JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 28, Number 4, 2018 Original Articles

Mary Ann Liebert, Inc.
Pp. 244–251
DOI: 10.1089/cap.2017.0120

Olanzapine Versus Risperidone in Children

and Adolescents with Psychosis:
A Meta-Analysis of Randomized Controlled Trials

Lei Xia, MD,1,2 Wen-Zheng Li, MD,2 Huan-Zhong Liu, MD, PHD,1,2,
Rui Hao, MD,1,2 and Xiang-Yang Zhang, MD, PHD1–3

Abstract
Objective: To compare the efficacy and safety of olanzapine and risperidone in children and adolescents (aged £18 years) with
psychosis by conducting a meta-analysis of randomized controlled trials (RCTs).
Methods: Several English and Chinese databases were searched for studies published before February 8th, 2017. Two
independent investigators screened the studies according to prespecified criteria and extracted the data. Review Manager 5.3
was used to conduct the data synthesis.
Results: Eight RCTs involving 457 participants (225 participants in the olanzapine group and 232 participants in the
risperidone group) were included. No significant differences were observed in the mean scores on the Positive and Negative
Syndrome Scale/Brief Psychiatric Rating Scale (standard mean difference [SMD] = -0.06, 95% confidence intervals
[CI] = [-0.31, 0.19], p = 0.63), the positive symptom scores (SMD = -0.09, 95% CI = [-0.32, 0.15], p = 0.48), or the negative
symptom scores (SMD = -0.11 95% CI = [-0.34, 0.13], p = 0.38) between the two groups. Regarding adverse effects, the
mean increases in weight (MD = 2.90, 95% CI = [1.41, 4.39], p = 0.0001), body mass index (MD = 0.90, 95% CI = [0.42,
1.38], p = 0.0003), and incidence of hypersomnia (risk ratios [RR] = 1.98, 95% CI = [1.15, 3.43], p = 0.01) were higher in the
olanzapine group, while the incidence of insomnia (RR = 0.31, 95% CI = [0.11, 0.85], p = 0.02), prolactin elevation
(RR = 0.11, 95% CI = [0.01, 0.85], p = 0.03), myotonia (RR = 0.12, 95% CI = [0.03, 0.49], p = 0.003), tremor (RR = 0.22, 95%
CI = [0.08, 0.63], p = 0.005), and akathisia (RR = 0.27, 95% CI = [0.12, 0.57], p = 0.0007) was higher in the risperidone group.
Conclusions: There is no significant difference in efficacy between olanzapine and risperidone for the treatment of children
and adolescents with psychosis, but the side effect profiles of these two medications differ. High-quality RCTs are needed
before recommending clinical treatment in children and adolescents.

Keywords: olanzapine, risperidone, antipsychotics, children and adolescents, meta-analysis

Introduction rate (Ropcke and Eggers 2005; Remschmidt et al. 2007). More safe
and effective treatments are needed for these vulnerable youths.

S chizophrenia and other psychoses often present in child-

hood and adolescence with consequent impairments in psy-
chosocial functioning and quality of life. Early-onset psychosis (EOP,
Antipsychotic medication is the mainstay for the clinical treat-
ment of mental diseases and functions differently in youths and
adults. Weight gain and metabolic disturbances are more likely to
age of onset before 18 years) is considered a more severe disorder than occur in children and adolescents than in adults who take anti-
adult-onset psychosis and is accompanied by a higher level of nega- psychotic drugs (Arango et al. 2016; Baeza et al. 2017). The use of
tive and nonspecific symptoms (Garcı́a et al. 2013). Patients with EOP antipsychotics in children and adolescents has been controversial.
have a poor prognosis, severe depressive symptoms, and a high death In Europe and the United States, the clinical trials are expensive.

