CNS Drugs
Withdrawal Symptoms and Rebound Syndromes Associated with Switching
and Discontinuing Atypical Antipsychotics
Theoretical Background and Practical Recommendations
Anja Cerovecki, Richard Musil, Ansgar Klimke, Florian Seemüller, Ekkehard Haen, Rebecca Schennach, Kai-Uwe Kühn, Hans-Peter Volz and
Michael Riedel
Corresponding author: Richard Musil, Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstr. 7, 80336 Munich,
Germany.E-mail: Richard.musil@med.uni-muenchen.de
Electronic Supplementary Material
Table a
Overview of switching trials reporting on a switch to amisulpride, trials investigating a switch from only one compound are followed by trials
investigating switches from several compounds; trials are further stratified in alphabetical order of authors
Switching
from
Switching
to
Author
Study
type/Patients
N
Reason for
switch
Withdrawal/Rebound
Treatment emergent
adverse events (>5 %)
Main outcomes/Comment
Design
Weight and BMI dropped
significantly in switch-group vs.
non-switch control group; lipid
Different
Open-label;
levels improved in switch-group;
Overweight or
Crossatypical
Amisulpride
Lin et al.1
stable
46
Not explicitly mentioned
prolactin levels increased in
obesity
taper
antipsychotics
inpatients
switch-group; fasting glucose
and HOMA-IR levels improved
in switch-group; prevalence of
metabolic syndrome decreased
Patient compliance and
psychopathology overall
improved after switching;
preswitch noncompliant patients
Drug utilization
Various reasons
improved in EPMS scores,
Conventional
Not menAmisulpride
Linden et al.2
study;
570
(e.g. insufficient
Not mentioned
Not explicitly mentioned
psychopathology and
antipsychotics
tioned
outpatients
efficacy, EPMS)
compliance, postswitch noncompliant patients worsened;
psychopathology worsened in
pre- and postswitch
noncompliant patients
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch)
7 patients dropped due
to exacerbation of
psychotic symptoms;2
patients dropped due to
EPMS (not discussed as
withdrawal or rebound
phenomena)
Duration of
switch
4
weeks
Not
mentioned
Table b
Overview of switching trials reporting on a switch to aripiprazole, trials investigating a switch from only one compound are followed by trials
investigating switches from several compounds; trials are further stratified in alphabetical order of authors
Switching
from
Risperidone
Olanzapine,
risperidone
Amisulpride or
risperidone
Atypical
antipsychotics
Switching
to
Aripiprazole
Aripiprazole
Aripiprazole
Aripiprazole
Author
Ryckmans et
al.3
(BMS,
Otsuka)
Study
type/Patients
Randomized,
open-label;
outpatients
Byerly et al.4
(BMS,
Otsuka)
Post-hoc sub
analysis of
open-label
study;
outpatients
Lee et al.5
Open-label;
stable female
patients
Kim et al.6
Open-label,
stable in- and
outpatients
N
400
164,
105
7
61
Treatment emergent
adverse events (>5 %)
Main outcomes/Comment
Design
Duration of
switch
Four patients dropped
due to worsening of
symptoms (1 in titrated
switch and 3 in fixeddose switch group) – not
discussed as withdrawal
syndromes
TEAEs were insomnia,
anxiety, headache and
EPMS
Rates of AEs and drop-outs
were similar between titrateddose and fixed-dose strategies;
PANSS, CGI, SWN-K and SAS
scores improved significantly
and did not differ between
switching groups, weight
dropped in both groups
Titrated
dose vs.
fixeddose
switching
, descending
taper
4
weeks
Adverse events
(hyperprolactinemi
a)
Not reported, but 11
patients had occurrence
of psychosis as serious
adverse event
TEAEs encompassed
insomnia, nausea,
anxiety, psychosis,
headache, somnolence,
akathisia and upper
respiratory infection
(switched from
olanzapine); insomnia,
akathisia, nausea, lightheadedness,
somnolence, agitation,
anxiety and psychosis
(switched from
risperidone)
Similar rates of adverse events
regardless of switching strategy
or prior medication, reduction in
prolactin levels even during
cross-over phases
Three
different
switch
strategie
s (abrupt,
descending
taper and
crosstaper)
14
days
Hyperprolactinemi
a
Two patients
experienced aggravation
of auditory hallucinations
and discontinued
treatment with
aripiprazole
Not reported
Hyperprolactinemia and related
symptoms resolved in all
patients, PANSS and CGI
scores were stable in patients
successfully switched
Abrupt
N/A
Insufficient
efficacy, adverse
events or poor
compliance
One patient with
exacerbation of
symptoms after abrupt
switch from LAIR
resulting in completed
suicide
TEAE (> 5 %) were
insomnia, agitation,
weight loss, sedation,
nausea, myalgia,
obsessive-compulsive
symptoms, fatigue (five
drop outs)
Cognitive functions significantly
improved (verbal learning test,
WST, TMT A), PANSS, SOFAS,
DAI, SAS and AIMS scores
improved, metabolic parameters
and weight improved, tardive
dyskinesia and
hyperprolactinemia improved
Crosstaper
based on
clinical
judgement
No
data
Reason for
switch
Withdrawal/Rebound
Insufficient
efficacy, adverse
events
Atypical
antipsychotics
Aripiprazole
Other
antipsychotics
(atypical and
typical)
Aripiprazole
Other
antipsychotics
Aripiprazole
vs.
Standard of
care
antipsychoti
cs
Conventional or
atypical
antipsychotics
Risperidone,
Sulpiride
Risperidone,
olanzapine,
amisulpride,
quetiapine,
zuclopenthixol,
clozapine
Risperidone,
olanzapine,
amisulpride,
quetiapine
Aripiprazole
Aripiprazole
Aripiprazole
Aripiprazole
Kim et al.7
Ganguli et al.8
(BMS)
Kim et al.9
Lin et al.10
Lu et al.11
Mir et al.12
Pae et al.13
Open-label
pilot study;
stable
outpatients
Open-label,
outpatients
Open-label;
stable
outpatients
Observational
study;
outpatients
Open-label;
stable female
patients
Open-label,
switching or
add-on
RCT, openlabel, partial
nonresponders
15
33
292
45
23
27
77
Weight gain
BMI ≥ 26, PANSS
60-90
Five patients were
restarted on previous
medication (olanzapine
or clozapine) due to
actual or fear of
symptom exacerbation
Not reported
CGI and PANSS scores
significantly improved in patients
successfully switched, metabolic
parameters and weight did not
change significantly
No significant symptom
improvement (PANSS, CGI);
weight, waist circumference and
LDL levels decreased, all were
successfully switched
Descending
taper
2
weeks
or
more
Crosstitration
2
weeks
or
more
Not reported
Not reported
Not reported
12.4 % of patients
experienced symptom
worsening
TEAEs in aripiprazole
group were insomnia,
nausea, headache,
anxiety
Overall psychopathology
improved in patients switched to
aripiprazole, prolactin-related
TEAE were lower in patients
switched to aripiprazole
compared to standard of care
antipsychotics
Descending
taper
2
weeks
Insufficient
efficacy, adverse
events
42.9 % terminated
switching in early phase
of cross tapering likely
related to rebound
phenomena
TEAE included
insomnia, anxiety,
EPMS, akathisia and
headache
Type of preswitch antipsychotic
(FGAs had lowest success rate)
and duration of illness
determined successful
switching, most patients
switched due to metabolic side
effects
Abrupt
vs.
