756062

research-article2018
JOP0010.1177/0269881118756062Journal of Psychopharmacology 0(0)Zhou et al.

Original Article

Dose reduction of risperidone and olanzapine

can improve cognitive function and negative
symptoms in stable schizophrenic patients: Journal of Psychopharmacology

A single-blinded, 52-week, randomized

1­–9
© The Author(s) 2018
Reprints and permissions:
controlled study sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0269881118756062
https://doi.org/10.1177/0269881118756062
journals.sagepub.com/home/jop

Yanling Zhou1, Guannan Li2, Dan Li2, Hongmei Cui2 and Yuping Ning1

Abstract
Background: The long-term effects of dose reduction of atypical antipsychotics on cognitive function and symptomatology in stable patients with
schizophrenia remain unclear. We sought to determine the change in cognitive function and symptomatology after reducing risperidone or olanzapine
dosage in stable schizophrenic patients.
Methods: Seventy-five stabilized schizophrenic patients prescribed risperidone (≥4 mg/day) or olanzapine (≥10 mg/day) were randomly divided into
a dose-reduction group (n=37) and a maintenance group (n=38). For the dose-reduction group, the dose of antipsychotics was reduced by 50%; for
the maintenance group, the dose remained unchanged throughout the whole study. The Positive and Negative Syndrome Scale, Negative Symptom
Assessment-16, Rating Scale for Extrapyramidal Side Effects, and Measurement and Treatment Research to Improve Cognition in Schizophrenia
(MATRICS) Consensus Cognitive Battery were measured at baseline, 12, 28, and 52 weeks. Linear mixed models were performed to compare the Positive
and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects and MATRICS Consensus Cognitive
Battery scores between groups.
Results: The linear mixed model showed significant time by group interactions on the Positive and Negative Syndrome Scale negative symptoms,
Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, attention/vigilance, working memory and total
score of MATRICS Consensus Cognitive Battery (all p<0.05). Post hoc analyses showed significant improvement in Positive and Negative Syndrome Scale
negative subscale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, working memory and total
score of MATRICS Consensus Cognitive Battery for the dose reduction group compared with those for the maintenance group (all p<0.05).
Conclusions: This study indicated that a risperidone or olanzapine dose reduction of 50% may not lead to more severe symptomatology but can
improve speed of processing, working memory and negative symptoms in patients with stabilized schizophrenia.

Keywords
Cognitive function, symptomatology, dose reduction, antipsychotics, schizophrenia

