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Schizophrenia Bulletin Advance Access published January 1, 2017

Schizophrenia Bulletin
doi:10.1093/schbul/sbw171

Immediate vs Gradual Discontinuation in Antipsychotic Switching:


ASystematic Review and Meta-analysis

HiroyoshiTakeuchi*,13, NavotKantor4, HiroyukiUchida3,5, TakefumiSuzuki3,6, and GaryRemington1,2,7,8

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1
Schizophrenia Division, Complex Care & Recovery Program, Centre for Addiction and Mental Health, Toronto, ON, Canada;
2
Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 3Department of Neuropsychiatry, Keio University School of
Medicine, Tokyo, Japan; 4Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; 5Geriatric Mental Health Program, Centre
for Addiction and Mental Health, Toronto, ON, Canada; 6Department of Psychiatry, Inokashira Hospital, Tokyo, Japan; 7Institute
of Medical Science, University of Toronto, Toronto, ON, Canada; 8Campbell Family Mental Health Research Institute, Centre for
Addiction and Mental Health, Toronto, ON, Canada
*To whom correspondence should be addressed; Schizophrenia Division, Complex Care & Recovery Program, Centre for Addiction and
Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; tel:+1-416-535-8501 (ext. 30547), fax: +1-416-979-4292, e-mail:
hirotak@dk9.so-net.ne.jp

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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chotic switching occurs, this question remains no less rel- attempt to obtain additional information.
evant. In order to update information on this clinically There are 2 points that should be noted in the data
important topic, we conducted a systematic review and extraction. First, since Lee et al17 did not clearly report
meta-analysis of RCTs examining immediate vs gradual the number of patients who discontinued the study due
antipsychotic discontinuation in patients with schizo- to inefficacy, we used 0 for both groups, estimated by sub-
phrenia undergoing a switch. tracting the total number of patients who discontinued
the study due to specific causes from those discontinuing
Methods due to all causes in each group. Second, Kinon etal9 did
not report somnolence but rather drowsiness, which we
Literature Search and Study Selection treated as synonomous. In addition, various descriptors
Two authors (H.T. and N.K.) independently conducted of insomnia were reported including shortened sleep,
a systematic literature search in accordance with the difficulty falling asleep, interrupted sleep, and early
PRISMA (Preferred Reporting Items for Systematic waking9; we chose to use shortened sleep for insomnia
Reviews and Meta-analyses) Statement.26 MEDLINE, but also conducted sensitivity analyses using each of the
Embase, and Cochrane Central Register of Controlled descriptors.
Trials (CENTRAL) were searched using the following
keywords: (schizophr* OR schizoaff*) AND antipsy- Data Analysis
chotic* AND switch* AND (strateg* OR tactic* OR
techni* OR procedure*), with a limitation of English Meta-analyses were performed using Review Manager
language (last search: August 30, 2016). Studies that met (RevMan) version 5.3. Outcome data were combined and
the following eligibility criteria were selected: (1) RCTs; compared between immediate and gradual antipsychotic
(2) studies including patients with schizophrenia and/or discontinuation groups. For dichotomous and continu-
schizoaffective disorder; and (3) studies including both ous outcomes, pooled estimates of risk ratios (RRs) and
immediate and gradual antipsychotic discontinuation standardized mean differences (SMDs) were calculated
arms in antipsychotic switching. Risk of bias for each with 2-sided 95% confidence intervals (CIs) using a ran-
included study was assessed according to the Cochrane dom-effects model, respectively.
Handbook for Systematic Reviews of Interventions Because we were able to obtain from Pfizer the individ-
(available at http://handbook.cochrane.org). ual data on all 3 studies included in a pooled analysis,19
we treated this pooled analytic study as 3 separate studies
(ie, Weiden 2003a, Weiden 2003b, and Weiden 2003c); in
Data Extraction addition, to evaluate the impact of treating one pooled
Two authors (H.T.and N.K.) independently extracted the study as 3 separate studies, we conducted sensitivity anal-
following clinical outcome data in both immediate and yses using pooled results. If any study included another
gradual antipsychotic discontinuation groups from the switching strategy, we disregarded these group(s) as we
selected studies: (1) the number of patients who discon- were focused on comparing the immediate and gradual
tinued the study due to all causes, lack of efficacy, and antipsychotic discontinuation strategies (supplementary
adverse events; (2) mean SD changes from baseline to table 2). Since Kinon et al9 compared 4 antipsychotic
endpoint in the Positive and Negative Syndrome Scale switching strategies: (1) immediate antipsychotic discon-
(PANSS)27 or the Brief Psychiatric Rating Scale (BPRS)28 tinuation + immediate antipsychotic initiation; (2) imme-
total and positive symptom, the PANSS negative sub- diate antipsychotic discontinuation + wait-and-gradual
scale, and the Clinical Global Impression-Severity scale antipsychotic initiation; (3) gradual antipsychotic discon-
(CGI-S)29 scores as psychopathology measures, and the tinuation + immediate antipsychotic initiation; and (4)
Simpson-Angus Scale (SAS)30 total, the Barnes Akathisia gradual antipsychotic discontinuation + wait-and-grad-
Rating Scale (BARS)31 total or global, and the Abnormal ual antipsychotic initiation, we treated this investigation
Involuntary Movement Scale (AIMS)29 total or Item 8 as 2 separate studies (ie, Kinon 2000a and Kinon 2000b)