Descendingtaper
No
data
Not reported
2 drop-outs due to AEs
(sleep disturbance,
excessive anxiety); other
AEs were reduced
duration of sleep,
tension, nausea,
akathisia, tremor
Prolactin levels and menstrual
cycle normalized; PANSS and
CGI scores did not change
significantly
Plateau
crosstaper
Mean
7.9
weeks
Not mentioned
Prolactin levels significantly
decreased, libido improved,
erectile and ejaculatory
difficulties and menstrual
dysfunctions improved; 54.5 %
received aripiprazole as add-on
strategy; psychopathology and
side effects improved
Crosstaper,
some
abrupt
No
data
Severity of side effects
did not change
significantly
Overall symptoms improved,
Baseline severity predicted
symptom worsening at weeks 1,
2 and 4; lesser disease severity
at baseline predicted worsening
after switching to aripiprazole,
taper switch was better tolerated
than abrupt switch
3
different
strategies:
abrupt,
descending
taper or
plateau
descending
Up to
6
weeks
Symptomatic
hyperprolatinemia
Insufficient
efficacy, adverse
events
Insufficeint
efficacy, adverse
events
Not mentioned
Patients with abrupt
switch showed increase
of symptoms at week 1
taper
Conventional
and atypical
antipsychotics
Other atypical
antipsychotics
Olanzapine,
quetiapine,
risperidone
Risperidone,
olanzapine and
other
antipsychotics
Aripiprazole
Aripiprazole
Aripiprazole
Aripiprazole
Sarin et al.14
Randomized.
open-label,
outpatients
Spurling et
al.15
Retrospective
chart review on
outpatients
(schizophrenia
and other
diagnoses)
Stroup et al.16
Takeuchi et
al.17
RCT, stable
patients,
double-blind
Randomized,
open-label
TEAE included fatigue,
insomnia, somnolence,
headache, nausea,
vomiting and diarrhea,
tremor, rigidity,
constipation
PANSS scores, EPMS, prolactin
levels and weight improved
Descending
taper
7 days
Various
Various
136
Insufficient
efficacy, adverse
events
24
Metabolic adverse
events
Not reported
Not reported
Total cholesterol, LDL and
weight significantly decreased,
patients switching from
olanzapine benefited most
Metabolic risk
factors (BMI ≥ 27),
non-HDL
cholesterol ≥ 130
mg/dl
Switching to aripiprazole
was associated with
higher rate of treatment
discontinuation (16.8 %
vs. 7.5 %), eight
switchers and five
stayers were
hospitalized due to
psychiatric reasons
TEAEs in switch group
were insomnia (stayers
had more sleepiness,
hypersomnia, nausea,
dry mouth, increased
appetite and akinesia)
Switchers lost more weight and
had higher non-HDL cholesterol
reduction compared to stayers;
rates of efficacy failure were
similar between groups
Crosstaper
3
weeks
TEAEs included
insomnia and akathisia
CGI, EPMS, SWN did not differ
between switching strategies,
both were well tolerated,
metabolic parameters improved
significantly (weight, total
cholesterol, triglycerides,
prolactin)
Plateau
descending
taper vs.
Descending
taper
Up to
12
weeks
109
(switch)
vs. 106
(mainta
ined on
current
antipsy
chotic)
53
Comparison of 2
switching
strategies
Not reported
None (discussed as
being related to slow
switching strategy)
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch)
Table c
Overview of switching trials reporting on a switch to olanzapine, trials investigating a switch from only one compound are followed by trials
investigating switches from several compounds; trials are further stratified in alphabetical order of authors
Switching
from
Clozapine
Switching
to
Olanzapine
Author
Study
type/Patients
Dossenbach
et al.18
(Eli-Lilly)
Open-label,
chronic
treatmentresistant
patients
Reason for
switch
Withdrawal/Rebound
Treatment emergent
adverse events (>5 %)
Main outcomes/Comment
Design
Duration of
switch
48
Adverse events,
insufficient efficacy
One patient was
hospitalized due to
psychosis (not
discussed as rebound
phenomenon)
2 drop-outs due to
insufficient efficacy, one
due to adverse events;
TEAEs included
psychosis, liver function
test abnormality
PANSS, BPRS and SAS scores
dropped significantly
Descending
taper
switch
No
data
Dyskinesia
7 patients required
hospitalization, slow
taper was not protective
Plateau
cross
taper
Sev.
weeks
Crosstaper
No
data
No
data
N
Clozapine
Olanzapine
Henderson et
al.19
Open-label;
outpatients
19
Pats. request for
switch, insufficient
efficacy, adverse
events
Clozapine
Olanzapine
Littrel et al.20
Open-label;
outpatients
20
Adverse events,
but clozapine
responders
Not reported
Adverse events,
insufficient efficacy
Two patients dropped
due to insufficient
efficacy and two due to
adverse events
(worsening of psychosis,
suicide attempt) (not
discussed as rebound
phenomena)
Risperidone
Risperidone
Risperidone
Olanzapine
Olanzapine
Olanzapine
Dossenbach
et al.21
(Eli-Lilly)
Open-label
Faries et al.22
(Eli-Lilly)
Post-hoc
analysis of
open-label
randomized
trial; mainly
outpatients
Kim et al.
23
Female
patients
34
43
Insufficient
efficacy, adverse
events
20
Menstrual
disturbance,
galactorrhea or
sexual dysfunction
Not reported
Not reported
BPRS scores overall worsened;
pats. successfully switched
were treated with clozapine for
shorter period of time and lower
dose; new adverse events:
sedation, constipation
Equal efficacy of olanzapine and
clozapine in 90 %, rates of
adverse events dropped
TEAEs comprised
abnormal liver function
tests, weight gain
PANSS total and subscores
decreased significantly,
olanzapine was well tolerated,
ESRS scores dropped
Switch
after
discontinuation
and
wash-out
over 4
days
Weight gain
Switchers from risperidone to
olanzapine and non-switchers
did not differ significantly in
BPRS scores, QoL scores and
absolute weight, weight
increased
Mostly
abrupt
N/A
Not reported
Serum prolactin levels
decreased; PANSS, AIMS and
SAS decreased, improvements
in menstrual functioning
Crosstaper
2
weeks
Risperidone
Haloperidol
Conventional
depot
antipsychotics
(Haloperidol,
Fluphenazine)
Conventional
antipsychotics
or risperidone
Olanzapine
Olanzapine
Olanzapine
Olanzapine
Takahashi et
al.24
Costa e Silva
et al.25
Godleski et
al.26
(Eli-Lilly)
Kinon et al.