1
Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, China.
2
Department of Psychiatry, Anhui Psychiatric Center, Anhui Medical University, Hefei, China.
3
Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas.
Funding: This study was funded by the open project foundation of the Collaborative Innovation Center for Neuropsychiatric Diseases and Mental
Health in Anhui Medical University: Neuropsychological Study of Childhood Schizophrenia (Code: NDMHCI-16-02).
ª Lei Xia et al. 2018; Published by Mary Ann Liebert, Inc. This article is available under the Creative Commons License CC-BY-NC (http://
creativecommons.org/licenses/by-nc/4.0). This license permits non-commercial use, distribution and reproduction in any medium, provided the original
work is properly cited. Permission only needs to be obtained for commercial use and can be done via RightsLink.

244
OLANZAPINE VERSUS RISPERIDONE IN CHILDREN AND ADOLESCENTS 245

Many ethical restrictions and no clear financial incentive to perform lescents with schizophrenia, followed by risperidone (21.9%).
pediatric efficacy or safety trials support have resulted in a lack of Thus, we conducted this meta-analysis of RCTs obtained from both
relevant clinical trials. In the United States, only five new antipsy- English and Chinese language databases to compare the efficacy
chotics (i.e., aripiprazole, olanzapine, paliperidone, quetiapine, and and safety of olanzapine and risperidone for the treatment of chil-
risperidone) have been approved by the American Food and Drug dren and adolescents with psychosis.
Administration for the treatment of schizophrenia in children and
adolescents. Second-generation antipsychotics (SGAs) are preferred Methods
over first-generation antipsychotics for the treatment of children and
Search strategy and selection criteria
adolescents due to their typical lower rates of extrapyramidal
symptoms (EPS) and tardive dyskinesia (Correll et al. 2006; Correll We systematically searched English (i.e., PubMed, Embase, and the
and Kane 2007). Previous knowledge regarding SGAs was largely Cochrane Library) and Chinese (i.e., VIP service platform, Chinese
obtained from studies involving adults with psychosis. Clinical trials, Biomedical Literature Service System [CBM], Chinese National
particularly active-controlled trials involving children and adolescents Knowledge Infrastructure [CNKI], and WANFANG DATA) data-
with psychosis, have been limited, and their sample sizes have been bases for RCTs that compared the efficacy and safety of olanzapine
small. It turns out that active-control trials with large samples in and risperidone in the treatment of children and adolescents with
pediatric patients do exist, but they are usually industry sponsored or psychosis and were published before February 8, 2017 using the fol-
drug companies tend not to publish unless their drug does better. lowing terms and combinations of Chinese equivalent words: ‘‘olan-
Olanzapine and risperidone, which are the two most commonly zapine’’ AND ‘‘risperidone’’ AND (‘‘children’’ OR ‘‘adolescent’’)
used SGAs, play important roles in the treatment of children and AND (‘‘schizophrenia’’ OR ‘‘psychosis’’ OR ‘‘schizophrenia spectrum
adolescents with psychosis. A systematic review and meta-analysis and other psychotic disorders’’). To avoid omissions, we inspected the
(Kumar et al. 2013) of studies obtained from the Cochrane Library references of all identified studies to identify additional relevant
compared olanzapine with risperidone in youth, but included only studies.
2 randomized controlled trials (RCTs) with merely 111 participants. According to the principle of PICOS in evidence-based medi-
Furthermore, few RCTs have been included in other relevant re- cine, studies were included if they met the following criteria:
views or meta-analyses (Seida et al. 2012; Harvey et al. 2016), and Participants: all subjects aged £18 years with a diagnosis of a
all have been obtained from English-language databases. Accord- schizophrenia spectrum or other psychotic disorder; Intervention
ing to a 5-year survey (Yan and Cui 2016), olanzapine has been and Comparison: olanzapine and risperidone; Outcomes: efficacy
used most frequently (24.6%) in China to treat children and ado- and safety; and Study design: only RCTs. The following studies and

FIG. 1. Flowchart of study selection.

