Antipsychotic Withdrawal Syndrome – Understanding the Hyperbolic Curve and Tapering Antipsychotic Treatment to Reduce the Risk of Relapse

CLINICAL MANIFESTATIONS OF ANTIPSYCHOTIC WITHDRAWAL SYNDROME

Depending on the antipsychotic drug’s target receptor, both first and second-generation antipsychotics [Read mechanisms of action of antipsychotics] can be associated with the following clinical features:  [Horowitz et al 2021]

• Adrenergic: Headache, anxiety or agitation, hypertension, tachycardia, angina, palpitations, pre-syncope, tremulousness, sweating, and risk of myocardial infarction. 
• Cholinergic: Agitation, insomnia, anxiety or depression, dizziness, tachycardia, nausea, diarrhoea, tremors, restlessness, myalgia, paraesthesia, hallucinations, confusion, hypothermia, sweating. 
• Dopaminergic (nigrostriatal): Withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia. 
• Dopaminergic (mesolimbic/striatal): Auditory hallucinations, persecutory delusions, and other psychotic symptoms. 
• Histaminergic: Irritability, insomnia, agitation, loss of appetite or nausea, tremulousness, incoordination, lethargy, and amnesia. 
• Serotonergic: Flu-like symptoms, dizziness, tachycardia, paraesthesia, anxiety, agitation, low mood, insomnia, nausea, diarrhoea, confusion, and lack of concentration. 

PHARMACOLOGY OF ANTIPSYCHOTIC WITHDRAWAL

Research shows that the longer the exposure to antipsychotics the higher the risk of developing withdrawal-associated psychosis on discontinuation. [Robinson et al 1999]; [Tiihonen et al 2018]

Tiihonen et al showed that the risk of relapse doubles after 1–2 years, triples after 2–5 years and increases 7 times after 8 years of antipsychotic exposure. This correlation may not be causal as patients with more severe illnesses are likely to be on antipsychotics for longer periods. [Tiihonen et al 2018]

One study reported that 48% of relapses occur in the first 12 months after antipsychotic discontinuation (40% in the first 6 months), with only 2% per year after this period. [Viguera et al., 1997]

• Furthermore, patients who show tolerance to antipsychotic dose increases are also more likely to have withdrawal symptoms. [Chouinard et al 2017] 
• This type of drug tolerance occurs due to the lessening of the drug’s therapeutic effect with continued treatment and the need for an increased dose to achieve the same beneficial effect. 

Neurobiology of Withdrawal: 

There is evidence of people with no previous history of psychosis who can develop psychotic symptoms after abrupt cessation of dopamine antagonists in a non-psychiatric setting (e.g reserpine, metoclopramide, domperidone).

• Antipsychotic dopamine antagonism over prolonged periods leads to hypersensitivity of dopamine receptors.
• When the antagonist is abruptly withdrawn, physiological levels of dopamine can cause overstimulation of the sensitised receptors, leading to withdrawal or rebound symptoms.

In patients with schizophrenia, the preexisting increased presynaptic dopaminergic synthesising capacity (DSC) combined with post antipsychotic cessation elevated post-synaptic dopamine sensitivity can increase the risk of relapse. [Chouinard et al 2017]

During the phase of post antipsychotic cessation, relapses occur due to a rebound effect which is a combination of neuroadaptations that take months and years to resolve combined with an increased vulnerability to life events and other stressors.

THE HYPERBOLIC CURVE AND MITIGATING ANTIPSYCHOTIC WITHDRAWAL SYMPTOMS

Linear dose reductions produce hyperbolic changes in D2 receptor occupancies, i.e. the reductions at lower doses tend to have the most significant drops in D2 receptor occupancies, increasing the propensity for withdrawal symptoms.

To mitigate the symptoms of antipsychotic withdrawal, the dose is gradually reduced or tapered to the minimum effective dose.

Gradual tapering involves a slow tapering in dose to allow drug-induced neuroadaptations to return to baseline.