Open-label;
first episode
patients
Open-label; inand outpatients
Open-label,
RCT;
outpatients
27
Open-label,
randomized;
outpatients,
clinically stable
58
94
26 (13
vs. 13)
209
Insufficient
efficacy
Not reported
7 Patients discontinued
due to adverse events;
46.6 % of patients had
significant weight gain
(>7 %), other TEAEs
were excessive appetite,
headache, somnolence,
dry mouth, insomnia,
constipation, blurred
vision, dizziness and
nausea
EPMS
30.9 % symptom
exacerbation, seizures,
headache, anxiety,
dizziness, insomnia
discussed as attributable
to
haloperidol/anticholinerg
ic discontinuation;
akathisia, dyskinesia,
movement disorder
discussed as potential
rebound phenomena
TEAEs were
somnolence, increased
appetite, weight gain,
headache, anxiety,
dizziness, insomnia,
EPMS
Symptoms and EPMS
significantly improved (PANSS;
CGI; SAS, BAS, AIMS); 90.5 %
of patients were successfully
switched
Direct
switch
N/A
Not reported
Improvement in PANSS general
and negative scores, CGI and
GAF scores in switch group to
oral olanzapine, weight gain in
olanzapine group, no other
difference in adverse events
Plateau
cross
taper
(chosen
as quite
safe
strategy)
No
data
TEAEs included
shortened sleep,
difficulty falling asleep,
increased perspiration,
interrupted sleep, early
waking, drowsiness
Comparison of abrupt or gradual
discontinuation and double-blind
comparison of immediate
initiation or up-titration
Gradual discontinuation and
initiation of full dose showed
best efficacy and tolerability;
significant decrease in prolactin
levels in all groups;
No differences in
antiparkinsonian medication or
use of benzodiazepines
Four
switching
strategies
Up to
3
weeks
No optimal
cuntioning
Not reported
Efficacy of
olanzapine
switching
strategies
Sleep disturbances
(abrupt discontinuation
and stepwise initiation);
drowsiness (abrupt
discontinuation and
immediate initiation);
worsening of symptoms
(highest while abrupt
discontinuation and
stepwise initiation),
discussed as potential
withdrawal syndromes
29.3 % were responders,
symptomatology significantly
decreased (BPRS); ESRS and
BAS scores dropped; prolactin
levels dropped significantly;
relative absence of positive
symptoms at baseline predicted
good response
Crosstaper
2
weeks
Conventional
antipsychotics
or risperidone
Other
antipsychotic
compounds
(mono- and
polypharmacy)
Long-acting
injectable
antipsychotics
Predominantly
typical
antipsychotics
Haloperidol,
Olanzapine,
Clozapine,
Risperidone
Conventional
antipsychotics
(mainly
haloperidol,
chlorpromazine,
perphenazine)
Olanzapine
Olanzapine
Kinon et al.28
(Eli-Lilly)
Kluge et al.29
Open-label,
randomized;
stable patients
Open-label
Labelle et al.30
Open-label;
stable
outpatients
Olanzapine
Lee et al.31
Open-label;
randomized;
inpatients and
outpatients
Olanzapine
Lindenmayer
et al.32
Open-label;
inpatients
Lu et al.33
Observational
trial; in- and
outpatients
Olanzapine
Olanzapine
54
198
25
Hyperprolactinemi
a
Not reported
(hallucinations occurred
in 11 % in both patients
switched to olanzapine
or remaining on current
medication)
TEAE in both groups did
not differ significantly,
TEAEs in patients
switched to olanzapine
were hallucinations,
rhinitis, somnolence
Serum prolactin levels
decreased in patients switched
to olanzapine compared to
patients remaining on previous
medication; improvements in
sexual functioning in both
genders, weight increased and
SAS scores improved in
patients switched to olanzapine
Crosstaper
2
weeks
Insufficient
efficacy or
insufficient
tolerability
Psychotic
decompensation (1
patient; paranoid
reaction (1 patient);
hallucinations (6
patients);
authors discussed TEAE
as related to olanzapine
Restlessness, insomnia
(1 patient); anxiety,
agitation (1 patient);
sleep disorder (9
patients); nervousness
(7 patients), dizziness (5
patients)];
authors discussed TEAE
as related to olanzapine
Immediate initiation of 10 mg
olanzapine; 89 % of patients
improved in CGI or were
unchanged; subjective wellbeing improved significantly;
EPMS scores decreased;
Abrupt
switch
N/A
Feasibility of
switching from
long-acting
substances to
olanzapine
Exacerbation of
psychosis (2 pat.); No
differences in
parkinsonism, dystonia
and dyskinesia between
completers and noncompleters
Increased anxiety (2
pat.); depressed mood
(1 pat.); insomnia (2
pat.)
Significant improvements on
CGI, PANSS-scores and
parkinsonism; weight gain was
reported in 8 patients
Immediate
initiation
of 10 mg
olanzapine on
day of
scheduled
injection
No
data
TEAEs were similar in
both switching groups
Improvement in symptoms and
EPMS (SAS, BAS), weight
increased, no difference in
switching strategies
Abrupt
switch
vs. Starttaper
switch
2
weeks
Not reported
Only PANSS cognitive factor
significantly improved; Nonsignificant decrease in EPMS,
sign. increase in weight
Crosstitration
2
weeks
Not reported
93.3 % of completers (n=954)
responded to olanzapine; AIMS
scores dropped, mean weight
increased; QoL increased
(fastest during first 8 weeks)
At discretion of
treating
psychiatrist
No
data
108
Various reasons
45
Insufficient
efficacy
1267
Insufficient
efficacy
Not reported
Not reported
Not reported
Focus on
switches from
and to
Olanzapin or
non-olanzapine
antipsychotics
Olanzapine
Novick et al.34
(Eli-Lilly)
Observational
study;
outpatients
10972
Several reasons
Not reported
Patients switching from
olanzapine were more
likely to display EPMS
and loss of libido;
patients switching to
olanzapine had higher
weight gain
Patients switching from
olanzapine were less likely to
respond than patients switching
to olanzapine which had overall
better outcome
Not
reported
Not
reported
In both groups improvement in
parkinsonism, in olanzapine
6 patients developed
Non-significant trend of
treated patients improvement of
Olanzapine
TD; Cholinergic rebound
increased sedation and
dyskinetic movements;
Open-label,
Conventional
(or
discussed
in
risperidone
postural
Cross4
symptomatology improved in
Ritchie et al.35
randomized;
66
EPMS
antipsychotics
Risperidone
arm as possibly related
hypotension/dizziness in
taper
weeks
both groups with no differences;
elderly patients
)
to gastrointestinal
olanzapine arm, weight
QoL improved in patients
symptoms
increased in both arms
switched to olanzapine more
than in patients switched to
risperidone
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief
Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch)
Table d
Overview of switching trials reporting on a switch to quetiapine, trials investigating a switch from only one compound are followed by trials
investigating switches from several compounds; trials are further stratified in alphabetical order of authors
Switching
from
Main outcomes/Comment
Design
Duration of
switch
Not reported
Not reported
Small decrease in weight, no
alterations in symptoms
(PANSS) or new adverse events
Crosstaper
switch
over 4
weeks
4
weeks
None, but generally
discussed
Not reported
Improvement in EPMS (BAS,
SAS) and symptoms (PANSS)
in pats. switched to quetiapine
Crosstaper
1
month
s
Insufficient
efficacy, adverse
events
Not reported
TEAE were somnolence,
constipation and
dizziness, asthenia,
anxiety, insomnia, dry
mouth, weight gain
(from Ris/Hal)
Improvement in symptoms
(PANSS) and EPMS (SAS,
BAS)
Crosstaper
switch
7 days
74
25 patients with
hyperprolactinemi
a
8 patients dropped due
to exacerbation of
psychotic symptoms
during eight weeks of
treatment
Not reported
Serum prolactin levels dropped
significantly in patients
successfully switched, PANSS
levels remained stable in these
patients; successful switching
was associated with lower
positive symptoms before switch
Crosstaper
2
weeks
497
To show noninferiority of
switching to
quetiapine XR
compared to
maintaining
quetiapine IR
One patient switched to
Quetiapine XR
experienced aggression
and psychotic disorder
AE rates were similar in
both groups, no TEAE
occurred with frequency
≥5%
Efficacy remained without
significant adverse events; noninferiority was shown in perprotocol population
abrupt
N/A
Insufficient
efficacy, adverse
events (e.g.
