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Clozapine and gastrointestinal adverse effects - a pain in the gut?

Graylands Hospital
Pharmacy Department Brockway Road Mount Claremont WA 6010 Telephone (08) 9347 6400 Email Fax (08) 9384 4586 Antipsychotic Switching: When, How, Why?
Graylands Hospital Drug Bulletin 2006 Vol. 14 No. 1 March ISSN 1323-1251
There are currently no definitive antipsychotic • Switching between antipsychotics is not switching guidelines, however, certain strategies indicated if an exacerbation of symptoms may be more appropriate in individual cases(1). represents an unacceptable risk to the patient or This bulletin will review the reasons for switching, evaluate various switching methods • Compliance should be assessed before Switching Strategies
Switching Rationale
Table 1 details the advantages and disadvantages ● Persistent positive or negative symptoms ● Partial or non-compliance (for switches to pharmacodynamic interactions, pharmacokinetic Situations where switching should be interactions and neuroleptic malignant syndrome and (8). All medication switches should include • Avoid switches for patients who have recently appropriate monitoring for these effects. recovered from a psychotic episode for 3 to 6 A recent systematic review with meta-analysis • Patients that are compliant on a depot suggests that there is no evidence that gradual preparation with a history of oral non-compliance discontinuation and replacement is safer or more should not be switched to oral medication for at effective than abrupt change(9). However, the drug properties of both antipsychotics involved in Table 1: Antipsychotic switching strategies(3, 4)
Withdraw the first drug gradually and begin the second drug following a wash-out period Side-effects of the second drug are less likely to be confused with commence the second drug at usual starting Required when the patient has had a serious adverse effect to the first drug e.g. blood dyscrasias with clozapine Cross titration: Over 2-4 weeks, gradually decrease the first drug, whilst starting the Useful for switches from high potency antipsychotics to low If taper is too quick, both drugs may be Useful for switches where cholinergic rebound may occur given at sub-therapeutic doses Risk of medication errors Overlap: Maintain first drug at usual dose Suitable if relapse prevention is of greatest concern for 2-3 weeks, initiate and up-titrate second Most appropriate if the patient has recently recovered from acute drug to therapeutic dose, then gradually Potential risk of continued polypharmacy Graylands Hospital Drug Bulletin 2006 Vol 14 No.1
the switch should be considered in each case(10). treatment compared to a gradual reduction in dose Aside from drug property considerations, (reduction over two weeks to two months)(16). In individual patient factors should be considered particular, rapid withdrawal of drugs that are before switching. Special populations such as the loosely bound to the D2 receptor, such as elderly, neuroleptic naive, or those with renal or clozapine and quetiapine are associated with a high incidence of rebound psychosis(11, 16). The potential problems of discontinuing the first antipsychotic during a medication switch include antipsychotics will influence the choice of switch discontinuation effects and psychotic relapse. Table 2 from Weiden et al lists the common withdrawal syndromes that can occur during Switch strategies 3 and 4 may be associated with antipsychotic or anticholinegic discontinuation. higher rates of adverse effects, especially when the adverse effects are shared between the two Table 2: Antipsychotic discontinuation effects(3)
antipsychotics. In particular, the adverse effects of Category
sedation, orthostatic hypotension, EPSE, prolactin withdrawal/
elevation, lowered seizure threshold and QT Cholinergic
interval prolongation may be worsened. Hence, a washout period may be required in cases where there is an additive adverse effect burden. This may be necessary for switches in high-risk patients involving drugs with marked effects on akathisia
the QT interval(17). In contrast, switch strategy 3 antipsychotic. This is necessary for antipsychotics with orthostatic effects or for high potency drugs parkinsonism
significant differences between the properties of the two drugs. Rebound insomnia may occur when switching from a sedating antipsychotic to a Withdrawal
less-sedating antipsychotic(19). Rebound insomnia may require management with short- term benzodiazepine use(19). As mentioned earlier, discontinuation effects may be more pronounced during switches to antipsychotics When discontinuing antipsychotics with with different affinities for D2 or cholinergic significant anticholinergic activity, a slow taper strategy is recommended (3). If anticholinergic medications were used to treat EPSE before a The potential for pharmacokinetic interactions switch, these should be discontinued over a three week period after the first antipsychotic has been discontinued to prevent rebound parkinsonism Cytochrome P450 isoenzymes are involved in the metabolism of many antipsychotics. Caution is In addition to withdrawal effects, relapse or required when cross-tapering antipsychotics destabilization may occur after abrupt eliminated by the same cytochrome subsystem(7). discontinuation of an antipsychotic(14, 15). The proportion of patients relapsing per month may be The risk of neuroleptic malignant syndrome threefold greater after abrupt discontinuation of (NMS) is present during any switch between Graylands Hospital Drug Bulletin 2006 Vol 14 No.1
high potency antipsychotic, the first drug should autonomic instability, EPSE, hyperpyrexia and be slowly discontinued to prevent cholinergic altered mental state. A sudden blockade of D2 receptors is considered to be a contributing factor recommended when switching from a typical in NMS(20). In 66% of cases, NMS occurs within antipsychotic to an atypical antipsychotic, as a two weeks of initiation or change in antipsychotic gradual onset of action may occur with some atypicals(11). When switching from an atypical antipsychotic to a typical antipsychotic, a slow discontinuation of the atypical is recommended to ● The first antipsychotic should be ceased within three months of commencing any cross- It may take several months for a depot preparation ● Target symptom response should be assessed to reach steady state. During this time, interim after 3-6 weeks for an acute psychotic episode, or oral supplementation may be required(25). The after 3 months for stable patients following time to steady state for the typical depots: ● Flupenthixol decanoate, 10-12 weeks; Women treated with conventional ● Fluphenazine decanoate, 6-12 weeks; antipsychotics, risperidone or amisulpride often experience amenorrhoea and galactorrhoea. ● Zuclopenthixol decanoate, 10-12 weeks(5). Normalization of prolactin levels following Direct switches from one typical depot to another medication change leads to return of menses and For switches from a depot to oral antipsychotic, a one month cross-titration taper has been shown to Specific Medication Switches
Atypical Antipsychotics
antipsychotics that may influence the choice of Risperidone long-acting injection (RLAI) switching method. A brief discussion on specific It takes 3-4 weeks for the first RLAI to produce switching strategies for various antipsychotics is therapeutic plasma levels(17). Patients must be maintained on a full dose of their previous oral antipsychotic for at least three weeks after the Typical Antipsychotics
administration of the first injection(12). If changing from a conventional depot, give RLAI Chlorpromazine dose equivalents can be used to one week before the last depot injection is given determine an equivalent dose for switching or in place of the last depot injection(12, 26). In between typical antipsychotics(5). When general, the starting dose of RLAI should be switching from a low potency antipsychotic to 25mg every two weeks(12). The dose of RLAI should not be increased until after the patient has Table 3: Relative Effects of Antipsychotics (5, 8, 12, 21-23)