However, given it can take 2–5 years for 60-90% of symptoms associated with TD to resolve, it has also been suggested that tapering periods also need to be as prolonged. [Horowitz et al. 2021] 

A recent meta-analysis showed that the tapering period had an inverse relationship with the rate of relapse over 12 months: no tapering, 77% of patients relapsed; 1–2 week taper, 57% of patients relapsed; 3–10 week taper, 47% of patients relapsed; and > 10-week taper, 31% of patients relapsed. [Bogers et al. 2020] 

Furthermore, the relationship between the dose of antipsychotic and its effect at the receptor may also be informative for creating a tapering schedule.

Here, receptor occupancy calculations at a given dose can provide insights into the effect a linear or hyperbolic reduction in dose has on receptor occupancy. [Lako et al. 2013]

When using haloperidol as an example: 

• Linear dose reductions: 4 mg (79% D2 occupancy), 3 mg (76% D2 occupancy), 2 mg (69% D2 occupancy), 1 mg (55% D2 occupancy), 0.5 mg (40% D2 occupancy), and 0.25 mg (25.5% D2 occupancy. 
• Hyperbolic dose reductions: 4.4 mg (80% D2 occupancy), 1.2 mg (60% D2 occupancy), 0.50 mg (40% D2 occupancy), and 0.18 mg (20% D2 occupancy). 

Here, it can be seen that a linear dose reduction schedule produces an increasingly more significant reduction in percentage points of D2 dopamine antagonism, i.e., there is a greater risk of dopaminergic rebound. It is also worth noting that the smallest tablet is 0.5 mg for haloperidol, and the step down from half of this tablet (0.25 mg) to 0 mg will produce a perilously considerable 25.5% point reduction. 

To overcome this significant drop, liquid formulations and tapering strips have recently been developed to provide small tablet formulations and intermediate doses between commonly prescribed dosages. [Groot and van Os 2020] 

Olanzapine Dose and Hyperbolic curve: 

Risperidone dose and Hyperbolic curve: 

APPLYING AN ANTIPSYCHOTIC TAPERING REGIMEN

Horowitz et al. recently published a method for tapering antipsychotics to minimise the risk of relapse. It was suggested that this should be done gradually over months, even years, and should incorporate hyperbolic dose reductions where necessary to provide a more even reduction of D2 blockade. [Horowitz et al. 2021]

Overall, intervals of 3-6 months are suggested with the aim of reducing by ¼ or ½ of the most recent dose, which should be equal to a reduction of 5 or 10 percentage points of D2 occupancy. The following table provides a pharmacologically informed tapering regimen over 10 steps for 6 antipsychotics, with the starting dose representing the lowest recommended dose for multiple episodes of psychosis:

Finally, as there are likely to be several demographic and clinical variables that affect this tapering process, it is suggested that the process is personalised by observing the patients response to tapering. However, given any dose reduction is likely to have side effects, these should resolve over time as the underlying neuroadaptations slowly resolve back to baseline. [Gupta et al. 2018] 

The final dose of medication before complete cessation may also predict relapse because it might represent a large “step down” in dopaminergic (or other targets) blockade. Thus, final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a significant decrease in D2 blockade when stopped.

According to Horowitz et al.: 

Many patients may tolerate dose reductions of 25%–50% of the most recent dose (corresponding approximately to 5–10 percentage point decrements of D₂ occupancy) every 3–6 months. Smaller reductions (such as 10% of the most recent dose) made every month may be more tolerable in the aim of producing more “evenly spread” perturbation to the equilibrium.

Due to their long half-life and therefore long duration in reaching steady-state levels, Depot medications provide a form of “in-built” tapering.

For example, 3-monthly paliperidone depot takes 52 weeks to reach a steady-state and may be tapered over 3 years by yearly dose reductions equivalent to approximately 30% D₂ occupancy (equivalent to reducing by 10 percentage points of D₂ occupancy every 4 months), with the time taken to reach a steady-state providing time for neural adaptation. Very small doses of the depot would be required for final dosing (eg, 90 mg, equivalent to 30% D₂ occupancy).