EPMS, weight
gain)
Not reported, serious
AEs (akathisia and
EPMS, psychosis,
exacerbation of
psychosis) – were
related to Que XR; 8 %
EPMS related AEs
(tremor, akathisia)
TEAE were somnolence,
sedation, dizziness, dry
mouth, constipation,
headache, insomnia;
AEs leading to
discontinuation were
sedation, dizziness,
psychotic disorder (4 %),
schizophrenia (0.8 %)
Improvement in symptoms,
improvement in BAS and SAS
scores, less anticholinergic
medication, improvement in
prolactin levels
Crosstitration
1-4
days
Author
Olanzapine
Quetiapine
Gupta et al.36
(AstraZeneca)
Open-label;
stable patients
16
Weight gain, BMI
> 25 kg/m2
Several
antipsychotics
Quetiapine
Cortese et
al.37
Open-label,
randomized
22
EPMS
164
Haloperidol,
olanzapine,
risperidone
Conventional
antipsychotics
Quetiapine IR
Conventional
antipsychotics,
Olanzapine,
Risperidone or
other atypical
antipsychotics
Quetiapine
Quetiapine
Quetiapine
XR
Quetiapine
XR
Larmo et al.38
Nakajima et
al.39
Möller et al.40
(Astrazeneca)
Ganesan et
al.41
(AstraZeneca)
Study
type/Patients
Treatment emergent
adverse events (>5 %)
Switching
to
Open-label
Open-label;
female patients
Double-blind,
randomized;
stable
outpatients
Open-label; Inand outpatients
N
135,
79,
122, 73
Reason for
switch
Withdrawal/Rebound
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch)
Table e
Overview of switching trials reporting on a switch to risperidone, trials investigating a switch from only one compound are followed by trials
investigating switches from several compounds; trials are further stratified in alphabetical order of authors
Switching
from
Olanzapine
Olanzapine
Clozapine
Switching
to
Risperidone
Risperidone
Risperidone
Author
Ganguli et
al.42
(Janssen)
Meyer et al.43
Still et al.44
Study
type/Patients
Open-label;
randomized;
rater-blinded;
outpatients
Rater-blinded,
open-label,
retrospective;
stable out- or
inpatients
Open-label;
treatmentresistant
inpatients
N
123
123
10
Reason for
switch
Withdrawal/Rebound
Insufficient
efficacy, BMI > 26
kg/m2 or glucose
dysregulation
Nausea, vomiting,
agitation, movement
disorders attributed as
potential withdrawal
symptoms (low
incidence);
Incidence of aggravated
psychosis highest in
abrupt group (13 % vs. 0
% and 5 % in gradual 1
and 2), similar with
anxiety symptoms,
mean reduction in
standing diastolic RR,
possibly related to
cholinergic rebound
Insufficient
efficacy, abnormal
metabolic status
Not reported
Insufficient
efficacy, adverse
events
Adverse events
(cognitive impairment,
irritability) were
attributed to risperidone,
withdrawal symptoms
were noticed (2 pat.); 5
patients showed
exacerbation of
psychosis
Treatment emergent
adverse events (>5 %)
TEAE comprised
insomnia, anxiety,
sedation, somnolence,
headache, aggravated
psychosis
10 patients withdrew
due to adverse events
TEAEs were decreased
concentration, impaired
memory and irritability,
akathisia, confusion
Main outcomes/Comment
Design
Duration of
switch
Improvement in symptoms;
Significantly more patients in
abrupt (25 %) and gradual 1 (28
%) group discontinued early
compared to strategy gradual 2
(12 %), hypnotic/sedative drugs
were more often prescribed in
first two groups
3
switching
strategies:
abrupt,
gradual 1
(1 week)
or
gradual 2
(2
weeks)
Up to
2
weeks
Prevalence of metabolic
syndrome decreased; PANSS
scores dropped significantly
only in patients without
metabolic syndrome
3
different
switching
strategie
s: abrupt
discontinuation,
gradual
taper
over 1 or
2 weeks
Up to
2
weeks
Crosstaper
switch
10
days
tapering
clozapine
from
565
mg
No patient improved, switch
from clozapine to risperidone in
treatment-resistant pat. Not
recommended by authors
Various
antipsychotics
(mainly
conventional)
Typical
antipsychotics
Risperidone
Kirov et al.45
Risperidone
46
Malla et al.
Open-label; inand outpatients
Retrospective
open-label;
outpatients
41
Investigation of
specific switching
strategy;
insufficient efficacy
or adverse events
31
Insufficient
efficacy or due to
adverse events
(mainly EPMS)
Four patients had
recurrence of EPMS
after switching, a more
gradual taper of
previous anticholinergic
medication was
suggested as being
helpful by the authors
Not reported
TEAEs included
insomnia, headache,
dizziness and dystonia,
1 patient dropped due to
dizziness, 1 due to
orthostatic hypotension
and 3 due to ejaculatory
dysfunction
64 % of patients were switched
successfully (completions of
study and no worsening of any
rating scale); overall symptoms
improved and side effects got
better (SAS); more gradual
taper of previous medication
would have been better for
certain patients
Abrupt
with
uptitration of
risperidone and
gradual
taper of
anticholinergic
medication
Immed
iate
Not reported
Symptomatology improved;
EPMS overall improved; mean
hospital admissions and days in
hospital dropped
No data
No
data
Symptomatology decreased
3
significantly (predominantly
different
negative symptoms); use of
switching
Risperidone
antiparkinsonian drugs
strategie
(monothera
decreased, rate of patients with
s:
py or in
Residual
polypharmacy decreased; lower
Up to
Conventional
Nakanishi et
Stable in- and
Discussed, but none
Discussed, but none
ascendin
combination
54
symptoms,
pre-switch
antipsychotic
dosage
8
antipsychotics
al.47
outpatients
reported
reported
g or
with other
adverse events
was associated with successful
weeks
descendi
compounds
switch to risperidone
ng cross
)
monotherapy; more gradual
taper,
switching may have resulted in
abrupt
higher frequencies of successful
switch
switching to monotherapy
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch)
Table f
Overview of switching trials reporting on a switch to paliperidone palmitate or risperidone long-acting injectable (RLAI), trials investigating a switch
from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of
authors
Switching
from
Switching
to
Oral risperidone
Paliperidon
e palmitate
Author
Study
type/Patients
N
Reason for
switch
Withdrawal/Rebound
Treatment emergent
adverse events (>5 %)
Main outcomes/Comment
Design
Duration of
switch
Sliwa et al.48
Post-hoc
analysis of
double-blind
placebocontrolled trial
216
Insufficient
efficacy
Not reported
TEAEs comprised
insomnia, anxiety and
headache
PANSS, CGI and PSP scores
improved
Abrupt
N/A
Different
antipsychotics
Risperidone
long-acting
injectable
(RLAI)
Hawley et al.49
(Janssen)
Conventional
antipsychotics
Long-acting
Risperidone
50
Oral atypical
antipsychotics
(mainly
risperidone)
Risperidone
long-acting
injectable
(RLAI)
Van Os et al.