 Table 1. Study Characteristics

Clinical
Diagnosis response
Dose Age Trial excellence,
OLA/RIS OLA/RIS Sample duration Blind SCH Adverse improvement Dropout
Study Group (mg/day) (years) size (weeks) assessment Criteria N (%) Efficacy effects N (%) N (%)

Sikich et al. (2004) OLA 12.3 – 4.5 14.6 – 3.1 16 8 DB K-SADS 5 (31)a BPRS-C AIMS 14 (88) 3 (18.8)
RIS 3.3 – 1.5 14.6 – 2.9 19 SCID 13 (68)a CRPS SAS 14 (74) 11 (57.9)
HAL CGI
Huang et al. (2006) OLA 7.8 – 3. 4 14.1 – 1.7 34 8 OL CCMD-3 34 (100) BPRS TESS 21 (61.8), 29 (85.3) 1 (2.9)
RIS 3.5 – 1.6 13.7 – 2.1 32 32 (100) 17 (53.1), 25 (78.1) 3 (9.4)
Mozes et al. (2006) OLA 8.18 – 4.41 11.5 – 1.64 12 12 OL K-SADS 6 (50) PANSS SAS 5 (41.7), 8 (66.7) 1 (8.3)
RIS 1.62 – 1.02 10.71 – 1.43 13 DSM-IV 9 (69) BPRS BAS 4 (30.8), 6 (46.2) 4 (30.7)
Sikich et al. (2008) OLA 11.4 – 5.0 8–19 35 8 DB DSM-IV 22 (63) PANSS SAS 12 (34) 18 (51.4)

246
RIS 2.8 – 1.4 41 BA 28 (68) BPRS-C BAS 19 (46)
MOL CGI AIMS 13 (31.7)
Wei (2010) OLA 10–20 15.1 – 1.7 28 8 OL CCMD-3 28 (100) BPRS TESS 16 (57.1), 25 (89.3) 0 (0)
RIS 2–6 14.8 – 1.9 27 27 (100) 15 (55.6), 22 (81.5) 1 (3.6)
Liu and Yan (2015) OLA £ 20 13.6 – 3.2 30 8 NA CCMD-3 30 (100) PANSS TESS 24 (80), 28 (93.3) NA
RIS £5 11.4 – 2.9 30 30 (100) 24 (80), 27 (90.0)
Qi et al. (2016) OLA 11.8 – 2.9 7–16 40 8 BA CCMD-3 40 (100) PANSS TESS 21 (52.5), 35 (87.5) NA
RIS 3.4 – 1.1 40 40 (100) 24 (60.0), 36 (90.0)
Jiang and Gu (2016) OLA £ 15 10. 1 – 4.2 30 8 NA NA 30 (100) BPRS TESS 14 (46.7), 28 (93.3) NA
RIS £4 9. 5 – 4.1 30 30 (100) PANSS 12 (40.0), 26 (86.7)
a
The study only reported the number of patients with schizophrenia spectrum disorders.
NA, no information available; OLZ, olanzapine; RIS, risperidone; HAL, haloperidol; MOL, molindone; SCH, schizophrenia; DB, double blind; OL, open label; BA, blind assessor; AIMS, Abnormal Involuntary
Movement Scale; BAS, Barnes Akathisia Rating Scale; BPRS, the Brief Psychiatric Rating Scale; BPRS-C, the Brief Psychiatric Rating Scale for Children total score; CCMD-3, 3rd edition of Chinese Classification of
Mental Disorders; CGI, Clinical Global Impression; CRPS, the Children’s Psychiatric Rating Scale; DSM-IV, 4th edition of Diagnostic and Statistical Manual of Mental Disorder; K-SADS, Kiddies Schedule for
Affective Disorders and Schizophrenia; PANSS, Positive and Negative Syndrome Scale; SAS, Simpson-Angus scale; SCID, the Structured Clinical Interview for DSM-IV; TESS, Treatment Emergent Symptoms Scale.
OLANZAPINE VERSUS RISPERIDONE IN CHILDREN AND ADOLESCENTS 247

Table 2. Risk of Bias and Jadad Scores

Random Blinding of Blinding of Incomplete

sequence Allocation participants outcome outcome Selective Other Jadad
Study generation concealment and personnel assessment data reporting biases score

