Thread by @markhoro

(Thread) Today we have published a paper on a way to reduce antipsychotics to minimise withdrawal effects and possibly relapse in @SchizBulletin. bit.ly/31bc8Eg with thanks to co-authors Robin Murray, David Taylor, @sameerjauhar and Sridhar Natesan. (1/n)

It extends our work on risperidone to more antipsychotic drugs bit.ly/3tMFdSV
It provides some examples of pharmacologically rational tapering regimes for haloperidol, risperidone, olanzapine, clozapine, quetiapine and amisulpride which takes into account 2/n

their pharmacological characteristics and clinical trials. We suggest reducing dose by 5 or 10 percentage points of D2 occupancy (equivalent to about one quarter or one half of the dose) every 3-6 months. (3/n)

Some patients may be better with 10% reductions a month, or slower (depending on how they tolerate the process and how long they have been on the drug for – people on it for short periods will be able to taper much quicker) (4/n)

Antipsychotics are recommended because they reduce symptoms in short term studies and reduce relapse in discontinuation studies. But as Murray and Moncrieff and others have argued most discon studies involve very quick stopping of antipsychotics (mostly <4 weeks) (5/n)

Therefore it is possible that these studies induced withdrawal effects or discontinuation-induced de-stabilisation of people prone to psychotic states. Therefore the relapse rate might be reduced by a more gradual tapering. (6/n)

There are studies that now find that relapse rates correlate with rate of reduction of antipsychotics bit.ly/3vKFvLM , consistent with slower tapering reducing relapse rates (7/n)

In fact there are some cases of people with no diagnosis of a psychotic disorder givenn dopamine antagonists (antipsychotics) for other conditions (eg problems with lactation, nausea) who on stopping antipsychotics developed psychotic symptoms for first time in their lives.(8/n)

These psychotic symptoms involve cardinal symptoms of psychosis – Capgras delusions, auditory hallucinations, etc – and sometimes require re-starting the antipsychotic and tapering more slowly. Therefore it is possible that psychotic symptoms are 1 of the withdrawal symptoms(9/n)

from antipsychotics.

Slower tapering might reduce the chance of these withdrawal effects (and withdrawal-associated de-stabilisation) (10/n)

As people on antipsychotics report many unpleasant adverse effects such as emotional blunting, weight gain, cognitive dysfunction, sedation and akathisia they often ask to reduce or stop their medication.
(11/n)

Given that these medications cause reduction in brain volume, increase metabolic disease and tardive dyskinesia we should seek to minimise people’s exposure to only necessary treatment – which means treatment at the lowest dose possible for the shortest period of time. (12/n)

Relationship between dose of antipsychotic and its effect on D2 dopamine receptors (and other receptor targets) is hyperbolic and so linear reductions (eg 4mg, 3mg, 2mg, 1mg, 0mg) will cause increasingly large changes in D2 occupancy which might increase risk of relapse(13/n)

It seems more reasonable to reduce by even amounts of effect on the brain (eg D2 receptor occupancy) which involves hyperbolic dose reductions (smaller and smaller dose reductions eg for olanzapine 7.5, 6.0, 4.5, 3.5, 2.5, 2.0, 1.5, 0.9, 0.4, 0mg). (14/n)

To provide these small doses liquid formulations of the drug (widely available for most antipsychotics) or tapering strips might be useful. There is a trial of a hyperbolic dose reduction of antipsychotics happening in Taiwan. (15/n)

What period of tapering makes sense? Withdrawal effects are thought to arise because of adaptations to the drug made by the brain during treatments (as for other substances like benzos, opioids or antidepressants). (16/n)

Therefore tapering might need to take many months or years for longer term patients in order to minimise the disruption caused by reduction. Patients treated shorter term may be able to reduce their medication in weeks or months (less adaptation to the medication) (17/n)

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