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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

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sons); (3) switching to olanzapine (N=2); (4) switching to
ziprasidone (N=2); and (5) switching to aripiprazole (N=2). There was no significant difference in scores for the
All effect sizes with a P < .05 were considered signifi- SAS (SMD = 0.12, 95% CI = 0.11 to 0.35), BARS
cant. Study heterogeneities were quantified using I2 sta- (SMD = 0.16, 95% CI = 0.33 to 0.65), or AIMS
tistic with I2s 50% indicating significant heterogeneity. (SMD = 0.27, 95% CI = 0.03 to 0.56) between the 2
groups (figure 3). Although not statistically significant,
Results the AIMS score tended in favor of gradual antipsychotic
discontinuation (P = .07); however, both baseline and
Included Studies endpoint AIMS Item 8 (ie, global) scores were <1 (mini-
A total of 9 studies9,1724 involving 1416 patients (n=714 mal) for all studies included in the meta-analysis. No sig-
and n=702 for the immediate and gradual antipsychotic nificant heterogeneities were found in all EPS outcomes;
discontinuation, respectively) that met eligibility criteria however, there was a marginally significant study hetero-
were identified and included in the meta-analysis (supple- geneity for the BARS (P=.06).
mentary figure1). The characteristics of these studies are
summarized in table 1. All studies represented parallel- Treatment-Emergent AdverseEvents
group RCTs with a relatively short duration, ranging There were no significant differences in the number of
from 3 to 12 weeks, and were published in 2000 or later. patients who experienced any TEAEs (ie, akathisia, anxi-
Only 1 study was conducted in a double-blind fashion, 3 ety, diarrhea, headache, insomnia, nausea, and somno-
were performed with raters blinded, and the remaining lence) between the immediate and gradual antipsychotic
5 were open-label studies. In the majority of studies, ris- discontinuation groups (figure 4); however, the former
peridone, olanzapine, or haloperidol were prescribed as tended to have a less favorable outcome in terms of
the current antipsychotic prior to randomization; risperi- insomnia (P = .09). None of the study heterogeneities
done (N=1), olanzapine (N=2), ziprasidone (N=2), for any TEAEs was significant. Although all types of
aripiprazole (N = 2), iloperidone (N = 1), or clozapine insomnia reported in Kinon et al9 were separately used
(N = 1) were introduced as the new antipsychotic. In for insomnia in sensitivity analyses, none was significant
terms of gradual antipsychotic discontinuation proce- (data not shown).
dures, the current antipsychotic were discontinued in 1,
2, 3, and 4 weeks in 3, 4, 1, and 1 report(s), respectively.
Sensitivity Analyses
In terms of initiation strategies of the new antipsychotic,
8 out of 12 comparisons used immediate initiation, while No significant differences in any clinical outcomes were
4 used gradual or wait-and-gradual initiation (table1 and observed between the 2 groups in the following study data
supplementary table2). sets: blinding raters; adopting an immediate antipsychotic
The results of risk of bias assessment are displayed in initiation strategy; and switching to aripiprazole (all Ps > .05)
supplementary figure2. (data not shown). In addition, no significant differ-
ences were found in either data set using Kinon 2000a
or Kinon 2000b, and the data set using pooled results of
Study Discontinuation Weiden 2003a, Weiden 2003b, and Weiden 2003c. On the
There was no significant difference in the number of other hand, in switching to olanzapine there was a sig-
patients who discontinued the study due to all causes nificant difference regarding insomnia (RR=2.62, 95%
(RR=1.10, 95% CI=0.931.30), inefficacy (RR=1.14, CI=1.305.29, P=.007) in favor of gradual discontinu-
95% CI=0.622.09), or intolerability (RR=1.08, 95% ation, while in switching to ziprasidone there were sig-
CI=0.701.66) between the immediate and gradual anti- nificant differences in the SAS scores (SMD=0.33, 95%
psychotic discontinuation groups (figure1); no significant CI = 0.000.65, P = .05) and somnolence (RR = 0.25,
study heterogeneities were observed for all study discon- 95% CI = 0.060.97, P = .05) in favor of gradual and
tinuation outcomes among the studies. immediate discontinuation, respectively.
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Table1. Randomized Controlled Trials Examining Immediate vs Gradual Antipsychotic Discontinuation in Antipsychotic Switching in Patients With Schizophrenia