Kim et al.
51
Open-label;
stable in- and
outpatients
Open-label
Open-label;
stable patients
182
Insufficient
efficacy, adverse
events, poor
compliance
725
Fokus on 46
stable patients
36
Switching study
with focus on
cognitive functions
Not discussed
(potentially cases of
relapse, insomnia,
anxiety, movement
disorders)
TEAEs were headache,
relapse (mostly within
first 3 weeks), insomnia,
disease exacerbation,
anxiety, movementdisorders (2 %)
(akathisia, tremor)
Significant improvement in
EPMS, modest weight gain
Not reported
TEAEs were anxiety,
insomnia, hyperkinesia,
depression and
psychosis
Symptomatology improved even
in stable patients, EPMS
decreased (ESRS)
Not reported
2 pat. dropped out due
to adverse events
(dystonia, skin rash),
one due to insufficient
efficacy; TEAE were
weight gain,
amenorrhea, headache,
fatigue, akathisia,
galactorrhea, pain at
injection side, tardive
dyskinesia
Cognitive functions improved
significantly (digit span test,
verbal learning test, WST, TMT
B); PANSS, SOFAS and SAS
scores improved significantly.
Weight and Prolactin increased.
Different
switching
strategies
depending on
oral
formulation or
depot
interval
First
conversation to
oral
risperidone
No data
No
data
Up to
3
weeks
31.5
days
in
mean
Oral or depot
conventional
antipsychotics
Risperidone
long-acting
injectable
(RLAI)
Conventional
depot
antipsychotics
Risperidone
long-acting
injectable
(RLAI)
Marinis et al.52
Lai et al.53
Sub analysis of
open-label trial;
stable patients
Open-label,
stable in- and
outpatients
100
(oral);
565
(depot)
25
Inadequate
efficacy, adverse
events, noncompliance and
other
Not reported
Not reported, but 5.3 %
disease exacerbation or
relapse and other
psychiatric symptoms
TEAEs were anxiety,
insomnia, weight
increase, EPMS,
depression (switching
from oral), weight
increase, disease
exacerbation (depot)
Overall PANSS total and
subscales, GAF, QoL improved
No data
No
data
Exacerbation of EPMS
in 13.6 % not discussed
as rebound phenomena
TEAEs were menstrual
irregularity, dizziness,
somnolence,
talkativeness
PANSS and ESRS scores
significantly improved (apart
from PANSS positive scores);
cholesterol and triglyceride
levels decreased, none
significant increase in weight
Abrupt
N/A
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch)
Table g
Overview of switching trials reporting on a switch to ziprasidone, trials investigating a switch from only one compound are followed by trials
investigating switches from several compounds; trials are further stratified in alphabetical order of authors
Switching
from
Aripiprazole
Quetiapine
Haloperidol,
olanzapine,
risperidone
Switching
to
Ziprasidone
Ziprasidone
Ziprasidone
Study
type/Patients
Author
Kim et al.
54
Karayal et
al.55
(Pfizer)
Alptekin et
al.56
(Pfizer)
Prospective,
open-label
study;
outpatients
Open-label;
outpatients
Open-label,
stable
outpatients
N
19
241
99, 82,
104
Reason for
switch
Insufficient
efficacy, adverse
events
Insufficient
efficacy, adverse
events
Insufficient
efficacy or adverse
events
Withdrawal/Rebound
Treatment emergent
adverse events (>5 %)
Main outcomes/Comment
Design
Duration of
switch
Not reported; one dropout due to insufficient
efficacy
One drop-out due to
agitation; TEAEs were
sedation, poor appetite,
weight loss, insomnia,
agitation and dystonia, 1
patient developed
tardive dyskinesia
PANSS negative scores,
SOFAS, CDSS and BDI scores
improved significantly, PANSS
positive and total scores
decreased in completers; weight
(- 3kg), BMI and waist/hip
circumferences decreased,
fasting glucose decreased,
prolactin increased
Crosstaper
4
weeks
TEAEs were
somnolence, insomnia,
sedation, headache,
dizziness, nausea,
akathisia, decreased
appetite
Decrease in weight,
improvement in lipid profiles and
decrease of PANSS, CGI,
CDSS scores, 45 % of patients
discontinued due to various
reasons – authors discussed
high rates as attributable to
cross-over titration and
exposure to high doses of two
compounds
Crosstaper
2
weeks
15.8 % of patients
dropped due to AEs,
more patients switching
from olanzapine
discontinued; TEAE
comprised somnolence,
dizziness, insomnia,
headache, nausea and
anxiety
Immediate discontinuation was
preferred; significant
improvements in BPRS, PANSS
and CGI scores in all three
groups and in AIMS, SAS and
BAS scores switching from
haloperidol or risperidone,
weight reduction in patients
switching from olanzapine or
risperidone
Three
different
switch
strategies:
abrupt,
descending
taper and
plateau
descending
taper
1
week
23 patients discontinued
due to schizophrenia or
psychotic disorder;
insomnia after switch
from quetiapine was
attributed to ziprasidone
Not reported
Conventional
antipsychotics,
risperidone or
olanzapine
Olanzapine,
risperidone and
other
conventional or
atypical
antipsychotics
Conventional or
atypical
antipsychotics
Conventional
antipsychotics
Ziprasidone
Ziprasidone
Ziprasidone
Ziprasidone
Harvey et al.57
(Pfizer)
Stable
outpatients, no
history of
treatment
resistance
Montes et al.58
(Pfizer)
Prospective
observational
study; stable
outpatients
Rossi et al.59
(Pfizer)
Stip et al.