Sikich et al. (2004) L NA L NA H NA NA 5

Huang et al. (2006) NA NA H NA L NA NA 2
Mozes et al. (2006) NA NA H NA H NA NA 2
Sikich et al. (2008) NA L L L H L NA 6
Wei (2010) NA NA H NA L NA NA 2
Liu and Yan (2015) L NA NA NA NA NA NA 3
Qi et al. (2016) NA NA NA L NA NA NA 2
Jiang and Gu (2016) NA NA NA NA NA NA NA 1

NA, no information available; L, low risk; H, high risk.

articles were excluded: observational studies, retrospective studies, tion (GRADE) (Guyatt et al. 2008). The overall level of each outcome
animal studies, reviews, and duplicate articles. was marked as ‘‘high,’’ ‘‘moderate,’’ ‘‘low,’’ or ‘‘very low.’’

Data extraction and outcome measures Data synthesis and statistical analysis

Potentially relevant studies were screened using Endnote X6 by Different effect measures were chosen and analyzed using Re-
two independent investigators (L.X. and W.-Z.L.) according to the view Manager Version 5.3 software according to the data type. We
prespecified criteria. The following data were extracted from the obtained the 95% confidence intervals (CIs) and drew forest maps
studies: authors, year of publication, group status (types and doses to perform the data analysis. The mean difference (MD) was cal-
of antipsychotics and sample size), duration, blind evaluation, age culated for continuous data acquired using the same methods (e.g.,
of subjects, diagnoses, and outcome measures. Any disagreements weight and BMI). The standard MD (SMD) was calculated for con-
were addressed by a discussion between the two investigators to tinuous data acquired using different methods (e.g., scores of different
reach a consensus. Otherwise, a third senior investigator (H.-Z.L.) scales). Risk ratios (RRs) with the 95% Cl were calculated for
was involved in the discussion as a final arbiter. dichotomous data (e.g., incidence of adverse events). Statistical
The main outcome measure of efficacy was the total score on the differences were considered significant at p < 0.05.
Positive and Negative Syndrome Scale (PANSS) (Kay et al. 1987) The study heterogeneity was estimated using I2 and chi-square test
or the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham of homogeneity (Higgins et al. 2003). If p > 0.10 and i2 < 50%, which
1962). The secondary outcomes were the scores on the positive and indicated homogeneity, a fixed-effect model was used. If p £ 0.10 or
negative symptom subscale of the PANSS or the Children’s Psy- 50%£I2 £ 75%, which indicated significant heterogeneity, a random-
chiatric Rating Scale (CPRS) (Fish 1985). The main outcome effect model was used. If I2 > 75%, we either conducted an exclusive
measures of side effects included changes in weight and body mass sensitivity analysis or abandoned the meta-analysis.
index (BMI) and the incidence of various adverse events.
Results
Quality assessment Study characteristics
The quality of each study was assessed using the Cochrane Risk of The search initially identified 1649 potentially relevant studies.
Bias (ROB) tool (Higgins and Julian 2008), including seven specific After removing duplicate records and screening according to the
aspects, and the Jadad scale (Jadad et al. 1996) (high quality ‡3 and low prespecified criteria, eight RCTs (Sikich et al. 2004, 2008; Huang
quality <3). The quality of the overall evidence was assessed using the et al. 2006; Mozes et al. 2006; Wei 2010; Liu and Yan 2015; Jiang
Grades of Recommendation, Assessment, Development, and Evalua- and Gu 2016; Qi et al. 2016) were ultimately included (Fig. 1).

FIG. 2. Forest plot used to compare the total scores on the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale
between the olanzapine and risperidone groups in children and adolescents with psychosis. SD, standard deviation; CI, confidence
interval.
248 XIA ET AL.

FIG. 3. Forest plot used to compare the subscale scores between the olanzapine and risperidone groups in children and adolescents
with psychosis. SD, standard deviation; CI, confidence interval.