Introduction
Schizophrenia is a chronic, repeated relapsing, serious mental
disorder with positive symptoms, negative symptoms and cogni-
tive impairment. During the maintenance stage, the most effec-
tive way to prevent relapse is adherence to maintenance
antipsychotic treatment (Mizuno et al., 2012; Remington et al.,
2006), but the dosage for this phase is still controversial. Some
treatment guidelines recommend that the dose of antipsychotics
given during the maintenance period should be less than during
the acute treatment phase (Baldessarini et al., 1995; Lehman
et al., 2004; Nagaendran et al., 2011). Conversely, some guide-
lines recommend the initial therapeutic atypical antipsychotics
dosage should not be changed during the whole course of treat-
ment (Kane et al., 2003; Lehman et al., 2010). However, no clear
recommendation for a reduction of antipsychotic dose during the
maintenance period has been given in most treatment guidelines
for schizophrenia (Barnes, 2011; Lehman et al., 2004).
In clinical practice, high doses of antipsychotic drugs are
widely prescribed to treat schizophrenia, even during mainte-
nance treatment. For example, 15-41% of acute patients with
schizophrenia in the USA were prescribed high-dose antipsy-
chotics (Dixon et al., 2010; Lehman et al., 2010), and up to 81%
of chronic patients in Japan received high-dose antipsychotics
(Suzuki et al., 2003). Furthermore, 17.9% of schizophrenic
patients were receiving high-dose antipsychotics in a multina-
tional survey within East Asia (Sim et al., 2009). However, high-
dose antipsychotic exposure was associated with extrapyramidal
symptoms, metabolic syndrome, poor adherence, and increased
1TheAffiliated Brain Hospital of Guangzhou Medical University
(Guangzhou Huiai Hospital), Guangzhou, China
2Guangzhou Civil Affairs Bureau Psychiatric Hospital, Guangzhou, China
Corresponding author:
Yuping Ning, The Affiliated Brain Hospital of Guangzhou Medical
University (Guangzhou Huiai Hospital), Mingxin Road #36, Liwan
District, Guangzhou, 510370, China.
Email: ningjeny@126.com
2 Journal of Psychopharmacology 00(0)
mortality (David et al., 2000; Gargoloff et al., 2003; Ho et al.,
2011; Torniainen et al., 2014).
Many studies suggested that high doses of antipsychotics
impair cognitive function over time in schizophrenic patients
(Elie et al., 2010; Knowles et al., 2010), and one study pointed
out that a low dose of conventional medications such as haloperi-
dol might improve cognitive function yet a higher dose might
neutralize or reverse cognitive function (Green et al., 2002).
Cognitive function was found to be negatively related to high
serum levels of antipsychotic drugs, which could represent levels
of dopamine receptor occupancy (Sakurai et al., 2013). A meta-
analysis combining data of first- and second-generation antipsy-
chotics reported a negative association between dosage and
cognitive processing speed (Knowles et al., 2010).
With regards to the potential benefit of neurocognition in
schizophrenic patients which might ascribed to antipsychotic
dose reduction, Kawai and colleagues found that cognitive func-
tion might improve with dose reduction in schizophrenic patients
who were taking high doses of multiple conventional antipsy-
chotics (Kawai et al., 2006). Similarly, a pilot study of stable
schizophrenic patients showed that if the dose of risperidone or
olanzapine was reduced by half, then this would benefit out-
comes, including an improvement in cognitive function, without
aggravating psychotic symptoms (Takeuchi et al., 2013).
However, the open-label design was a limitation of this study
because patients’ and raters’ expectation biases could have
unfairly affected the results. Besides, the six months of follow-up
may have been insufficient to reflect long-term relapse rates after
dose reduction in this chronic psychotic disorder.
The aim of this single-blinded, 52-week, randomized con-
trolled pilot study was to examine the changes in cognitive func-
tion and symptomatology after a 50% reduction of risperidone
and olanzapine in schizophrenic patients during the maintenance
treatment period. The hypothesis was that cognitive function may
improve and psychological symptoms may not get worse after
careful dose reduction. Olanzapine and risperidone were the two
most frequently prescribed second generation antipsychotics
(SGA) in previous research in different countries (Li et al., 2015;
Robinson et al., 2015), so patients who prescribed risperidone or
olanzapine were included in this study.
Material and methods
This pilot study was a single-blind (rater-blinded), parallel-
group, 52-week, randomized controlled trial. Participants were
enrolled from the Affiliated Brain Hospital of Guangzhou
Medical University and Guangzhou Civil Affairs Bureau
Psychiatric Hospital between July 2015–December 2016. This
research required careful ethical review and was approved by the
clinical research ethics committees at each research institute.
After an adequate description of the trial, each participant signed
a consent form prior to entering this trial. This trial was registered
in the Chinese Clinical Trials Registry (Registration Number:
ChiCTR-POC-15006642).
Subjects
The inclusion criteria for this study were as follows: (a) aged
18–60 years; (b) male or female; (c) diagnosed with schizophre-
nia meeting the Diagnostic and Statistical Manual of Mental
Disorders, 4th Edition, Text Revision (American Psychiatric
Association, 2000) (DSM-IV-TR) criteria at study entry; (d) sta-
bilized phase as defined by a score of ≤3 (mild) on all of the fol-
lowing four Positive and Negative Syndrome Scale (PANSS)
positive subscale items (P1 delusion, P2 conceptual disorganiza-
tion, P3 hallucinatory behavior, and P6 suspiciousness) (Takeuchi
et al., 2013); (e) prescribed the monotherapy antipsychotic of
either risperidone or olanzapine at a constant dose of ≥4 mg/day
or ≥10 mg/day, respectively, for at least three months; and (f)
could understand the aims of the study and sign the consent form.
The exclusion criteria included: (a) the use of antipsychotic poly-
pharmacy, but a combined intake of ≤50 mg/day of clozapine or
≤200 mg/day of quetiapine was allowed to aid sleep (combined
medications other than antipsychotics were allowed); (b) a his-
tory of or a current major medical or neurological disorder; (c)
substance abuse; and (d) pregnancy or lactation. There were four
patients receiving combined clozapine and quetiapine included in
this study, and two with combined clozapine in the maintenance
group and two with combined quetiapine in the reduction group.
Considering clozapine has a great impact on the white blood
cells, monitoring of white blood cells was required and it was
found to be normal throughout the whole study.
Procedures
Participants were divided into the dose-reduction group and
dose-maintenance group by a random-numbers chart. In the
dose-reduction group, the dose of risperidone or olanzapine was
reduced by 25% for the first four weeks, then reduced by 50% of
the original dose for the next 12 weeks, and then maintained at
this dose until the end of the study. For clinical safety, the dose
was not allowed to go below 2 mg/day for risperidone and 5 mg/
day for olanzapine, which is the minimum prescribed recom-
mended dose for maintenance treatment in schizophrenia. For the
dose-maintenance group, participants were prescribed the base-
line dose throughout the whole study. Concomitant medications
of all participants were maintained at the same dose throughout
the study period.
Outcome assessments
Symptoms were assessed using the PANSS and the 16-item ver-
sion of the Negative Symptom Assessment-16 (NSA-16) (Alphs
et al., 1989). The PANSS includes three subscales, positive, neg-
ative, and general psychopathology symptoms, and examines
symptomatology with scores ranging from 30–210, with higher
scores indicating more severe symptoms (Kay et al., 1987). The
NSA-16 examines negative symptoms including problems in
communication, emotion, motivation, and sociality on a series of
seven-point scales (0–6), with higher scores reflecting worse
symptomatology.
A Rating Scale for Extrapyramidal Side Effects (RSESE) was
used to assess extrapyramidal symptoms (Simpson and Angus,
1970). This scale examines extrapyramidal symptoms including
10 items on a series of five-point scales (0–4). Higher scores
reflect more severe extrapyramidal symptoms.
Cognitive function was assessed with the MATRICS
(Measurement and Treatment Research to Improve Cognition in
Schizophrenia) Consensus Cognitive Battery (MCCB) (Nuechterlein
et al., 2008), which includes seven domains: speed of processing,
Zhou et al. 3
attention/vigilance, working memory, verbal learning, visual learn-
ing, reasoning and problem solving and social cognition.
Standardized T scores (mean of T=50 and standard deviation=10)
were calculated for each domain score.
Course of assessment
At the start of the study, all raters were trained together to estab-
lish reliability, and the intraclass correlation coefficients for the
scores on the PANSS, NSA-16, RSESE and MCCB ranged from
0.80–0.89.
Clinical psychopathology, cognitive function, and extrapy-
ramidal symptoms were assessed at baseline, 12 weeks, 28
weeks, and 52 weeks. Patients withdrew from the study if their
drug treatment regimens were changed for any reason, such as a
relapse, suffered from a serious medical disease, became preg-
nant, or suffered from serious side effects.
In this study, relapse was defined as a score of ≥4 (moderate)
on at least one of the four items of delusion (P1), conceptual dis-
organization (P2), hallucinatory behavior (P3), and suspicious-
ness (P6) (Takeuchi et al., 2013) on the PANSS.
Statistical analyses
Baseline demographic and clinical characteristics were com-
pared between groups using Chi-squared test for the categorical
variables and Student’s t-test for the continuous variables.
Next, linear mixed model analysis was used to examine group
differences in the PANSS, NSA-16, RSESE score, and MCCB
T-score. Time×group interactions as well as main effects for time
and group were explored in this model. For significant interac-
tions, Bonferroni-corrected simple-effects post hoc tests were
used to calculate the group difference of timing. The linear mixed
model can make full use of information of missing repeated
measurement data (Krueger and Tian, 2004), because there were
10 patients who withdrew in this study and the data of the last
visit was missing.
Then, we compared PANSS negative symptoms, NSA-16,
speed of processing, working memory, and total score of MCCB
which was significant group difference between groups in post hoc
analyses using linear mixed model analysis with the RSESE score
as the covariate, in order to eliminate the effect of extrapyramidal
side effects in negative symptoms and cognitive function.
Finally, linear regression analysis was used to explore the
associations between baseline dose of antipsychotics and
improvement in main outcomes in the dose-reduction group. The
dose of olanzapine was equivalently converted to the dose of
risperidone.
All statistical analyses were performed using IBM SPSS
Statistics version 22, and p-values <0.05 were considered statisti-
cally significant.
Results
Rate of relapse
Seventy-five outpatients were enrolled in this study and were
randomly assigned to the reduction group (n=37) or the mainte-
nance group (n=38). Ten patients withdrew from the study before
the week 52 follow-up because of relapse and had to change drug
Figure 1.  Flow chart of the study.
treatment regimens. Four patients in the reduction group and six
patients in the maintenance group relapsed. Rates of relapse did
not differ significantly between groups (x2=0.402, p=0.526). A
flow chart of the study is shown in Figure 1.
Sociodemographic and clinical characteristics
The baseline characteristics are presented in Table 1. No signifi-
cant difference was found in age, gender, education, body mass
index, duration of illness, or number of hospitalizations between
the reduction group and the maintenance group.
Clinical symptoms and extrapyramidal side
effects, body mass index
Three PANSS subscales, NSA-16 or RSESE score at baseline did
not differ between the two groups (all p>0.05) (Table 2).
The linear mixed model with PANSS positive symptoms
showed no significant time by group interaction (F=2.365,
p=0.072) and no significant difference for the group main effect
(F=0.346, p=0.558), but there was a significant difference for the
time main effect (F=4.945, p=0.002). Post hoc tests showed no
significantly different positive symptoms between groups at each
follow-up (all p>0.05).
For the PANSS negative subscale, there was a statistically sig-
nificant time by group interaction (F=10.785, p<0.001), group
main effect (F=9.389, p=0.003), and time main effect (F=3.645,
p=0.014). Post hoc tests showed significantly fewer negative
symptoms for the reduction group than for the maintenance
group at 28 weeks (p<0.001) and at 52 weeks (p<0.001). In the
reduction group, no significant change was shown compared
with baseline (all p>0.05), but for maintenance subjects, a sig-
nificantly lower score was found at 28 weeks (p<0.001) and 52
weeks (p=0.001) compared with baseline (Table 3).
For the PANSS general psychopathology subscale, there was
a statistically significant time main effect (F=5.051, p=0.002),
but the time×group interaction (F=3.027, p=0.053) or the group
main effect (F=0.267, p=0.607) was not significant. Post hoc
tests showed no significant differences in general psychopathol-
ogy symptoms between groups from baseline to 52 weeks (all
p>0.05).
The linear mixed model for the NSA-16 showed a significant
group×time interaction (F=7.091, p<0.001) and a significant
group main effect (F=9.133, p=0.003), but no time main effect
4 Journal of Psychopharmacology 00(0)