60
Open-label,
chronic
schizophrenic
patients
Open-label,
chronic or sub
chronic
patients
Not reported
Mean total learning scores,
long-delay recall improved and
recognition discrimination
improved in all three groups,
effects on attention, vigilance,
executive function and verbal
fluency improved in only some
of the tests and switching
groups; there was no
deterioration in any domain after
switching; overall PANSS total
scores improved in all three
groups
Crosstaper or
abrupt
switch
7 days
Crosstaper or
abrupt
switch
Up to
4
weeks
270
Insufficient
efficacy, adverse
events
Not reported
84
Glucose
intolerance,
diabetes,
dyslipidemia,
weight gain
EPMS occurred in five
patients: akathisia,
oculogyric crisis, tremor
and rigidity, none
discussed as withdrawal
or rebound phenomenon
TEAEs encompassed
dizziness, tremor (3 %)
Overall weight (- 5.1 kg), BMI,
glucose, total cholesterol, LDL
and triglycerides levels
decreased (greatest in patients
switched from olanzapine);
psychopathology improved
Psychiatric symptoms in
22.8 % of patients
reported, not discussed
as withdrawal or
rebound phenomena
10.9 % drop-outs due to
adverse events; TEAEs
were heart rhythm
disorders,
gastrointestinal
discomforts, central or
peripheral nervous
system events
Overall PANSS total scores,
GAF, CGI, SWN scores and
Trail-making test improved; SAS
scores, sexual dysfunction, total
cholesterol, LDL and
triglycerides improved, weight
decreased
Crosstaper
1
week
Occurrence of
withdrawal-induced
dyskinesia in abrupt or
fast taper strategies
were discussed
TEAEs were evenly
distributed across
groups, two treatmentrelated drop-outs
(insufficient efficacy and
adverse event)
BPRS scores did not differ at
endpoint in any two switching
groups, but were greatest
reduced in slow taper group at
week one, fast taper was
superior in EPMS reduction
compared to slow taper, but
inferior to abrupt switch in BAS
scores
3
switching
strategies:
abrupt,
fast and
slow
taper
7 days
312
54
Insufficient
efficacy, adverse
events
Insufficient
efficacy, adverse
events
Different
switchstrategies:
abrupt;
TEAEs comprised
Improvement in EPMS, weight
Conventional
descenWeiden et
Insufficient
Insomnia after switch
insomnia, somnolence,
and prolactin levels;
antipsychotics,
Open-label;
108,
ding
Ziprasidone
al.57, 57, 61
efficacy, adverse
from olanzapine,
anxiety, nausea,
improvement in cognitive
olanzapine,
outpatients
104, 58
taper
(Pfizer)
events
attributed to ziprasidone
dizziness, headache,
functions
risperidone
(immedia
asthenia
te or
delayed
dose
reduction
)
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
Up to
2
weeks
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch)
Table h
Overview of case reports reporting on withdrawal/rebound phenomena; trials are further stratified in alphabetical order of authors
Switching
to
Author
Study
type/Patients
N
Reason for
switch
Withdrawal/Rebound
Treatment emergent
adverse events (>5 %)
Main outcomes/Comment
Design
Duration of
switch
Clozapine
Olanzapine
DelassusGuenault et
al.62
Refractory
schizophrenia
2
Insufficient
efficacy
Diaphoresis,
hypersialorrhea, brochial
obstruction, agitation,
anxiety, enuresis
Not further reported
Slow clozapine discontinuation
over 3 weeks with concurrent
anticholinergic treatment
Descending
taper
3
weeks
Typical
antipsychotic
Atypical
antipsychotic
Cook et al.63
Stable
outpatients
43
Various
Not reported
Not reported
Improvement in positive
symptoms, quality of life,
resource requirement
No data
No
data
Chen et al.64
Chronic
schizophrenic
inpatients
Descendingtaper
switch
8
weeks
taper
of
risperi
done
Gradual
crosstaper
Up to
four
weeks
abrupt
N/A
abrupt
N/A
No data
No
data
Switching
from
Case Reports
Risperidone
Zuclopenthixole
or risperidone
Aripiprazole
Aripiprazole
9
Sexual dysfunction
due to risperidone
Not reported
Not reported
Improvement in sexual function,
decrease in prolactin levels,
improvement in symptoms
5
Symptomatic
hyperprolactinemi
a (amenorrhea or
galactorrhea) and
psychotic
exacerbation
Not reported
No serious AEs during
or after switching were
observed
Hyperprolactinemia and
psychotic symptoms improved
(PANSS)
Not reported
Kuloglu et
al.65
Female
schizophrenic
inpatients
1
Oral dyskinesia
No cholinergic rebound
or side effects were
noted
Aripiprazole
Paliperidone
Lai66
Female
schizophrenic
patient
Risperidone
Paliperidone
Teng and
Lane67
Outpatient
1
Chronic hepatitis
Exacerbated catatonia
was discussed after
abrupt switching
3 weeks after switch
NMS developed
Risperidone
Paliperidone
Wei et al.68
Female
schizophrenic
patient
1
Side effects
Not reported
Tardive dyskinesia
Taper of aripiprazole did not
alter oral dyskinesia, after
switch to paliperidone, oral
dyskinesia subsided within 1
month; psychotic symptoms
remained stable
NMS subsided after intensive
care treatment; psychotic
symptoms were managed
thereafter with aripiprazole.
Switch from risperidone to
paliperidone should be done in
adequate dosing
First case of reported TD
associated with paliperidone
treatment. Dyskinesias subsided
after switch to clozapine
AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary
Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation
antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant
syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and
Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST:
Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch
Reference List
(1) Lin CC, Bai YM, Wang YC et al. Improved body weight and metabolic outcomes in
overweight or obese psychiatric patients switched to amisulpride from other atypical
antipsychotics. J Clin Psychopharmacol 2009 December;29(6):529-36.
(2) Linden M, Scheel T, Eich FX. Improvement of patient compliance after switching
from conventional neuroleptics to the atypical neuroleptic amisulpride. J
Psychopharmacol 2006 November;20(6):815-23.
(3) Ryckmans V, Kahn JP, Modell S et al. Switching to aripiprazole in outpatients with
schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with
risperidone: a randomized, multicentre, open-label study. Pharmacopsychiatry 2009
May;42(3):114-21.
(4) Byerly MJ, Marcus RN, Tran QV, Eudicone JM, Whitehead R, Baker RA. Effects of
aripiprazole on prolactin levels in subjects with schizophrenia during cross-titration
with risperidone or olanzapine: analysis of a randomized, open-label study. Schizophr
Res 2009 February;107(2-3):218-22.
(5) Lee BH, Kim YK, Park SH. Using aripiprazole to resolve antipsychotic-induced
symptomatic hyperprolactinemia: a pilot study. Prog Neuropsychopharmacol Biol
Psychiatry 2006 June;30(4):714-7.
(6) Kim SW, Shin IS, Kim JM et al. Effectiveness of switching to aripiprazole from
atypical antipsychotics in patients with schizophrenia. Clin Neuropharmacol 2009
September;32(5):243-9.
(7) Kim SH, Ivanova O, Abbasi FA, Lamendola CA, Reaven GM, Glick ID. Metabolic
impact of switching antipsychotic therapy to aripiprazole after weight gain: a pilot
study. J Clin Psychopharmacol 2007 August;27(4):365-8.
(8) Ganguli R, Brar JS, Garbut R, Chang CC, Basu R. Changes in weight and other
metabolic indicators in persons with schizophrenia following a switch to aripiprazole.
Clin Schizophr Relat Psychoses 2011 July;5(2):75-9.
(9) Kim CY, Chung S, Lee JN et al. A 12-week, naturalistic switch study of the efficacy
and tolerability of aripiprazole in stable outpatients with schizophrenia or
schizoaffective disorder. Int Clin Psychopharmacol 2009 July;24(4):181-8.
(10) Lin HC, Chong MY, Lee Y, Yeh WC, Lin PY. Switching of antipsychotics to
aripiprazole in the treatment of schizophrenia. Chang Gung Med J 2009
July;32(4):409-16.
(11) Lu ML, Shen WW, Chen CH. Time course of the changes in antipsychotic-induced
hyperprolactinemia following the switch to aripiprazole. Prog Neuropsychopharmacol
Biol Psychiatry 2008 December 12;32(8):1978-81.
