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Schizophrenia Bulletin
doi:10.1093/schbul/sbw171
Background: Antipsychotic switching is routine in clinical process in antipsychotic switching could end up in antipsy-
practice, although it remains unclear which is the preferable chotic polypharmacy.
switching method: immediate discontinuation of the cur-
rent antipsychotic or a gradual tapering approach. The first Key words: antipsychotics/discontinuation/schizophrenia/
strategy has been implicated in rebound/withdrawal symp- switching strategy
toms and emergence/exacerbation of symptoms, whereas
the gradual approach is thought to pose a risk of additive
Introduction
or synergistic side effects if employed in the context of a
crossover approach. Methods: MEDLINE, Embase, and Switching to a different antipsychotic agent frequently
Cochrane Central Register of Controlled Trials were sys- occurs in clinical practice during the treatment of schizo-
tematically searched. Randomized controlled trials exam- phrenia, most often related to suboptimal efficacy and/
ining immediate vs gradual antipsychotic discontinuation in or poor tolerability of the current agent.13 The process
antipsychotic switching in patients with schizophrenia and/ of antipsychotic switching provides the opportunity for
or schizoaffective disorder were selected. Data on clinical multiple strategies48 that arise from the fundamental
outcomes, including study discontinuation, psychopathol- options available for each drug (ie, immediate vs grad-
ogy, extrapyramidal symptoms, and treatment-emergent ual discontinuation of the current antipsychotic, as well
adverse events, were extracted. Results: A total of 9 stud- as full dose vs incremental titration of the new antipsy-
ies involving 1416 patients that met eligibility criteria were chotic). Variations can also include a gap between dis-
included in the meta-analysis. No significant differences in continuing the first and initiating the next antipsychotic.9
any clinical outcomes were found between the 2 approaches As summarized in supplementary table 1, immediate
(all Ps > .05). Sensitivity analyses revealed that the find- antipsychotic discontinuation has been associated with
ings remained unchanged in the studies where switching to the following risks: (1) dopamine supersensitivity syn-
aripiprazole was performed or where immediate initiation dromes (eg, supersensitivity psychosis and withdrawal
of the next antipsychotic was adopted, while some signifi- dyskinesia); (2) rebound syndromes related to cholin-
cant differences were observed in switching to olanzapine ergic, histaminergic, and serotonergic activity; and (3)
or ziprasidone. Conclusions: These findings indicate that emergence/exacerbation of symptoms.4,5,7,8,10,11 On the
either immediate or gradual discontinuation of the cur- other hand, the gradual discontinuation has been linked
rent antipsychotic medication represents a viable treatment with an increased risk of side effects that may be addi-
option. Clinicians are advised to choose an antipsychotic tive or synergistic when used in the context of a crossover
switching strategy according to individual patient needs. approach.4,5,7,8,11 It has been reported that clinicians are
This said, immediate discontinuation may be advantageous more likely to perform abrupt rather than cross-titration
both for simplicity and because a stalled cross-titration switching,1215 while previous reviews of antipsychotic
The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
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H. Takeuchi etal
switching strategies recommend gradual antipsychotic scores as extrapyramidal symptom (EPS) measures; and
discontinuation as a safer method in general7,8,10,11,16; such (3) the number of patients who experienced treatment-
endorsement is based on empirical evidence but not on emergent adverse events (TEAEs) that were reported in
actual data from clinical trials. 3 out of the identified 9 studies (these included akathi-
There have been several randomized controlled tri- sia, anxiety, diarrhea, headache, insomnia, nausea, and
als (RCTs) examining the 2 approaches.9,1724 In fact, a somnolence).
meta-analysis in 2004 by our group reported no differ- If reports on the studies did not provide sufficient data,
ences in either efficacy or safety25 although only 4 RCTs we contacted the corresponding authors and/or funding
met criteria for inclusion at that time.9,1719 However, a pharmaceutical company, accessed the ClinicalTrails.gov
further 5 RCTs comparing these approaches have since website, and/or applied to data-sharing organizations to
been reported.2024 In light of how common antipsy- which pharmaceutical companies sometimes belong in an
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Immediate vs Gradual Antipsychotic Discontinuation
and compared arm (1) with arm (3) in one study, and arm Psychopathology
(2) with arm (4) in the other study to match the antipsy- No significant differences were found in any psychopa-
chotic initiation strategies (supplementary table 2); in thology outcomes including the PANSS/BPRS total
addition, to evaluate the impact of treating one study as (SMD = 0.03, 95% CI = 0.17 to 0.11) and positive
2 separate studies, we conducted sensitivity analyses only symptom (SMD=0.00, 95% CI=0.14 to 0.14), PANSS
using either one (ie, Kinon 2000a or Kinon 2000b). As negative subscale (SMD = 0.05, 95% CI = 0.19 to
a consequence, a total of 12 comparisons of immediate 0.10), and CGI-S scores (SMD=0.02, 95% CI=0.14
and gradual antipsychotic discontinuation were yielded. to 0.10) between the 2 groups (figure2). All I2s were 0%,
As sensitivity analyses, we separately analyzed the follow- indicating no study heterogeneities.