Three articles (Sikich et al. 2004, 2008; Mozes et al. 2006) were and Gu 2016); reduction in the PANSS total score ‡50% and ‡25%,
published in English and five articles (Huang et al. 2006; Wei 2010; respectively (Liu and Yan 2015); and four grades of response as-
Liu and Yan 2015; Jiang and Gu 2016; Qi et al. 2016) in Chinese. sessments—cure, excellence, improvement, and failure (Huang et al.
Since we systematically searched four main Chinese databases, five 2006; Wei 2010; Qi et al. 2016). When necessary, two formulae were
out of the eight studies meeting our screening criteria were from the used to calculate the rates of clinical response:
Chinese-language literature.
Table 1 lists the eight RCTs, which involved 457 participants Rateexcellence ¼ (Ncure þ Nexcellence )=Ntotal · 100%;


(sample size range, 25–80 patients). The mean trial duration was Rateimprovent ¼ Ncure þ Nexcellence þ Nimprovent =Ntotal · 100%:
8.5 weeks (range, 8–12 weeks). Six studies included two groups,
that is, olanzapine versus risperidone, and two studies included three
groups. Among these studies, five studies were conducted in China
ROB and Jadad score
(n = 321), two studies in the United States (n = 111), and one study
in Israel (n = 25). Different scales were used to assess efficacy and The ROB in each study was assessed based on seven items
safety in these studies. (Table 2). Most items were considered ‘‘unclear risk’’ because of
The rates of clinical response in the groups per study are shown in the lack of specific details regarding the research methods used in
Table 1. Five studies (Sikich et al. 2004, 2008; Huang et al. 2006; the studies. Only one RCT reported the method of allocation con-
Mozes et al. 2006; Wei 2010) reported the rates and reasons of drop- cealment, specifically stating that the medications were packaged
outs in details. The criteria used to determine clinical response varied in identical color-coded capsules, and two RCTs described a rea-
across studies: CGI-I of ‘‘1’’ or ‘‘2’’ and reduction in the BPRS-C total sonable generation of a random sequence. In three non-Chinese
score ‡20% (Sikich et al. 2004); CGI-I of ‘‘1’’ or ‘‘2’’ and reduction in RCTs, many participants dropped out (Discontinuation: n ‡ 20%),
the PANSS total score ‡20% (Sikich et al. 2008); reduction in the and an intent-to-treat analysis was used for incomplete outcome
PANSS total score ‡50% and ‡30%, respectively (Mozes et al. 2006); data. Of these eight RCTs, two RCTs were double blind, three
reduction in the BPRS total score ‡75% and ‡30%, respectively ( Jiang RCTs were open label, and two RCTs used a blind assessor. The

Table 3. Comparisons of Weight Changes and Body Mass Index Changes Between
the Olanzapine and Risperidone Groups

No. of Sample Analytic Mean difference

Index (change) studies size I2 p model [95% CI]

Weight 4 211 62% 0.05 Random 2.90 [1.41, 4.39]

BMI 2 111 0% 1.00 Fixed 0.90 [0.42, 1.38]
Cholesterol 1 34 Not applicable — Fixed 30.10 [12.57, 47.63]
Triglycerides 1 33 Not applicable — Fixed 14.50 [-25.10, 54.10]
Prolactin 1 76 Not applicable — Fixed -21.00 [-30.39, -11.61]
QTc 1 76 Not applicable — Fixed -10.70 [0.09, 21.31]

Statistical differences are bold.

BMI, body mass index; QTc, QTc interval; CI, confidence interval.
OLANZAPINE VERSUS RISPERIDONE IN CHILDREN AND ADOLESCENTS 249

Table 4. Comparison of the Incidence of 33 Different Adverse Events Between

the Olanzapine and Risperidone Groups

No. of
Adverse event (incidence) studies Sample size I2, % p Analytic model Risk ratio [95% CI]

Excitement or agitation 2 135 0 0.83 fixed 0.25 [0.03, 2.15]