(12) Mir A, Shivakumar K, Williamson RJ, McAllister V, O'Keane V, Aitchison KJ.
Change in sexual dysfunction with aripiprazole: a switching or add-on study. J
Psychopharmacol 2008 May;22(3):244-53.
(13) Pae CU, Chiesa A, Mandelli L, Patkar AA, Gibiino S, Serretti A. Predictors of early
worsening after switch to aripiprazole: a randomized, controlled, open-label study.
Clin Drug Investig 2010;30(3):187-93.
(14) Sarin A, Nagpal J, Bohra NK et al. Open labeled, randomized, switch-over study of
two fixed doses (10/15mg) of aripiprazole : to evaluate its safety and efficacy in the
treatment of Indian patients of schizophrenia. Indian J Psychiatry 2004
January;46(1):64-71.
(15) Spurling RD, Lamberti JS, Olsen D, Tu X, Tang W. Changes in metabolic parameters
with switching to aripiprazole from another second-generation antipsychotic: a
retrospective chart review. J Clin Psychiatry 2007 March;68(3):406-9.
(16) Stroup TS, McEvoy JP, Ring KD et al. A randomized trial examining the effectiveness
of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce
metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J
Psychiatry 2011 September;168(9):947-56.
(17) Takeuchi H, Suzuki T, Uchida H et al. A randomized, open-label comparison of 2
switching strategies to aripiprazole treatment in patients with schizophrenia: add-on,
wait, and tapering of previous antipsychotics versus add-on and simultaneous tapering.
J Clin Psychopharmacol 2008 October;28(5):540-3.
(18) Dossenbach MRK, Beuzen JN, Avnon M et al. The effectiveness of olanzapine in
treatment-refractory schizophrenia when patients are nonresponsive to or unable to
tolerate clozapine. Clin Ther 2000 September;22(9):1021-34.
(19) Henderson DC, Nasrallah RA, Goff DC. Switching from clozapine to olanzapine in
treatment-refractory schizophrenia: safety, clinical efficacy, and predictors of
response. J Clin Psychiatry 1998 November;59(11):585-8.
(20) Littrell KH, Johnson CG, Hilligoss NM, Peabody CD, Littrell SH. Switching
clozapine responders to olanzapine. J Clin Psychiatry 2000 December;61(12):912-5.
(21) Dossenbach MR, Kratky P, Schneidman M et al. Evidence for the effectiveness of
olanzapine among patients nonresponsive and/or intolerant to risperidone. J Clin
Psychiatry 2001;62 Suppl 2:28-34.
(22) Faries DE, scher-Svanum H, Nyhuis AW, Kinon BJ. Switching from risperidone to
olanzapine in a one-year, randomized, open-label effectiveness study of schizophrenia.
Curr Med Res Opin 2008 May;24(5):1399-405.
(23) Kim KS, Pae CU, Chae JH et al. Effects of olanzapine on prolactin levels of female
patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002
May;63(5):408-13.
(24) Takahashi H, Kamata M, Yoshida K, Ishigooka J, Higuchi H. Switching to olanzapine
after unsuccessful treatment with risperidone during the first episode of schizophrenia:
an open-label trial. J Clin Psychiatry 2006 October;67(10):1577-82.
(25) Costa e Silva JA, Alvarez N, Mazzotti G et al. Olanzapine as alternative therapy for
patients with haloperidol-induced extrapyramidal symptoms: results of a multicenter,
collaborative trial in Latin America. J Clin Psychopharmacol 2001 August;21(4):37581.
(26) Godleski LS, Goldsmith LJ, Vieweg WV, Zettwoch NC, Stikovac DM, Lewis SJ.
Switching from depot antipsychotic drugs to olanzapine in patients with chronic
schizophrenia. J Clin Psychiatry 2003 February;64(2):119-22.
(27) Kinon BJ, Basson BR, Gilmore JA, Malcolm S, Stauffer VL. Strategies for switching
from conventional antipsychotic drugs or risperidone to olanzapine. J Clin Psychiatry
2000 November;61(11):833-40.
(28) Kinon BJ, Ahl J, Liu-Seifert H, Maguire GA. Improvement in hyperprolactinemia and
reproductive comorbidities in patients with schizophrenia switched from conventional
antipsychotics or risperidone to olanzapine. Psychoneuroendocrinology 2006
June;31(5):577-88.
(29) Kluge M, Wehmeier PM, Dittmann RW et al. A simple switching strategy for
inadequately treated patients with schizophrenia to olanzapine: changes in
psychopathology and subjective well-being. Pharmacopsychiatry 2005
January;38(1):6-12.
(30) Labelle A, Bourget D, Boulay LJ, Ellis J, Tessier P. Switching outpatients with
schizophrenia and related disorders on long-acting injectable antipsychotics to
olanzapine: an open-label naturalistic pilot study. J Clin Psychopharmacol 2002
December;22(6):545-53.
(31) Lee CT, Conde BJ, Mazlan M et al. Switching to olanzapine from previous
antipsychotics: a regional collaborative multicenter trial assessing 2 switching
techniques in Asia Pacific. J Clin Psychiatry 2002 July;63(7):569-76.
(32) Lindenmayer JP, Czobor P, Volavka J et al. Olanzapine in refractory schizophrenia
after failure of typical or atypical antipsychotic treatment: an open-label switch study.
J Clin Psychiatry 2002 October;63(10):931-5.
(33) Lu Z, Hu J, Chen CK et al. Effectiveness and safety of olanzapine in the treatment of
schizophrenia among Asian patients switching from conventional antipsychotics. Prog
Neuropsychopharmacol Biol Psychiatry 2007 January 30;31(1):32-40.
(34) Novick D, Haro JM, Suarez D, Marques-Teixeira J, Naber D. Clinical consequences
of switching antipsychotic drugs in outpatients with schizophrenia: 36-month results
from the European Schizophrenia Outpatient Health Outcomes study. Int Clin
Psychopharmacol 2008 July;23(4):203-8.
(35) Ritchie CW, Chiu E, Harrigan S et al. The impact upon extra-pyramidal side effects,
clinical symptoms and quality of life of a switch from conventional to atypical
antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia. Int J
Geriatr Psychiatry 2003 May;18(5):432-40.
(36) Gupta S, Masand PS, Virk S et al. Weight decline in patients switching from
olanzapine to quetiapine. Schizophr Res 2004 September 1;70(1):57-62.
(37) Cortese L, Caligiuri MP, Williams R et al. Reduction in neuroleptic-induced
movement disorders after a switch to quetiapine in patients with schizophrenia. J Clin
Psychopharmacol 2008 February;28(1):69-73.
(38) Larmo I, de NA, Windhager E et al. Efficacy and tolerability of quetiapine in patients
with schizophrenia who switched from haloperidol, olanzapine or risperidone. Hum
Psychopharmacol 2005 December;20(8):573-81.
(39) Nakajima M, Terao T, Iwata N, Nakamura J. Switching female schizophrenic patients
to quetiapine from conventional antipsychotic drugs: effects on hyperprolactinemia.
Pharmacopsychiatry 2005 January;38(1):17-9.