ing 5 sets of studies: (1) blinding raters (N=4); (2) adopting
an immediate antipsychotic initiation strategy (8 compari-
Extrapyramidal Symptoms
Switching Strategy
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H. Takeuchi etal
Casey 2003 Open-label 8 wk 104 RIS (37%), OLZ (55%), ID (reduce by 100% at day 0) APZ 30mg/d II (introduce 30mg/d at day 0)
TAPs (8%)
104 RIS (36%), OLZ (56%), GD (reduce by 50% at day 0, 75% at
TAPs (8%) week 1, and 100% at week 2)
Ganguli 2008 Rater-blind 6 wk 41 OLZ (100%) 14.4mg/d ID (reduce by 100% at day 0) RIS 4.3mg/d GI (introduce 2mg/d at day 0,
40 OLZ (100%) 15.5mg/d GD (reduce by 50% at day RIS 4.9mg/d increase to 4mg/d at day 3, and
0 and 100% at week 1) titrate the dose after week 1)
Kinon 2000a Open-label 3 wk 52 RIS (33%), HPD (31%), ID (reduce by 100% at day 0) OLZ 10mg/d II (introduce 10mg/d at day 0)
(discontinuing strategy) other TAPs (37%)
Double-blind 54 RIS (20%), HPD (28%), GD (reduce by 50% by week
(introducing strategy) other TAPs (52%) 1 and 100% by week 2)
Kinon 2000b 53 RIS (25%), HPD (28%), ID (reduce by 100% at day 0) WGI (introduce 5mg/d at week 1
other TAPs (47%) and increase to 10mg/d at week 2)
50 RIS (32%), HPD (22%), GD (reduce by 50% by week
other TAPs (46%) 1 and 100% by week 2)
Lee 2002 Open-label 6 wk 54 HPD (39%), ID (reduce by 100% at day 0) OLZ 12.2mg/d II (introduce 10mg/d at day 0 and
other APs (61%) then titrate 520mg/d)
54 HPD (41%), GD (reduce by 100% by week 2) OLZ 11.5mg/d
other APs (59%)
Pae 2009 Rater-blind 12 wk 31 RIS (35%), OLZ (42%), ID (reduce by 100% at day 0) APZ (dose not II (introduce 10mg/d at day 0 and
other AAPs (15%) reported) then titrate 1030mg/d)
29 RIS (52%), OLZ (36%), GD (reduce by 50% by week
other AAPs (12%) 2 and 100% by week 4)
Stip 2010 Open-label 6 wk 18 HPD (72%), other ID (reduce by 100% at day 0) ZIP 86.1mg/d II (introduce 80mg/d at day 0 and
TAPs (28%) titrate 80160mg/d after day 2)
18 HPD (67%), other GD (reduce by 50% at day ZIP 87.6mg/d
TAPs (33%) 0 and 100% at week 1)
Takeuchi 2016 Double-blind 8 wk 15 OLZ (67%), other ID (reduce by 100% at day 0) CLZ 342mg/d GI (introduce 12.5mg/d at day
(discontinuing strategy) APs (33%) 0, increase by 25mg/d everyday
Open-label 18 OLZ (44%), other GD (reduce by 25% at day 0, CLZ 292mg/d to 300mg/d at day 12, and titrate
(introducing strategy) APs (56%) 50% at week 1, 75% at week 2, after week 5)
and 100% at week 3)
Weiden 2003a Rater-blind 6 wk 35 TAPs (100%) ID (reduce by 100% at day 0) ZIP 90.3mg/d II (introduce 80mg/d at day 0 and
titrate 40160mg/d after day 2)
39 TAPs (100%) GD (reduce by 50% at day 0 ZIP 91.9mg/d
and 100% at week 1)
Weiden 2003b 34 OLZ (100%) ID (reduce by 100% at day 0) ZIP 88.6mg/d
36 OLZ (100%) GD (reduce by 50% at day 0 ZIP 91.1mg/d
and 100% at week 1)
Discussion
Note: AAPs, atypical antipsychotics; APs, antipsychotics; APZ, aripiprazole; CLZ, clozapine; GD, gradual discontinuation; GI, gradual introduction; HPD, haloperidol;
comes, including study discontinuation, psychopathology,
ID, immediate discontinuation; II, immediate introduction; ILO, iloperidone; OLZ, olanzapine; RIS, risperidone; TAPs, typical antipsychotics; WGI, wait-and-gradual
Introduction Strategy EPS, and TEAEs, significantly differed between immedi-
ate vs gradual discontinuation of the current agent when
switching antipsychotics in patients with schizophrenia.