Hypersomnia 5 276 0 0.71 fixed 1.98 [1.15, 3.43]
Insomnia 4 255 0 0.89 fixed 0.31 [0.11, 0.85]
Abnormal liver function/enzymes 3 201 41 0.03 fixed 1.71 [0.66, 4.42]
Prolactin increase 2 120 0 0.04 fixed 0.11 [0.01, 0.85]
Granulopenia 1 55 — — not applicable 0.19 [0.01, 3.85]
Myotonia 4 255 0 0.82 fixed 0.12 [0.03, 0.49]
Tremors 4 255 0 0.67 fixed 0.22 [0.08, 0.63]
Torsional motion 1 80 — — not applicable 0.14 [0.01, 2.68]
Akathisia 5 280 37 0.17 fixed 0.27 [0.12, 0.57]
EPS 2 91 89 0.003 not applicable 0.38 [0.04, 3.74]
Dry mouth 4 221 0 0.42 fixed 1.24 [0.53, 2.91]
Blurred vision 4 241 0 0.67 fixed 0.55 [0.19, 1.66]
Constipation 4 210 0 0.76 fixed 1.74 [0.55, 5.50]
Increased salivation 2 115 0 0.56 fixed 0.30 [0.05, 1.76]
Nausea 1 35 — — not applicable 0.17 [0.01, 3.03]
Sudation 1 80 — — not applicable 0.50 [0.05, 5.30]
Dizziness 4 236 0 0.49 fixed 1.41 [0.45, 4.41]
Sychnosphygmia 3 201 31 0.23 fixed 0.67 [0.21, 2.17]
Arrhythmia 2 120 20 0.26 fixed 0.71 [0.15, 3.50]
Abnormal T-wave 1 55 — — not applicable 3.12 [0.30, 32.03]
Skin symptom 2 90 0 0.95 fixed 0.18 [0.02, 1.43]
Weight gain 4 255 4 0.37 fixed 1.37 [0.65, 2.91]
Anorexia 1 55 — — not applicable 0.32 [0.01, 7.57]
Headache 3 155 0 0.90 fixed 0.79 [0.27, 2.30]
Abnormal electroencephalogram, 1 55 — — not applicable 0.96 [0.06, 14.65]
urinary retention 1 35 — — not applicable 3.53 [0.15, 81.11]
Nervousness 1 35 — — not applicable 2.38 [0.24, 23.84]
Dysuria 1 35 — — not applicable 3.53 [0.15, 81.11]
Weakness 1 35 — — not applicable 1.19 [0.08, 17.51]
Irregular mensesa 1 13 — — not applicable 0.86 [0.07, 10.96]
Musculoskeletal Pain 1 35 — — not applicable 2.38 [0.50, 11.32]
Decreased coordination 1 35 — — not applicable 3.53 [0.15, 81.11]

Statistical differences are bold.

a
The sample size of this item included the number of females only.
EPS, extrapyramidal symptoms.

