Graylands Hospital DRUG BULLETIN Pharmacy Department Brockway Road Mount Claremont WA 6010 Telephone (08) 9347 6400 Email [email protected] 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 others(7). switching, evaluate various switching methods • Compliance should be assessed before and recommend switching strategies for switching due to lack of efficacy(3). individual antipsychotic agents. Switching Strategies Switching Rationale Table 1 details the advantages and disadvantages Why switch antipsychotics? (2) of four switching paradigms. ● Persistent positive or negative symptoms ● Intolerable adverse effects The potential problems of switching ● Partial or non-compliance (for switches to antipsychotics include; discontinuation depots) syndromes, changes in psychopathology, ● Patient preference pharmacodynamic interactions, pharmacokinetic Situations where switching should be interactions and neuroleptic malignant syndrome reconsidered: 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 months(3). 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 least one year(3). drug properties of both antipsychotics involved in Table 1: Antipsychotic switching strategies(3, 4) Method Advantages Disadvantages 1 Withdraw the first drug gradually and begin Lowest interaction potential Risk of relapse the second drug following a wash-out period Side-effects of the second drug are less likely to be confused with Not feasible if patient is symptomatic withdrawal effects of the first drug(5) 2 Stop the first drug immediately and Low interaction potential Risk of withdrawal effects commence the second drug at usual starting Required when the patient has had a serious adverse effect to the Risk of relapse dose, increasing gradually first drug e.g. blood dyscrasias with clozapine Requires close supervision 3 Cross titration: Over 2-4 weeks, gradually In general, the preferred method(6) Risk of additive adverse effects and decrease the first drug, whilst starting the Useful for switches from high potency antipsychotics to low interactions second drug at a low dose and gradually potency antipsychotics If taper is too quick, both drugs may be increasing dose Useful for switches where cholinergic rebound may occur given at sub-therapeutic doses Risk of medication errors 4 Overlap: Maintain first drug at usual dose Suitable if relapse prevention is of greatest concern Risk of additive adverse effects and for 2-3 weeks, initiate and up-titrate second Most appropriate if the patient has recently recovered from acute interactions drug to therapeutic dose, then gradually relapse with the first drug Potential risk of continued polypharmacy withdraw the first drug over 1-2 weeks Risk of medication errors Graylands Hospital Drug Bulletin 2006 Vol 14 No.1 - 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 hepatic impairment may require a slow high incidence of rebound psychosis(11, 16). titration/switching strategy(8, 11). Commencing the Second Antipsychotic Discontinuing the First Antipsychotic The relative pharmacokinetic and The potential problems of discontinuing the first pharmacodynamic properties of the two antipsychotic during a medication switch include antipsychotics will influence the choice of switch discontinuation effects and psychotic relapse. strategy. 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 Description Timing Comments Anticholinergic Malaise, nausea, First few Occurs with rapid sedation, orthostatic hypotension, EPSE, prolactin withdrawal/ vomiting, days withdrawal of elevation, lowered seizure threshold and QT Cholinergic diarrhoea antipsychotics with rebound anticholinergic activity, interval prolongation may be worsened. Hence, a or for switches to less washout period may be required in cases where anticholinergic antipsychotics. there is an additive adverse effect burden. This Can be managed with may be necessary for switches in high-risk anticholinergics Rebound Symptoms of First few Occurs with patients involving drugs with marked effects on akathisia akathisia but days antipsychotic or the QT interval(17). In contrast, switch strategy 3 often anticholinergic indistinguishable withdrawal or 4 may be suitable where gradual dose from psychosis Use of propranalol, escalations are required for the second or anxiety cyproheptadine, benzodiazepines or antipsychotic. This is necessary for antipsychotics clonidine may be used to with orthostatic effects or for high potency drugs treat akathisia(12) Rebound Parkinsonian First Occurs when an that can induce EPSE (5, 18). parkinsonism symptoms of week anticholinergic is tremor, muscle discontinued at the same rigidity and time as a high-potency Problems may also occur where there are akinesia antipsychotic significant differences between the properties of May also occur after discontinuing low- the two drugs. Rebound insomnia may occur potency antipsychotics when switching from a sedating antipsychotic to a Withdrawal Choreoathetoid 1 to 4 Most likely to occur dyskinesia movements that weeks when switching from an less-sedating antipsychotic(19). Rebound are antipsychotic with a high insomnia may require management with short- indistinguishable May take D2 affinity to low D2 from tardive up to 6 affinity(13) A slow term benzodiazepine use(19). As mentioned dyskinesia months down-titration can earlier, discontinuation effects may be more to abate minimize risk(13) pronounced during switches to antipsychotics When discontinuing antipsychotics with with different affinities for D2 or cholinergic significant anticholinergic activity, a slow taper receptors. 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 should also be considered when two week period after the first antipsychotic has been antipsychotics are used concurrently. discontinued to prevent rebound parkinsonism Cytochrome P450 isoenzymes are involved in the and rebound anticholinergic effects(2). 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 - 2 - antipsychotics. NMS is characterized by 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 rebound(11). Switch strategy 3 or 4 is 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 treatment(20). atypicals(11). When switching from an atypical antipsychotic to a typical antipsychotic, a slow Post-switching Considerations discontinuation of the atypical is recommended to ● The first antipsychotic should be ceased minimize risk of rebound psychosis(11). within three months of commencing any cross- Typical Depot Antipsychotics titration(24). 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: complete antipsychotic switch(24). ● Flupenthixol decanoate, 10-12 weeks; ● Women treated with conventional ● Fluphenazine decanoate, 6-12 weeks; antipsychotics, risperidone or amisulpride