Table 1.  Demographic and clinical characteristics of patients in reduction and maintenance groups.

Variables Reduction (n =37) Maintenance (n=38) x2 p

n % n %

Gender (male) 22 59.5 23 60.5 0.009 0.925

Duration of illness 2.517 0.499
<2 years 8 21.6 8 21.1  
2≤Duration<5 years 15 40.5 10 26.3  
5≤Duration<10 years 6 16.2 11 28.9  
≥10 years 8 21.6 9 23.7  
Number of hospitalizations 0.756a 0.889
0 7 18.9 5 13.2  
1 9 24.3 11 28.9  
2 18 48.6 18 47.4  
≥3 3 8.1 4 10.5  
Patients treated with risperidone 27 73.0 29 76.3 0.111 0.739
Patients treated with olanzapine 10 27.0 9 23.7 0.111 0.739
Concomitant medications  
Clozapine or quetiapine 2 5.4 2 5.3 0.001a 0.682
Benzodiazepines 2 5.4 6 15.8 0.121a 0.262
Mood stabilizers 5 13.5 9 23.7 1.277a 0.375
Antidepressants 1 2.7 3 7.9 1.001a 0.615
Anticholinergic 22 59.5 21 55.3 0.135 0.713
Kinds of other antipsychotics used before 0.802a 0.670
0 14 37.8 13 34.2  
1 16 43.2 20 52.6  
≥2 7 18.9 5 13.2  
Relapse 4 10.8 6 15.8 0.402a 0.526

  Mean SD Mean SD t p

Age (years) 44.3 9.1 44.8 6.6 1.032 0.805

Year of education 10.5 2.8 9.7 2.8 −1.247 0.216
Dose of risperidone (mg/day) 5.1 0.9 4.9 0.9 −0.436 0.665
Dose of olanzapine (mg/day) 19.5 1.6 17.2 3.6 −1.809 0.089
Dose of risperidone after reduction (mg/day) 3.3 0.4 − − − −
Dose of olanzapine after reduction (mg/day) 7.8 0.8 − − − −

SD: standard deviation.

aFisher’s exact test.