mean Jadad score of the eight RCTs was 2.9 (range, 1–6) and the ference was observed in either the positive symptom score (SMD =
high-quality RCTs accounted for 37.5% (3/8 RCTs). -0.09, 95% CI = [-0.32, 0.15], p = 0.48) or the negative symptom
score (SMD = -0.11, 95% CI = [-0.34, 0.13], p = 0.38) between the
Efficacy two groups. According to the criteria of the GRADE approach, the
quality of the evidence of the outcome measures of the total, positive,
Since the outcome measure of efficacy was assessed using different
and negative symptom scores was rated as ‘‘moderate.’’
scales (PANSS: three RCTs; BPRS: three RCTs; and both: two
RCTs), the SMD was used in the meta-analysis. The I2-value was
Adverse side effects
acceptable. However, the corresponding p-value was too small
(I2 = 38%, p = 0.05). Hence, we used a random-effect model. The re- The adverse side effects were reported in all eight RCTs (Ta-
sults of the meta-analysis showed no significant differences in the total ble 1), five (Huang et al. 2006; Wei 2010; Liu and Yan 2015; Jiang
scores on the PANSS or BPRS between the two groups (SMD = -0.06, and Gu 2016; Qi et al. 2016) of which used the Treatment Emergent
95% CI = [-0.31, 0.19], p = 0.63) (Fig. 2). Furthermore, a sensitivity Symptoms Scale (TESS) (Zhang 1998). The changes in weight
analysis was performed after excluding Wei’s study as an outlier. The (MD = 2.90, 95% CI = [1.41, 4.39], p = 0.0001, kg) and BMI
I2 value was reduced to 5% (I2 = 5%, p = 0.39) and there was still no (MD = 0.90, 95% CI = [0.42, 1.38], p = 0.0003, kg/m2) were sig-
statistical difference in total score between olanzapine and risperidone nificantly higher in the olanzapine group than those in the risper-
groups (SMD = -0.13, 95% CI = [-0.33, 0.06], p = 0.19). idone group (Table 3). The quality of the evidence was rated as
The positive and negative symptom scores of the 276 patients in 5 ‘‘moderate’’ according to the GRADE criteria.
RCTs (Sikich et al. 2004, 2008; Mozes et al. 2006; Liu and Yan 2015; Table 4 displays a comparison of the incidence of 33 different
Qi et al. 2016) were compared using the SMD (CPRS: 1 RCTs and adverse events between the olanzapine and risperidone groups. The
PANSS: 4 RCTs). Figure 3 presents the homogeneity in both the RR is shown for each item, and a fixed-effect model was used. The
positive ( p = 0.72, I2 = 0%) and negative ( p = 0.66, I2 = 0%) symptom incidence of hypersomnia/sedation (RR = 1.98, 95% CI = [1.15,
scores. Therefore, a fixed-effect model was used. No significant dif- 3.43], p = 0.01) was higher in the olanzapine group, while the
250 XIA ET AL.

