps equal to 5–10 percentage of D 2 receptor occupancy [equivalent to about a 25% dose reduction, depending on the starting dose (Horowitz et al., Reference Horowitz, Jauhar, Natesan, Murray and Taylor2021)], monitor the effects on the patient for approximately two months and then proceed based on the tolerability of this first step. There are other considerations that should be taken into account as well such as interactions with other medications (e.g. plasma levels might change as antipsychotics are lowered due to overlapping metabolic pathways). It is advisable to generate a list of early warning signs (e.g. insomnia) with the patient before commencing the reduction. We have also observed in the course of conducting our antipsychotic reduction trials that some symptoms (e.g. insomnia, psychotic symptoms), that arise on reducing medications can be self-limiting – although sometimes they can persist for weeks or months – and may spontaneously resolve without any change in medication dose. Although, this has not been the subject of rigorous scientific study to date, this is a phenomenon that has been previously identified as fitting a rebound pattern, analogous to withdrawal dyskinesia (Cosci & Chouinard, Reference Cosci and Chouinard2020).
Clozapine
Clozapine has a well-defined withdrawal syndrome, which is known to include psychotic symptoms (Cosci & Chouinard, Reference Cosci and Chouinard2020; Verghese, DeLeon, Nair, & Simpson, Reference Verghese, DeLeon, Nair and Simpson1996), and it is reported to be more difficult to withdraw than other antipsychotics (Borison, Diamond, Sinha, Gupta, & Ajiboye, Reference Borison, Diamond, Sinha, Gupta and Ajiboye1988; Verghese et al., Reference Verghese, DeLeon, Nair and Simpson1996), which matches our clinical experience. It is particularly important to identify a tolerable rate of dose reduction, and to warn patients about the possible occurrence of withdrawal symptoms, which may include temporary worsening of psychotic symptoms (Borison et al., Reference Borison, Diamond, Sinha, Gupta and Ajiboye1988; Cosci & Chouinard, Reference Cosci and Chouinard2020; Verghese et al., Reference Verghese, DeLeon, Nair and Simpson1996). It may be prudent to taper clozapine by as little as 25 mg (or less) even at higher doses, or as little as 6.25 mg at lower doses depending on how the patient tolerates the reduction, made practical by widely available small dose formulations.
Definitions of success
For some people relapse may be important to avoid at all costs, yet others may tolerate an increased risk of relapse to benefit from reduced adverse effects of medication. Therefore, patients who experience reoccurrence of symptoms during discontinuation should not necessarily be considered to have ‘failed’. When they have re-stabilized, it may be reasonable to try reduction again, more gradually (smaller dose reductions spaced out at greater time periods) or with enhancement of non-pharmacological coping strategies. Some patients will see the process of relapsing as part of the process of determining a tolerable rate to taper the medication. Some patients may conclude that reaching the lowest possible dose is preferable to complete cessation. Others may prioritize symptom control and avoidance of relapse and therefore find their quality of life is improved by maintaining antipsychotics. Moreover, antipsychotic medication may reduce the chance of a dramatic reduction in quality of life that can be the consequence of a psychotic relapse.
Conclusion
For reducing antipsychotic medication, it is important to motivate patients to taper gradually, rather than precipitously, especially those who have been on medication for years. Gradual reductions might reduce the chance of withdrawal effects like insomnia, and possibly relapse. Prepare the patient for the ‘new normal’, including increased intensity of perceptions and emotions. As there are large individual differences in receptor occupancy, the effect of the first few steps needs to be monitored closely to determine tapering velocity for each patient.
As dose reduction should be done in a hyperbolic pattern, fluid preparations are convenient for the final small steps. Clozapine is different, as initial steps should already be small. Finally, success can be defined in different ways and the optimal situation may not be zero, but a low dose.
Author contribution
IS conceived the manuscript idea. MH and IS wrote the initial manuscript. JM, LdH, JB, SG, MK, WV all substantially revised and edited the manuscript and contributed substantially to the concepts outlined.
Financial support
MH is supported by a clinical research fellowship at North East London NHS Foundation Trust (NELFT) and University College London (UCL). This funding sources had no role in the writing of the manuscript or the decision to submit it for publication.
Conflict of interest
JM is the chief investigator of the National Institute of Health Research funded RADAR trial, co-chairperson of the Critical Psychiatry Network and board member of the Centre for Evidence-based Psychiatry. MH, LdH, JB, SG, MJ, WV and IS have no conflicts of interest.
Ethical standards
As no patients were involved in this research, no ethical clearance was required for this Commentary article.