(F=0.301, p=0.825). Post hoc tests showed significantly fewer
negative scores for the dose reduction group than the mainte-
nance group at 28 weeks (p=0.002) and at 52 weeks (p<0.001).
Significant group×time interaction (F=3.471, p=0.026) and
significant time main effect (F=3.283, p=0.022) were observed
for the RSESE, but no significant group main effect (F=2.196,
p=0.143). A significant group difference was noted at 52 weeks
in post hoc tests, and showed significantly fewer extrapyramidal
symptoms for the dose reduction group than the maintenance
group (p=0.012).
The linear mixed model with body mass index showed signifi-
cant group×time interaction (F=4.769, p=0.032), significant time
main effect (F=6.617, p=0.012) and group main effect (F=4.148,
p=0.045). Significant group difference was noted at 52 weeks in
post hoc tests, and showed significantly less body mass index for
the dose reduction group than the maintenance group (p=0.005).
When participants who received concurrent antipsychotics
(clozapine or quetiapine) and mood stabilizers were not taken
into account for analysis, the results were similar when the whole
sample was taken for analysis (see Supplementary Material
Tables 1–4).
Cognitive function
The MCCB T-scores for the subjects at baseline are summarized
in Table 2. No significant difference was noted between groups
for any of the baseline cognitive domains (all p>0.05).
The linear mixed model with the three cognition domains,
including speed of processing (F=3.163, p=0.026), attention/
vigilance (F=2.731, p=0.045) and working memory
(F=3.350, p=0.020), showed significant group×time interac-
tions. There were significant time main effects in these three
domains (speed of processing F=4.729, p=0.003; attention/
vigilance F=4.278, p=0.006; working memory F=4.155,
p=0.007), and significant group main effects in speed of pro-
cessing (F=7.059, p=0.010) and working memory (F=3.984,
p=0.042). Post hoc tests showed significantly better cogni-
tive function for the reduction subjects than for the
Zhou et al. 5

Table 2.  Comparison of Positive and Negative Syndrome Scale (PANSS), Negative Symptom Assessment-16 (NSA-16), Rating Scale for Extrapyramidal
Side Effects (RSESE) and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery
(MCCB) scores between groups using linear mixed model analysis.

Variables Group main effect Time main effect Time×group interactions

F p F p F p

PANSS score
Positive 0.346 0.558 4.945 0.002** 2.365 0.072
Negative 9.389 0.003** 3.645 0.014* 10.785 <0.001**
General psychopathology 0.267 0.607 5.051 0.002** 3.027 0.053
NSA-16 9.133 0.003** 0.301 0.825 7.091 <0.001**
RSESE 2.196 0.143 3.283 0.022* 3.471 0.026*
MCCB T score
Speed of processing 7.059 0.010* 4.729 0.003** 3.163 0.026*
Attention/vigilance 0.021 0.885 4.278 0.006** 2.731 0.045*
Working memory 3.984 0.042* 4.155 0.007** 3.350 0.020*
Verbal learning 0.002 0.964 4.707 0.003** 0.373 0.772
Visual learning 0.004 0.948 9.813 <0.001** 0.723 0.539
Reasoning and problem solving 0.126 0.724 3.855 0.010* 1.143 0.333
Social cognition 0.011 0.917 0.708 0.548 0.550 0.649
Total score 2.000 0.163 8.281 <0.001** 2.965 0.034*
Body mass index 4.148 0.045* 6.617 0.012* 4.769 0.032*

MCCB: Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery; NSA-16: Negative Symptom Assessment-16;
PANSS: Positive and Negative Syndrome Scale; RSESE: Rating Scale for Extrapyramidal Side Effects.
*p<0.05, **p<0.01.

Table 3.  Group difference of timing of clinical symptoms using Bonferroni-corrected simple-effects post hoc tests.

Variables Time (weeks) Reduction (n=37) Maintenance (n=38) t p

PANSS positive 0 12.7±5.6 12.4±6.8 0.187 0.852

  12 11.6±4.3 11.9±5.0 −0.315 0.753
  28 10.9±4.2 11.9±5.9 −0.841 0.404
  52 10.8±4.9 12.2±6.1 −1.050 0.298
PANSS negative 0 19.7±6.4 20.4±7.5 0.176 0.633
  12 20.1±7.1 22.2±6.6 −0.426 0.188
  28 18.8±6.4 25.7±4.5 4.344 <0.001**
  52 17.3±6.5 24.1±5.9 −3.770 <0.001**
PANSS general 0 33.8±9.6 33.7±9.6 0.471 0.976
psychopathology 12 32.5±9.5 33.6±10.5 −0.141 0.645
28 31.5±9.1 33.0±9.7 −0.157 0.557
  52 31.3±8.2 33.7±10.6 −0.532 0.323
NSA-16 0 64.0±12.2 64.5±11.2 −0.172 0.864
  12 61.0±12.2 65.8±9.3 −1.136 0.260
  28 61.9±13.1 68.5±12.4 −2.513 0.015*
  52 59.6±13.3 69.7±6.6 −3.855 <0.001**
RSESE 0 6.3±3.4 6.4±2.9 −0.109 0.914
  12 5.2±3.2 6.3±2.2 −1.548 0.127
  28 5.1±3.0 5.9±2.6 −1.078 0.285
  52 4.9±2.9 6.6±2.4 −2.597 0.012*
Body mass index 0 25.3±4.7 26.9±5.9 −0.772 0.199
  12 24.8±4.7 27.1±5.7 −0.511 0.054
  28 24.6±4.6 26.8±5.5 −0.529 0.063
  52 23.7±3.7 26.9±5.4 −0.346 0.005**

NSA-16: Negative Symptom Assessment-16; PANSS: Positive and Negative Syndrome Scale; RSESE: Rating Scale for Extrapyramidal Side Effects.
*p<0.05, **p<0.01.

maintenance subjects at 28 weeks and at 52 weeks in terms in the attention/vigilance domain at each follow-up (all
of speed of processing (p=0.010 and p=0.001, respectively) p>0.05) (Table 4).
and working memory (p=0.080 and p=0.024, respectively), No significant group×time interaction, group main effect or
but no significant difference was observed between groups time main effect was examined in other cognition domains,
6 Journal of Psychopharmacology 00(0)

Table 4.  Group difference of timing of cognitive function using Bonferroni-corrected simple-effects post hoc tests.