More caution may be required for drugs with short half-lives or ‘hit and run’ characteristics, like clozapine or quetiapine, which can lead to rebound psychosis following withdrawal. It may be necessary to reduce doses by 2.5–5 percentage points of D₂ (or cholinergic or histaminergic) occupancy every 6–12 weeks, depending on individual responses.

Recent evidence shows that drugs like aripiprazole that are partial agonists at the D₂ receptor are less likely to induce dopaminergic hypersensitivity and thus less likely to lead to a relapse post discontinuation.

SWITCHING PRINCIPLES AND STRATEGIES

In contrast to switching antidepressants, a drug-free period between stopping the first antipsychotic and starting the second is not recommended due to the risk of relapse.

Switching Strategies: [Keks et al, 2019]

Refer to the interactive switching tool

1.Direct Switch: 

• The first AP is stopped abruptly and the second AP started the next day.
• Quick but expertise is required.
• Discontinuation symptoms risk is present depending on the choice of the second AP.
• Half-lives of each agent should be taken into account.
• Avoid this strategy when stopping clozapine, olanzapine or quetiapine due to the high risk of anticholinergic and antihistaminergic rebound.
• A possible strategy for switching one partial agonist to another partial agonist, e.g. Aripiprazole to Brexpiprazole (dose adjustments are required for the second AP added)
• Also applicable to switching from Aripiprazole or Brexpiprazole to Cariprazine. (Dose adjustments and monitoring of side effects if recommended due to the overlap of the two medications when using this strategy)

2.Cross Titration / Cross Taper Switch: 

• The first AP is gradually reduced and stopped
• The second AP is introduced at a low dose at some stage during the reduction of the first AP so that the patient is taking both AP simultaneously.
• The dose of the second AP  is gradually increased to the therapeutic dose when the first AP has been stopped.
• Considered in patients with a high risk of relapse
• Risk of medication interactions
• Increased risk of adverse reactions due to combinations
• Consider the pharmacokinetics of each medication
• Clinicians should base cross-tapering based on the half-lives of the APs.
• Cross-taper and reduction in a short period should be avoided with clozapine, olanzapine or quetiapine.

3. Continuation with slower titration and subsequent discontinuation:

• First antipsychotic is continued at the usual dose or slightly reduced dose while the second AP is gradually titrated up to near therapeutic dose.
• Then, first AP is gradually reduced and stopped, while dose of the second AP is increased to its therapeutic dose.
• Most conservative strategy suitable for patients with a high risk of relapse.
• Significant overlap of the two APs with a likelihood of adverse effects during the switch.
• Risk that the planned discontinuation of the first antipsychotic never takes place or the therapeutic dose of the second antipsychotic is not reached.
• Strategy may be applicable to switch from Olanzapine, Risperidone or Lurasidone to a Pip.
• In switching from Pine or Done to a Pip, clinicians should recognise that based on the hyperbolic curve reductions of Pine’s should be done gradually and over a longer period than shown in the diagrams. This reduction should be individualised to the patient.

4. Stop and Start Second AP at Middle Dose: 

• Can be used when switching from a long half-life agent (e.g Aripiprazole, Brexpiprazole or Cariprazine) to a Pine or Done.
• Can be used in the case of Depot to Oral transition.
• Start the oral drug (except clozapine) when the depot antipsychotic was next due.
• Clozapine requires a very slow titration at the start of therapy. Continue the depot antipsychotic until clozapine has reached therapeutic plasma concentrations or has shown a significant clinical effect.

SUMMARY

The risk of relapse after discontinuation of antipsychotic therapy may be reduced by gradual dose tapering over a prolonged period.

The tapering process should be in linear increments, to begin with, but then in a hyperbolic manner to evenly reduce D2 receptor blockade; this process should allow sufficient time for the underlying neuroadaptations to resolve. 

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