This was the case for the vast majority of the individual
studies included in this meta-analysis, which resulted in
no study heterogeneities across all clinical outcomes over-
all. These findings are consistent with a previous meta-
New Antipsychotics
APZ (33%)
If reported.
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H. Takeuchi etal
antipsychotic and initiation of the next agent. Sensitivity immediate and gradual antipsychotic discontinuation
analysis including 8 comparisons that used an immedi- strategies in those studies switching to aripiprazole, while
ate introduction approach of the next antipsychotic in switching to olanzapine or ziprasidone some significant
found no significant differences in any clinical outcomes differences were found, suggesting that clinicians need to
between immediate and gradual discontinuation of the take into account the pharmacological profiles of the next
current antipsychotic. This left only 4 comparisons that antipsychotic, in particular for antipsychotics that have a
used other types of introduction strategies, hampering sedative effect such as olanzapine. However, each involves
any conclusions that can be drawn regarding how to only 2 reports and further studies are clearly needed.
introduce the new antipsychotic. There are limitations to the present study that warrant
In addition, differences in dose equivalents as well comment. First, we were not able to obtain certain addi-
as pharmacological properties must also be taken into tional data, including the number of patients who dis-
consideration when performing an antipsychotic switch. continued in one of the largest studies of Kinon etal.9 In
For example, a switch to aripiprazole or, alternatively, a addition, 1 RCT examining immediate vs wait-and-grad-
switch from quetiapine/clozapine calls into play issues ual discontinuation of the current antipsychotic with a
not relevant to switches involving other antipsychotics, switch to sertindole36 was not included in the meta-analysis
the former related to aripiprazoles partial dopamine because no usable data were presented; this study reported
agonist properties and low affinity vis-a-vis other recep- no significant differences in the vast majority of clinical
tors, while the latter must take into account their low D2 outcomes between the 2 strategies. Second, there were
receptor affinity.8 Sensitivity analyses revealed that none some variations in duration of gradual antipsychotic dis-
of the clinical outcomes significantly differed between continuation strategies among the studies, as noted in the
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Immediate vs Gradual Antipsychotic Discontinuation
Page 7 of 10
Fig.3. Extrapyramidal symptoms.
Fig.2.Psychopathology.
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Immediate vs Gradual Antipsychotic Discontinuation
Results section. Third, only 1 study was conducted in a fees from Sumitomo Dainippon Pharma. Mr Kantor
double-blind fashion, which may have influenced findings. has no competing interests to disclose. Dr Uchida has
Fourth, study durations were relatively short, although received grants from Astellas, Eisai, Eli Lilly, Meiji-
rebound/withdrawal symptoms are reported to usually Seika Pharma, Mochida, Otsuka, Shionogi, Sumitomo
occur within weeks following an antipsychotic switch.4 Dainippon Pharma, and Yoshitomi Yakuhin, and
Fifth, despite the frequency of antipsychotic switching in speakers honoraria from Eli Lilly, Janssen, Meiji-Seika
actual clinical practice, the number of studies investigating Pharma, MSD, Otsuka, Pfizer, Shionogi, Sumitomo
this issue remains limited, raising the possibility of type II Dainippon Pharma, and Yoshitomi Yakuhin. Dr Suzuki
error. Lastly, most of the studies were presumed to largely has received manuscript or speakers honoraria from
recruit patients with chronic schizophrenia, as reflected in Astellas, Eli Lilly, Elsevier Japan, Janssen, Meiji Seika
the established mean age of approximately 3545years (ill- Pharma, Novartis, Otsuka, Sumitomo Dainippon
Page 9 of 10
H. Takeuchi etal
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or haloperidol: an international, multicenter study. Int Clin is the evidence? Schizophr Res. 2005;76:267272.
Psychopharmacol. 2009;24:229238. 26. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group.
14. Cazorla P, Mackle M, Zhao J, Ha X, Szegedi A. Safety Preferred reporting items for systematic reviews and meta-
and tolerability of switching to asenapine from other analyses: the PRISMA statement. BMJ. 2009;339:b2535.
antipsychotic agents: pooled results from two randomized 27. Kay SR, Fiszbein A, Opler LA. The positive and negative
multicenter trials in stable patients with persistent nega- syndrome scale (PANSS) for schizophrenia. Schizophr Bull.
tive symptoms in schizophrenia. Neuropsychiatr Dis Treat. 1987;13:261276.
2012;8:247257. 28. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale.
15. de Smidt C, Haffmans J, Hoencamp E. Antipsychotics Psychol Rep. 1962;10:799812.
switching strategies in real life: a longitudinal study in clinical 29. Guy W. ECDEU Assessment Manual for Psychopharmacology.
practice. Eur J Psychiatry. 2012;26:4149. Rockville, MD: National Institute of Mental Health; 1976.
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