Variables Time (weeks) Reduction (n=37) Maintenance (n=38) t p

Speed of processing 0 34.2±7.6 34.2±7.3 −0.244 0.998

  12 38.9±6.4 34.7±6.9 1.462 0.091
  28 40.5±8.8 34.2±8.7 2.749 0.010*
  52 43.3±8.8 35.4±7.6 2.991 0.001**
Attention/vigilance 0 39.0±8.2 39.8±9.6 −0.742 0.162
  12 38.4±6.7 42.0±7.8 −1.257 0.960
  28 41.0±9.5 41.1±8.7 −0.289 0.198
  52 45.2±8.8 41.9±7.9 1.075 0.644
Working memory 0 37.3±7.5 38.5±8.0 −0.784 0.436
  12 42.3±9.2 38.8±8.2 1.092 0.279
  28 45.1±7.6 37.9±8.9 3.255 0.008**
  52 45.8±8.3 39.8±9.2 2.162 0.024*
Verbal learning 0 38.0±9.2 36.6±7.6 0.403 0.623
  12 40.9±8.5 41.7±7.6 −0.324 0.760
  28 37.7±6.9 38.8±7.7 −0.427 0.700
  52 41.3±6.7 41.1±7.4 0.012 0.952
Visual learning 0 37.2±8.2 36.3±8.7 0.509 0.670
  12 39.9±6.5 40.1±7.6 −0.104 0.909
  28 41.3±8.4 39.9±7.2 0.627 0.519
  52 42.0±7.8 43.6±8.6 −0.687 0.453
Reasoning and 0 39.9±6.9 41.4±8.4 −0.472 0.467
problem solving  12 42.7±8.9 42.5±8.2 0.468 0.916
28 42.0±7.6 40.6±9.4 1.101 0.476
  52 44.8±6.6 42.8±8.4 1.113 0.319
Social cognition 0 42.4±8.5 44.3±8.9 −1.050 0.476
  12 43.6±8.2 43.0±7.9 −0.052 0.819
  28 44.9±8.0 43.3±8.2 0.393 0.578
  52 44.8±7.0 45.9±7.3 3.121 0.698
Total score of MCCB 0 32.4±11.4 32.1±12.9 0.112 0.912
  12 34.6±13.0 34.9±11.5 −0.099 0.921
  28 38.8±8.1 32.8±11.4 2.362 0.022*
  52 42.2±10.2 35.7±11.6 2.530 0.014*

MCCB: Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery.
*p<0.05, **p<0.01.

including verbal learning, visual learning, reasoning and problem subjects at 28 weeks and at 52 weeks in these variables (all
solving, and social cognition (all p>0.05). No group difference p<0.05).
was noted in these cognition domains from baseline to 52 weeks
in post hoc tests (all p>0.05).
When participants who received concurrent antipsychotics Associations between baseline dose of
(clozapine or quetiapine) and mood stabilizers were not taken antipsychotics and improvement in outcomes
into account for analysis, the results also showed significant
Linear regression analysis was used to explore the associations
improvement in speed of processing, working memory and total
between baseline dose of antipsychotics and improvements in
score of MCCB for the dose reduction group compared with
negative symptoms and speed of processing, working memory.
those for the maintenance group (all p<0.05) (see Supplementary
No significant association was found between them (see
Material Tables 1–4).
Supplementary Material Table 5).