incidence of insomnia (RR = 0.31, 95% CI = [0.11, 0.85], p = 0.02), ciated with activity that occurs at several different receptors (i.e.,
prolactin elevation (RR = 0.11, 95% CI = [0.01, 0.85], p = 0.03), H1, 5-HT2A, 5-HT2C, M3, and adrenergic receptors). Currently,
myotonia (RR = 0.12, 95% CI = [0.03, 0.49], p = 0.003), tremor more attention is focused on the H1 receptor (Roerig et al. 2011).
(RR = 0.22, 95% CI = [0.08, 0.63], p = 0.005), or akathisia Due to the widespread interpersonal variation in the sensitivity to
(RR = 0.27, 95% CI = [0.12, 0.57], p = 0.0007) was higher in the antipsychotics, there are no drugs or fixed doses that can achieve a
risperidone group. The quality of this evidence was rated as ‘‘low.’’ clinical response without any side effects. Further studies that
specifically target the pediatric population are needed. Moreover,
Discussion the rates of response for both SGAs are generally <50% in children
and adolescents, with some side effects. Thus, we should individ-
Main findings
ualize the drug choice and dosage regimen for the treatment of
This meta-analysis of 8 RCTs involving 457 participants found no these pediatric patients. However, it is noteworthy that the D2 re-
significant differences in the mean score on the PANSS/BPRS or in ceptor occupancy argument for efficacy and adverse effects is
the positive or negative symptom scores between the olanzapine and complicated. The presence of EPS and neuroleptic malignant syn-
risperidone groups. Based on the GRADE criteria, the quality of this drome with antipsychotics is prima facie evidence that all of them are
evidence was ‘‘moderate.’’ Altogether, there is no difference in effi- capable of occupying sufficient D2 receptors to induce side effects.
cacy between olanzapine and risperidone for the treatment of children Disparate results have been generated based on species (humans,
and adolescents with psychosis. However, it is worthy of mention that monkeys, and rats), imaging modality (PET vs. SPECT), and
it is hard to interpret the study results without evaluating the ‘‘ade- dosing. Functional features such as intrinsic efficacy likely play a
quacy’’ of the included trials. From the literature, we did not know substantial role in efficacy and adverse effects, independent of re-
whether they all reached therapeutic doses (chlorpromazine equiva- ceptor occupancy (Iyo et al. 2013; Marazziti et al. 2016).
lent) and sustained these therapeutic doses for sufficient duration, and
whether those doses were maximal efficacy (which can exceed 30 mg Limitations
for olanzapine). Thus, this conclusion that risperidone and olanzapine
There are several limitations to our study. First, few RCTs evalu-
are equivalent in efficacy may be statistically accurate; however,
ating the use of SGAs in children or adolescents were found, and most
Figure 2 suggests a clear trend toward olanzapine superiority for total
studies involving adults were removed during the screening process.
PANSS and BPRS scores. Taken together, whether the clinical effi-
The use of antipsychotics in the pediatric population remains con-
cacy of olanzapine for the treatment of children and adolescents with
troversial, and conditions are difficult to control in clinical trials.
psychosis is equivalent or superior to risperidone will need to be
Second, the overall quality of the studies included was low. Most
confirmed in the new and large sample size of clinical trials in future
studies did not provide specific details about their research methods. In
investigation before a firm conclusion could be drawn.
particular, in the Chinese RCTs, the generation of a random sequence
Regarding the adverse side effects, the changes in weight and
and allocation concealment were questionable. In addition, many
BMI were significantly higher in the olanzapine group than in the
participants dropped out in the non-Chinese RCTs, which may be
risperidone group. These results are consistent with those reported
related to this clinical situation in which Chinese patients are hospi-
in a previous meta-analysis of 14 RCTs, which showed that olanzapine
talized for a longer period of time than others. Third, we could not
was associated with the greatest weight increase, aripiprazole with the
collect data regarding the effects of therapeutic doses and treatment
lowest weight increase, and risperidone in between (Almandil et al.
duration due to inadequate information. Finally, children and adoles-
2013). In addition, there were significant differences in the inci-
cents with psychosis need a full-course therapy, and we cannot assess
dence of hypersomnia/sedation, insomnia, prolactin elevation,
the medium and long-term prognoses based on trials that lasted only a
myotonia, tremor, and akathisia between the two groups. In sum-
few weeks. These limitations reduce the credibility of our conclusions.
mary, olanzapine has a greater impact on body weight and BMI,
while risperidone displays more side effects in the areas of myo- Clinical Significance
tonia, tremor, akathisia, and other EPS.
Olanzapine and risperidone, which are similar to other SGAs, The results of this meta-analysis indicate that olanzapine and ris-
exert their antipsychotic effect by blocking dopamine D2 and se- peridone are not significantly different in their efficacy in the treatment
rotonin 5-HT2A receptors (Mauri et al. 2014). Certain pharmaco- of children and adolescents with psychosis, but the side effect profiles
logical mechanisms can explain the similarity in their efficacy and of the two medications differ. These findings have implications for the
the difference in their side effects (Buckley 2007). First, targeted selection of antipsychotic drugs in clinical practice. However, this is a
dopaminergic blockade occurs in different locations within the preliminary study with several limitations. Also, selecting more rea-
brain. EPS result from dopamine antagonism in the forebrain basal sonable treatment plans according to the patients’ specific situations
nuclei, and elevated prolactin results from the inhibition of the D2 and designing more rational studies with larger sample sizes, partic-
receptor in the anterior pituitary gonadotropic cells. Second, D2 ularly involving children and adolescents, are necessary.
receptor occupancy can predict different reactions to the drugs,
such as a clinical response (‡65%), elevated prolactin (*72%), and Acknowledgment
EPS (>78%). Although SGAs achieve the level of binding required We thank Professor Chun-Bo Li for guidance and suggestions.
for efficacy, only some SGAs, such as risperidone and not olan-
zapine, achieve the high level of binding that results in side effects. Disclosure
In addition, olanzapine has a strong binding affinity to histamine H1
and muscarinic acetylcholine M receptors. Thus, olanzapine has a No competing financial interests exist.
considerable sedative effect (Miller 2004). Its anticholinergic ac-
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