Switching Strategy

Current Antipsychotics New Antipsychotics

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H. Takeuchi etal

Type (Frequency) Type and


Study Blinding Duration N and Mean Dosea Discontinuation Strategy Mean Dose Introduction Strategy

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)

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Immediate vs Gradual Antipsychotic Discontinuation

Discussion

increase to 12mg/d by day 4, and


GI (introduce 2mg/d at day 0,

titrate 1224mg/d after day 4)


Our meta-analysis revealed that none of the clinical out-

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

analysis of 4 RCTs published in 2005,25 adding 5 more

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RCTs and a more robust methodology.
ILO 16.7mg/d
ZIP 97.3mg/d
ZIP 92.7mg/d

These findings are notably at odds with numerous


Mean Dose

reviews of antipsychotic switching strategies that recom-


Type and

mend gradual discontinuation of the current antipsy-


chotic to avoid rebound/withdrawal symptoms.7,8,10,11,16
One possible explanation relates to the fact that the
GD (reduce by 50% at day 0, 75% at

half-life for antipsychotic-related dopamine D2 receptor


occupancy centrally, as assessed with positron emission
ID (reduce by 100% at day 0)

ID (reduce by 100% at day 0)

tomography (PET), is considerably longer than plasma


week 1, and 100% at week 2)
GD (reduce by 50% at day 0

half-life.32,33 This, in turn, may act as a buffer in the face


Discontinuation Strategy

of abrupt antipsychotic discontinuation. It should be


and 100% at week 1)

noted, though, that marginally significant differences


in tardive dyskinesia and insomnia were observed, at
face value favoring gradual antipsychotic discontinua-
tion although the severity of tardive dyskinesia at both
baseline and endpoint was minimal (ie, <1 in the AIMS
global score) for all studies included in the meta-analysis.
However, this finding could as well reflect different phar-
macological properties beyond dopamine, as well as dose
260 RIS (36%), OLZ (29%),

240 RIS (34%), OLZ (33%),


Current Antipsychotics

equivalents, between the current and new antipsychotic


Switching Strategy

being initiated.7,8,10,11,16 For example, insomnia may be


Type (Frequency)
and Mean Dosea

caused by a rapid switch to an antipsychotic agent with


17 RIS (100%)
20 RIS (100%)

less potential to antagonize histamine H1 receptors.8,10,11,16


APZ (35%)

APZ (33%)

Notably, no differences in psychopathology were found


between immediate and gradual antipsychotic discon-
tinuation in switching, which is of interest given that lit-
erature suggests dopamine supersensitivity psychosis can
N

occur if patients stop antipsychotics abruptly.34 Finally, a


switch that entails moving to a more effective or tolerable
Duration

antipsychotic may mitigate risk of clinical worsening or


12 wk

adverse effects regardless of switching strategy.


In this meta-analysis, we focused on immediate and
gradual discontinuation of the current antipsychotic.
Nonetheless, 1 RCT35 and 4 arms of the included RCTs1922
comparing gradual vs wait-and-gradual discontinuation
introduction; ZIP, ziprasidone.

(supplementary table2) failed to demonstrate significant


Open-label

differences in the majority of clinical outcomes between


Blinding

the 2 strategies, which further supports the notion that


discontinuation strategies of the current antipsychotic
Table1. Continued

do not have any substantial clinical impact. As dis-


Weiden 2003c

cussed, how the new antipsychotic is introduced is also


Weiden 2014

If reported.

important. Strategies can vary as a function of dose


and titration strategies, and on occasion strategies may
Study

also employ a gap between discontinuation of the first


a

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H. Takeuchi etal

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Fig.1. Study discontinuation.

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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Fig.4. Treatment-emergent adverse events.


H. Takeuchi etal

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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

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ness duration was provided in only 3 studies), which may Pharma, and Wiley Japan. Dr Remington has received
limit the generalizability of the present findings. Further research support from Novartis and consultant fees from
long-term, double-blind RCTs in patients with schizophre- Synchroneuron.
nia at various stages of the illness are needed.
In conclusion, the current meta-analysis of 9 RCTs
examining antipsychotic switching strategies demon- References
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