Anticholinergic Extrapyramidal Hypotension Cardiac Chlorpromazine ++
Effect: 0, absent/very low; +, low; ++, moderate; +++, high.
Graylands Hospital Drug Bulletin 2006 Vol 14 No.1
clozapine dose up (17). Particular caution is Patients who have stabilized on a high dose of required when switching from a drug that is conventional depot may require a starting dose of known to be myelosupressive or that can reduce the seizure threshold, as these effects may be The last dose of RLAI will stop releasing risperidone six weeks later, any new drug should antipsychotic or risperidone to olanzapine, the Switching strategies 2 or 3 are suitable for most effective strategy is to add a therapeutic amisulpride(17, 27). If a cross-titration approach dose of olanzapine (up to 10mg/day) while is used, the first antipsychotic should be reduced gradually discontinuing prior medication over two over 1-4 weeks(27). A starting dose of 100- weeks(31). Although clozapine and olanzapine 300mg is recommended if negative symptoms have similar affinities for muscarinic receptor predominate or in the case of relapse due to non- subtypes, cholinergic rebound has been described compliance, a starting dose of up to 800mg can be Aripiprazole can be switched to by: 1) immediate Quetiapine has low D2 antagonistic properties and initiation of 30mg/day with simultaneous low anticholinergic activity. These characteristics immediate discontinuation of current must be considered during the switch process, as antipsychotic; 2) immediate initiation of withdrawal dyskinesia may be more common 30mg/day of aripiprazole while tapering current when switching to quetiapine than with other antipsychotic over two week; or 3) up-titrating atypicals, due to reversal of chronic D2 aripiprazole to 30mg/day over two weeks, while simultaneously tapering off current antipsychotic Method four may be suitable in many cases for switches to quetiapine because of the minimal risk There have been case reports of worsening of of inducing EPSE with quetiapine(13). Rapid psychosis during switches to aripiprazole(29). switching from haloperidol, risperidone or Aripiprazole functions as a weak partial agonist at thioridazine has been generally well tolerated the postsynaptic D2 receptor in hypodopaminergic with patients remaining clinically stable(13). states and as an antagonist when dopaminergic However, discontinuation effects of the first activity is increased. Psychosis may be worsened antipsychotic should always be considered. during a switch by the combination of a large Quetiapine should be administered twice daily post-synaptic D2 receptor availability and a hypodopaminergic state following discontinuation of the first antipsychotic combined with the D2 Switch strategy 3 is recommended for switches to agonist action of aripiprazole(29). Nausea, risperidone(17). Due to the alpha-blocking vomiting and initial restlessness have also been activity of risperidone, orthostatic hypotension reported when aripiprazole has been initiated at can occur, especially during the initial dose titration period. Consequently, medication should be titrated gradually in view of this risk (17). When switching from a previous antipsychotic to Caution is required with switches involving clozapine, switch strategy 1 is recommended(17). clozapine, as risperidone can elevate clozapine The first antipsychotic should be tapered down over one week. Once the first antipsychotic has been discontinued for 24 hours, clozapine can be commenced at a dose of 12.5mg and tapered up to therapeutic levels over 2 weeks(17). If prior discontinuation of the first antipsychotic is not a realistic option, combination therapy can be used This article was prepared by Karolina Golebiewski, Drug Information Pharmacist and reviewed by members of the Pharmacy Department with caution during the transition period. The dose of the first antipsychotic should be tapered Comments are welcome at the e-mail address: down over a week, while gradually tapering the Graylands Hospital Drug Bulletin 2006 Vol 14 No.1


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