Results of linear mixed model analysis with Discussion

the RSESE score as the covariate
The linear mixed model analysis with the RSESE score as the
covariate similarly showed significant group×time interaction
and group main effect in PANSS negative symptoms, NSA-16,
speed of processing, working memory, total score of MCCB (all
p<0.05), and post hoc tests also showed significantly better
improvement for the reduction subjects than for the maintenance
From this single-blinded, 52-week, randomized controlled pilot
study, there were two main findings: (a) speed of processing,
working memory, and overall cognitive function improved after
reducing the doses of risperidone or olanzapine; and (b) relapse
rate did not increase and negative symptoms improved after
reducing the doses of risperidone or olanzapine over a 52-week
interval in stable schizophrenic patients.
Zhou et al. 7
Cognitive function
The cognitive performance of 75 stable patients with schizophre-
nia in this study was measured with the MCCB, which is now
accepted as a standard by the US Food and Drug Administration
(Nuechterlein et al., 2004). Speed of processing, attention/vigi-
lance, working memory, and overall cognitive function signifi-
cantly improved after dose reduction compared with baseline.
Moreover, speed of processing, working memory, and overall
cognitive function had a more perceptible improvement in the
dose-reduction group than in the dose-maintenance group, even if
we included extrapyramidal symptoms as covariates in the multi-
variate analyses. Our results were similar with a 28-week pilot
study showing that both verbal memory and processing speed
improved after the antipsychotic dose was reduced, although cog-
nitive function in this previous study was measured with a differ-
ent assessment tool (the Repeatable Battery for the Assessment of
Neuropsychological Status) (Takeuchi et al., 2013). Other studies
also reported that the dose of antipsychotics negatively correlated
with cognitive function, and considered that higher doses of antip-
sychotics led to serious damage to cognitive function in schizo-
phrenic patients (Elie et al., 2010; Green et al., 2002; Knowles
et al., 2010). This evidence led to the conclusion that one reason
why cognitive impairment persisted was due to the damaging
effect of antipsychotics on cognition. Therefore, dose reduction of
antipsychotics was the most simple and effective means to
improve cognitive function in schizophrenia, especially in the
domains of speed of processing and working memory.
Our understanding of the mechanisms underlying the cognitive
deficits of schizophrenia remains limited. The effects of antipsy-
chotics on cognitive function could be related to the following two
possible explanations. One possible mechanism is the monoaminer-
gic system, specifically antipsychotic-related high estimated dopa-
mine (D2) receptor occupancy. Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) data revealed that the degree of
D2 receptor occupancy, which could reflect the plasma concentra-
tions of antipsychotic drugs, was associated with vigilance as well
as general neurocognitive function in schizophrenia (Sakurai et al.,
2013). Likewise, another study demonstrated that the blockade of
D2 receptors by risperidone was negatively correlated with atten-
tion in schizophrenia (Uchida et al., 2009). Another possible mech-
anism is the anticholinergic effects, which are known to impair
cognitive performance including attention, memory, and executive
functioning (Bottiggi et al., 2006; Minzenberg et al., 2004).
Anticholinergic agents are typically used to minimize extrapyrami-
dal side effects when patients are taking high doses of antipsychotic
drugs, although atypical antipsychotics are associated with a lower
risk of extrapyramidal side effects than their typical counterparts.
However, regardless of the mechanism, it is necessary for clinicians
to prescribe the smallest possible dose of atypical antipsychotics to
minimize or prevent cognitive impairment.
Rate of relapse
The relapse rate and the risk of worsened clinical psychopatholo-
gies were not increased in this study. Previous studies suggested
that the relapse rate did not increase after a dose reduction by
25–50%, and even decreased the incidence of side effects
(Rouillon et al., 2008; Uchida et al., 2011a). Furthermore, a
seven-year follow-up study showed that early dose reduction in
first-episode schizophrenia might contribute to higher long-term
recovery rates and less risk of relapse (Wunderink et al., 2013).
Similarly, Lane and colleagues found that both low (3 mg/day)
and high (6 mg/day) doses of resperidone showed the same
favorable efficacy in a pilot double-blind, six-week study for
first-episode schizophrenia (Lane et al., 2001). They also found
that when resperidone was reduce from 6 mg/day to 3.6 (±0.9)
mg/day because of intolerable side-effects, the response rates in
low dose group was higher than that in a high-dose group of
patients with acute exacerbation of schizophrenia (Lane et al.,
2000). This favorable result may be due to the following two rea-
sons. The first is that our study did not allow the dose of risperi-
done to go below 2 mg/day or the dose of olanzapine to go below
5 mg/day, in accordance with the Guidelines for the Prevention
and Treatment of Schizophrenia in China (Chinese Medical
Association, 2015). Several studies recommend a therapeutic
dose of 2–6 mg/day for risperidone and 5–20 mg/day for olan-
zapine in adults with schizophrenia (McGlashan et al., 2006;
Procyshyn et al., 2000). One study even found that the optimal
lower dose limit during maintenance treatment was 0.5 mg/day
for risperidone and 2.5 mg/day for olanzapine (Yoshimura et al.,
2017). In addition, although approximately 65–80% D2 receptor
occupancy was required for a clinical response in acute stage
treatment, the requirement for continued occupancy of the D2
receptor during the maintenance phase of treatment was consid-
ered to be lower than that of the acute phase (Uchida et al.,
2011b). Studies also suggested that D2 receptor occupancy <65%
was effective in preventing psychotic relapse during maintenance
treatment (Mizuno et al., 2012; Remington et al., 2006).
Negative symptoms
Another prominent result in this study was that negative symp-
toms assessed by the PANSS or NSA-16 showed significant
improvement after dose reduction. Atypical antipsychotics have
already proved to provide an effective improvement in primary
negative symptoms in acute schizophrenia (Burton, 2006;
Kopelowicz et al., 2000), and this superiority was one of the rea-
