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 DrugInformation.Graylands@health.wa.gov.au 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 Anticholinergic
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 dyskinesia
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 ++ Flupenthixol Fluphenazine Haloperidol Pericyazine Thioridazine Trifluoperazine Zuclopenthixol Amisulpride Aripiprazole Clozapine Olanzapine Quetiapine Risperidone 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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