(40) Moller HJ, Johnson S, Mateva T et al. Evaluation of the feasibility of switching from
immediate release quetiapine to extended release quetiapine fumarate in stable
outpatients with schizophrenia. Int Clin Psychopharmacol 2008 March;23(2):95-105.
(41) Ganesan S, Agambaram V, Randeree F, Eggens I, Huizar K, Meulien D. Switching
from other antipsychotics to once-daily extended release quetiapine fumarate in
patients with schizophrenia. Curr Med Res Opin 2008 January;24(1):21-32.
(42) Ganguli R, Brar JS, Mahmoud R, Berry SA, Pandina GJ. Assessment of strategies for
switching patients from olanzapine to risperidone: a randomized, open-label, raterblinded study. BMC Med 2008;6:17.
(43) Meyer JM, Pandina G, Bossie CA, Turkoz I, Greenspan A. Effects of switching from
olanzapine to risperidone on the prevalence of the metabolic syndrome in overweight
or obese patients with schizophrenia or schizoaffective disorder: analysis of a
multicenter, rater-blinded, open-label study. Clin Ther 2005 December;27(12):193041.
(44) Still DJ, Dorson PG, Crismon ML, Pousson C. Effects of switching inpatients with
treatment-resistant schizophrenia from clozapine to risperidone. Psychiatr Serv 1996
December;47(12):1382-4.
(45) Kirov GK, Murray RM, Seth RV, Feeney S. Observations on switching patients with
schizophrenia to risperidone treatment. Risperidone Switching Study Group. Acta
Psychiatr Scand 1997 May;95(5):439-43.
(46) Malla AK, Norman RM, Kotteda V, Zirul S. Switching from therapy with typical
antipsychotic agents to risperidone: long-term impact on patient outcome. Clin Ther
1999 May;21(5):806-17.
(47) Nakanishi S, Kunugi H, Murray RM, Nojima S, Ogawa T, Takahashi T. Effects of
switching from conventional antipsychotics to risperidone in Japanese patients with
chronic schizophrenia. Psychiatry Clin Neurosci 2006 December;60(6):751-7.
(48) Sliwa JK, Bossie CA, Ma YW, Alphs L. Effects of acute paliperidone palmitate
treatment in subjects with schizophrenia recently treated with oral risperidone.
Schizophr Res 2011 October;132(1):28-34.
(49) Hawley C, Turner M, Latif MA, Curtis V, Saleem PT, Wilton K. Switching stable
patients with schizophrenia from depot and oral antipsychotics to long-acting
injectable risperidone: reasons for switching and safety. Hum Psychopharmacol 2010
January;25(1):37-46.
(50) van OJ, Bossie CA, Lasser RA. Improvements in stable patients with psychotic
disorders switched from oral conventional antipsychotics therapy to long-acting
risperidone. Int Clin Psychopharmacol 2004 July;19(4):229-32.
(51) Kim SW, Shin IS, Kim JM et al. Effects of switching to long-acting injectable
risperidone from oral atypical antipsychotics on cognitive function in patients with
schizophrenia. Hum Psychopharmacol 2009 October;24(7):565-73.
(52) Marinis TD, Saleem PT, Glue P et al. Switching to long-acting injectable risperidone
is beneficial with regard to clinical outcomes, regardless of previous conventional
medication in patients with schizophrenia. Pharmacopsychiatry 2007
November;40(6):257-63.
(53) Lai YC, Huang MC, Chen CH, Tsai CJ, Pan CH, Chiu CC. Pharmacokinetics and
efficacy of a direct switch from conventional depot to risperidone long-acting injection
in Chinese patients with schizophrenic and schizoaffective disorders. Psychiatry Clin
Neurosci 2009 August;63(4):440-8.
(54) Kim SW, Shin IS, Kim JM, Bae KY, Yang SJ, Yoon JS. Effectiveness of switching
from aripiprazole to ziprasidone in patients with schizophrenia. Clin Neuropharmacol
2010 May;33(3):121-5.
(55) Karayal ON, Glue P, Bachinsky M et al. Switching from quetiapine to ziprasidone: a
sixteen-week, open-label, multicenter study evaluating the effectiveness and safety of
ziprasidone in outpatient subjects with schizophrenia or schizoaffective disorder. J
Psychiatr Pract 2011 March;17(2):100-9.
(56) Alptekin K, Hafez J, Brook S et al. Efficacy and tolerability of switching to
ziprasidone from olanzapine, risperidone or haloperidol: an international, multicenter
study. Int Clin Psychopharmacol 2009 September;24(5):229-38.
(57) Harvey PD, Meltzer H, Simpson GM et al. Improvement in cognitive function
following a switch to ziprasidone from conventional antipsychotics, olanzapine, or
risperidone in outpatients with schizophrenia. Schizophr Res 2004 February 1;66(23):101-13.
(58) Montes JM, Rodriguez JL, Balbo E et al. Improvement in antipsychotic-related
metabolic disturbances in patients with schizophrenia switched to ziprasidone. Prog
Neuropsychopharmacol Biol Psychiatry 2007 March 30;31(2):383-8.
(59) Rossi A, Vita A, Tiradritti P, Romeo F. Assessment of clinical and metabolic status,
and subjective well-being, in schizophrenic patients switched from typical and atypical
antipsychotics to ziprasidone. Int Clin Psychopharmacol 2008 July;23(4):216-22.
(60) Stip E, Zhornitsky S, Potvin S, Tourjman V. Switching from conventional
antipsychotics to ziprasidone: a randomized, open-label comparison of regimen
strategies. Prog Neuropsychopharmacol Biol Psychiatry 2010 August 16;34(6):9971000.
(61) Weiden PJ, Daniel DG, Simpson G, Romano SJ. Improvement in indices of health
status in outpatients with schizophrenia switched to ziprasidone. J Clin
Psychopharmacol 2003 December;23(6):595-600.
(62) Delassus-Guenault N, Jegouzo A, Odou P et al. Clozapine-olanzapine: a potentially
dangerous switch. A report of two cases. J Clin Pharm Ther 1999 June;24(3):191-5.
(63) Cook PE, Goldberg JO, Van Lieshout RJ. Benefits of switching from typical to
atypical antipsychotic medications: a longitudinal study in a community-based setting.
Can J Psychiatry 2002 November;47(9):870-4.
(64) Chen CY, Lin TY, Wang CC, Shuai HA. Improvement of serum prolactin and sexual
function after switching to aripiprazole from risperidone in schizophrenia: a case
series. Psychiatry Clin Neurosci 2011 February;65(1):95-7.
(65) Kuloglu M, Ekinci O, Albayrak Y, Caykoylu A. Benefits of switching women
schizophrenic patients to aripiprazole: a case study and brief review of the literature.
Arch Womens Ment Health 2010 October;13(5):443-7.
(66) Lai CH. Improvement of oral dyskinesia after switching from aripiprazole to
paliperidone: a case report. J Neuropsychiatry Clin Neurosci 2011;23(3):E18.
(67) Teng PR, Lane HY. Emergence of neuroleptic malignant syndrome while switching
between risperidone and paliperidone. J Neuropsychiatry Clin Neurosci 2011
September 1;23(4):E16-E17.
(68) Wei HT, Lai YW, Chen MH, Chen YS. Oral-paliperidone-induced tardive dyskinesia:
a case report. Gen Hosp Psychiatry 2011 December 8.