sons why olanzapine and risperidone became widely used in
mental health services worldwide. However, some negative
symptoms which were considered secondary were associated
with depression, drug side-effects such as extrapyramidal symp-
toms, and sedation which were dose-related in most of the atypi-
cal antipsychotics in a previous study (Gargoloff et al., 2003),
and these secondary negative symptoms were difficult to distin-
guish from primary negative symptoms (Peralta et al., 2000). In
the present study, negative symptoms were found to be improved
after dose reduction of risperidone or olanzapine, and this signifi-
cant improvement still existed even after RSESE score was
treated as a covariate. But we could not further examine whether
other factors such as depression and excessive sedation might
affect negative symptoms after dose reduction of antipsychotics
because of a lack of data.
Prescribers should re-evaluate the treatment outcome when
planning to use high doses of atypical antipsychotic drugs to pre-
vent relapse during maintenance treatment. The present results
suggested that such high-dose treatment strategies do not provide
any superiority for managing psychotic symptoms, but can lead
to more serious damage to the cognitive function of schizo-
phrenic patients. Rather, careful dose reduction may help to
improve negative symptoms and cognitive rehabilitation.
8 Journal of Psychopharmacology 00(0)
Additionally, lower doses of risperidone and olanzapine are
expected to mitigate the side-effects related to extrapyramidal
symptoms, weight gain, and elevated prolactin levels.
Limitations
Several limitations of the present study cannot be ignored. First,
with only 75 subjects, the sample size was small and might have
contributed to some type 2 errors. Second, the results were based
on risperidone and olanzapine only, and therefore were not appli-
cable to other antipsychotic drugs. Third, the single-blind design
could have unfairly affected the results. Fourth, the different
course of illness indicated that the subjects might be heterogene-
ous in terms of disease stages, some still at a relatively early stage
whereas others were at a later stage. Patients at different stages of
schizophrenia might be different in psychotherapy, social support,
and might respond differently to dosage reduction. But, the com-
parison of stratification by duration of illness and history of previ-
ous hospitalization between patients in reduction and maintenance
groups was not statistically significant, which meant the groups
were overall similar in terms of disease stage. Finally, medication
adherence was an important factor that may affect recurrence.
However, objective information about medication adherence was
not gathered in this study. Further studies with more samples
should be conducted to explore the specific relation between a
variety of antipsychotic drugs and cognitive function.
Conclusions
Our findings show that careful dose reduction during mainte-
nance treatment does not lead to a higher risk of relapse and can
improve cognitive function and alleviate the psychopathological
syndrome, particularly negative symptoms. Thus, the dose of
atypical antipsychotics may be reduced during the maintenance
phase for patients with schizophrenia, although these preliminary
findings were based on risperidone and olanzapine only and
should be confirmed in further studies that include other antipsy-
chotic drugs.
Acknowledgements
The authors wish to acknowledge the patients participating in the trial and
contributions of all investigators. Contributors to the article were as fol-
lows: Yuping Ning wrote the study protocol; Yanling Zhou, Guannan Li,
Dan Li, and Hongmei Cui collected the data; Yanling Zhou undertook the
statistical analysis and wrote the first draft of the manuscript; Yuping Ning
carried out final preparation. All authors contributed to, and have approved,
the final manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: This study
was supported by the Planed Science and Technology Projects of
Guangzhou (grant number 201607010131), Guangzhou Municipal
Key Discipline in Medicine (2017-2019), Science and Technology
Department of Guangdong Province major science and technology
(grant number 2016B010108003) and National R&D program focused
on precision medical research of China (grant number
2016YFC0906302). The funding sources had no role in the study
design, analysis, or interpretation of data, or in the preparation of the
report or decision to publish.
References
Alphs LD, Summerfelt A, Lann H, et al. (1989) The negative symp-
tom assessment: A new instrument to assess negative symptoms of
schizophrenia. Psychopharmacol Bull 25: 159–163.
American Psychiatric Association (2000) Diagnostic and statistical
manual of mental disorders (4th ed., text revision). Washington, DC:
American Psychiatric Association.
Chinese Medical Association (2015) Guideline for the Prevention and
Treatment of Schizophrenia in China, 2nd edn. Beijing: Chinese
Medical Association.
Baldessarini RJ, Viguera AC, Faedda GL, et al. (1995) Neuroleptic
withdrawal in schizophrenic patients. Arch Gen Psychiatry 52:
200–202.
Barnes TR (2011) Evidence-based guidelines for the pharmacological
treatment of schizophrenia: Recommendations from the British Asso-
ciation for Psychopharmacology. J Psychopharmacol 25: 567–620.
Bottiggi KA, Salazar JC, Yu L, et al. (2006) Long-term cognitive impact
of anticholinergic medications in older adults. Am J Geriatr Psychia-
try 14: 980–984.
Burton S (2006) Symptom domains of schizophrenia: The role of atypical
antipsychotic agents. J Psychopharmacol 20(Suppl 6): 6–19.
David SR, Taylor CC, Kinon BJ, et al. (2000) The effects of olanzapine,
risperidone, and haloperidol on plasma prolactin levels in patients
with schizophrenia. Clin Ther 22: 1085–1096.
Dixon LB, Dickerson F, Bellack AS, et al. (2010) The 2009 schizophre-
nia PORT psychosocial treatment recommendations and summary
statements. Schizophr Bull 36: 48–70.
Elie D, Poirier M, Chianetta J, et al. (2010) Cognitive effects of antipsy-
chotic dosage and polypharmacy: A study with the BACS in patients
with schizophrenia and schizoaffective disorder. J Psychopharmacol
24: 1037–1044.
Gargoloff PR, O’Halloran RA, Boland JM, et al. (2003) Change in clini-
cal status and side effects of patients treated with either olanzapine or
risperidone: Six-month results from the three-year intercontinental
schizophrenia outpatient health outcomes (IC-SOHO) observational
study. Schizophr Res 60: 283–284.
Green MF, Marder SR, Glynn SM, et al. (2002) The neurocognitive
effects of low-dose haloperidol: A two-year comparison with risperi-
done. Biol Psychiatry 51: 972–978.
Ho BC, Andreasen NC, Ziebell S, et al. (2011) Long-term antipsychotic
treatment and brain volumes: A longitudinal study of first-episode
schizophrenia. Arch Gen Psychiatry 68: 128–137.
Kane JM, Leucht S, Carpenter D, et al. (2003) Optimizing pharmacologic
treatment of psychotic disorders. Introduction: Methods, commen-
tary, and summary. J Clin Psychiatry 64: 1–100.
Kawai N, Yamakawa Y, Baba A, et al. (2006) High-dose of multiple anti-
psychotics and cognitive function in schizophrenia: The effect of dose-
reduction. Prog Neuropsychopharmacol Biol Psychiatry 30: 1009–1014.
Kay SR, Fiszbein A and Opler LA (1987) The positive and negative
syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:
261–276.
Knowles EE, David AS and Reichenberg A (2010) Processing speed def-
icits in schizophrenia: Reexamining the evidence. Am J Psychiatry
167: 828–835.
Kopelowicz A, Zarate R, Tripodis K, et al. (2000) Differential efficacy of
olanzapine for deficit and nondeficit negative symptoms in schizo-
phrenia. Am J Psychiatry 157: 987–993.
Krueger C and Tian L (2004) A comparison of the general linear mixed
model and repeated measures ANOVA using a dataset with multiple
missing data points. Biol Res Nurs 6: 151–157.
Zhou et al. 9
Lane HY, Chang WH, Chiu CC, et al. (2001) A pilot double-blind, dose-
comparison study of risperidone in drug-naive, first-episode schizo-
phrenia. J Clin Psychiatry 62: 994–995.
Lane HY, Chiu WC, Chou JC, et al. (2000) Risperidone in acutely exac-
erbated schizophrenia: Dosing strategies and plasma levels. J Clin
Psychiatry 61: 209–214.
Lehman AF, Kreyenbuhl J, Buchanan RW, et al. (2010) The schizophre-
nia Patient Outcomes Research Team (PORT): Updated treatment
recommendations 2003. Schizophr Bull 36: 94.
Lehman AF, Lieberman JA, Dixon LB, et al. (2004) Practice guideline
for the treatment of patients with schizophrenia, second edition. Am
J Psychiatry 161(Suppl 2): 1–56.
Li Q, Xiang YT, Su YA, et al. (2015) Antipsychotic polypharmacy in schizo-
phrenia patients in China and its association with treatment satisfaction
and quality of life: Findings of the third national survey on use of psy-
chotropic medications in China. Aust N Z J Psychiatry 49: 129–136.
McGlashan TH, Zipursky RB, Perkins D, et al. (2006) Randomized, dou-
ble-blind trial of olanzapine versus placebo in patients prodromally
symptomatic for psychosis. Am J Psychiatry 163: 790–799.
Minzenberg MJ, Poole JH, Benton C, et al. (2004) Association of anti-
cholinergic load with impairment of complex attention and memory
in schizophrenia. Am J Psychiatry 161: 116–124.
Mizuno Y, Bies RR, Remington G, et al. (2012) Dopamine D2 receptor
occupancy with risperidone or olanzapine during maintenance treat-
ment of schizophrenia: A cross-sectional study. Prog Neuropsycho-
pharmacol Biol Psychiatry 37: 182–187.
Nagaendran K, Chen LH, Chong MS, et al. (2011) Ministry of health
clinical practice guidelines: Dementia. Singapore Med J 52: 293–298.
Nuechterlein KH, Barch DM, Gold JM, et al. (2004) Identification of sep-
arable cognitive factors in schizophrenia. Schizophr Res 72: 29–39.
Nuechterlein KH, Green MF, Kern RS, et al. (2008) The MATRICS con-
sensus cognitive battery, part 1: Test selection, reliability, and valid-
ity. Am J Psychiatry 165: 203–213.
Peralta V, Cuesta MJ, Martinezlarrea A, et al. (2000) Differentiating pri-
mary from secondary negative symptoms in schizophrenia: A study
of neuroleptic-naive patients before and after treatment. Am J Psy-
chiatry 157: 1461–1466.
Procyshyn DRM, Thompson D and Tse G (2000) Pharmacoeconomics of
clozapine, risperidone and olanzapine. CNS Drugs 13: 47–76.
Remington G, Mamo D, Labelle A, et al. (2006) A PET study evaluating
dopamine D2 receptor occupancy for long-acting injectable risperi-
done. Am J Psychiatry 163: 396–401.
Robinson DG, Schooler NR, John M, et al. (2015) Medication p­ rescription
practices for the treatment of first episode s­ chizophrenia-spectrum
disorders: Data from the national RAISE-ETP study. Am J Psychia-
try 172: 237–248.
Rouillon F, Chartier F and Gasquet I (2008) Strategies of treatment with
olanzapine in schizophrenic patients during stable phase: Results of
a pilot study. Eur Neuropsychopharmacol 18: 646–652.
Sakurai H, Bies RR, Stroup ST, et al. (2013) Dopamine D2 receptor
occupancy and cognition in schizophrenia: Analysis of the CATIE
data. Schizophr Bull 39: 564–574.
Sim K, Su HC, Fujii S, et al. (2009) High-dose antipsychotic use in
schizophrenia: A comparison between the 2001 and 2004 Research
on East Asia Psychotropic Prescription (REAP) studies. Br J Clin
Pharmacol 67: 110–117.
Simpson GM and Angus JW (1970) A rating scale for extrapyramidal
side effects. Acta Psychiatr Scand Suppl 212: 11–19.
Suzuki T, Uchida H, Tanaka KF, et al. (2003) Reducing the dose of
antipsychotic medications for those who had been treated with
high-dose antipsychotic polypharmacy: An open study of dose
reduction for chronic schizophrenia. Int Clin Psychopharmacol
18: 323–329.
Takeuchi H, Suzuki T, Remington G, et al. (2013) Effects of risperi-
done and olanzapine dose reduction on cognitive function in stable
patients with schizophrenia: An open-label, randomized, controlled,
pilot study. Schizophr Bull 39: 993–998.
Torniainen M, Mittendorferrutz E, Tanskanen A, et al. (2014) Anti-
psychotic treatment and mortality in schizophrenia. Schizophr Bull
41: 656.
Uchida H, Rajji TK, Mulsant BH, et al. (2009) D2 receptor blockade by
risperidone correlates with attention deficits in late-life schizophre-
nia. J Clin Psychopharmacol 29: 571–575.
Uchida H, Suzuki T, Takeuchi H, et al. (2011a) Low dose vs standard
dose of antipsychotics for relapse prevention in schizophrenia: Meta-
analysis. Schizophr Bull 37: 788–799.
Uchida H, Takeuchi H, Graffguerrero A, et al. (2011b) Dopamine D2
receptor occupancy and clinical effects: A systematic review and
pooled analysis. J Clin Psychopharmacol 31: 497–502.
Wunderink L, Nieboer RM, Wiersma D, et al. (2013) Recovery in remit-
ted first-episode psychosis at 7 years of follow-up of an early dose
reduction/discontinuation or maintenance treatment strategy: Long-
term follow-up of a 2-year randomized clinical trial. JAMA Psychia-
try 70: 913–920.
Yoshimura Y, Takeda T, Kishi Y, et al. (2017) Optimal dosing of ris-
peridone and olanzapine in the maintenance treatment for patients
with schizophrenia and related psychotic disorders: A retrospective
multicenter study. J Clin Psychopharmacol 37: 296–301.