Olanzapine, risperidone, and aripiprazole use in children and adolescents with Autism Spectrum Disorders

Research in Autism Spectrum Disorders 72 (2020) 101520

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Olanzapine, risperidone, and aripiprazole use in children and adolescents with Autism Spectrum Disorders

T

Selma Tural Hesapcioglu, Mehmet Fatih Ceylan, Meryem Kasak, Cansu Pınar Sen Ankara Yildirim Beyazit University Faculty of Medicine, Child and Adolescent Psychiatry, Ankara, Turkey

A R T IC LE I N F O

ABS TRA CT

Keywords: Antipsychotic Aripiprazole Autism Spectrum Disorders Irritability Olanzapine Risperidone

Background: The aim of this study is to examine the use of olanzapine, risperidone and aripiprazole in autism spectrum disorders (ASD) in terms of their effects and side effects. Methods: ASD patients that had been initiated to be treated with one of the three antipsychotics that continued for a minimum of eight weeks were included in the study, retrospectively. The participants were recruited with 20 olanzapine using patients (2.5−10 mg/day) in comparison with 42 risperidone (1−4 mg/day) and 40 aripiprazole (3−15 mg/day) using patients that are using the matched equivalent chlorpromazine doses of the antipsychotics between the same time period. Results: All three antipsychotics significantly decreased all of the ABC subscales scores in eight weeks. Sleepiness/sedation, increased duration of sleep, and weight gain were the most common side effects of the three antipsychotics and they were more frequent with olanzapine than with the others (X2 = 26.9, p < 0.0001; X2 = 20.8, p < 0.0001; X2 = 8.4, p = 0.01, respectively). Discussion: Our results reveal that risperidone, aripiprazole, and olanzapine are effective in treatment of irritability, hyperactivity, social withdrawal, stereotypy, and inappropriate speech in ASD. But the side effects are more frequent with olanzapine and it should be considered when choosing antipsychotics for ASD.

1. Introduction Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by impairment in social communication and interaction and by restricted and repetitive behaviors, interests, and activities (American Psychiatric Association, 2013). ASD symptoms are present in the early developmental period, and they affect daily activities and important areas of current functioning (American Psychiatric Association, 2013; Park et al., 2016). The prevalence of ASD is currently estimated to be 1 %–2 % (Baxter et al., 2015; Autism & Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, 2014Autism & Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, 2014; Kim et al., 2011). Autism occurs predominantly in males, with a male: female ratio of 4:1 (Chakrabarti & Fombonne, 2001). Intellectual disability comorbidity is common in ASD (Autism & Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, 2014Autism & Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, 2014; Simonoff et al., 2008). Serious behavioral disturbances associated with the autistic disorder include irritability, which may manifest as aggression, tantrums, and deliberate self-injury. These symptoms further impair social interaction and communication, represent a significant burden to individuals and their families, and disrupt school and family environments (Volkmar, Cook, Pomeroy, Realmuto, & Tanguay, 1999). Owing to the severe and chronic nature of the disorder, different treatment

E-mail address: [email protected] (S. Tural Hesapcioglu). https://doi.org/10.1016/j.rasd.2020.101520 Received 19 September 2019; Received in revised form 27 January 2020; Accepted 29 January 2020 1750-9467/ © 2020 Elsevier Ltd. All rights reserved.

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strategies, such as behavior modification, educational interventions, various psychopharmacologic treatments, and dietary change (Volkmar, Lord, Klin, Schultz, & Cook, 2007), are being attempted. However, until recently, problems in study design and sample selection have made it difficult to assess many treatments systematically (Volkmar et al., 1999). Antipsychotic drugs are commonly used in children and adolescents with ASD (Olfson, King, & Schoenbaum, 2015). No psychopharmacologic drugs targeting the core symptoms of ASD have been approved by the Food and Drug Administration (FDA) yet (Myers & Johnson, 2007). However, risperidone and aripiprazole are approved by the FDA for the treatment of pediatric patients with irritability associated with autistic disorder, including symptoms of aggression toward others, self-injuriousness, temper tantrums, and quickly changing moods (Aripiprazole: (Abilify) U.S. Full Prescribing Information, 2009; Risperidone: (Risperdal) U.S. Full Prescribing Information, 2006). Studies showed that antipsychotic agents decrease behavioral problems and increase the adaptation of the individual with ASD to the environment (Volkmar et al., 2007). ASD patients could benefit from risperidone in terms of irritability, tantrums, aggression, and/or self-injurious behavior (Arnold et al., 2010; Levine et al., 2016; Research Units on Pediatric Psychopharmacology Autism Network, 2005). Social skills on Vineland Adaptive Behavior Scale (VABS) improvement was also reported with risperidone (Aman et al., 2015). Moreover, Ghanizadeh, Sahraeizadeh, and Berk (2014) reported that the safety and efficacy of aripiprazole and risperidone were comparable in their head-tohead comparison study. A few studies examined the effectiveness and adverse effects of olanzapine in children and adolescents with ASD (Hollander et al., 2006; Potenza, Holmes, Kanes, & McDougle, 1999; Yoon, Wink, Pedapati, Horn, & Erickson, 2016). Potenza et al. (1999) conducted a 12-week, open-label trial of olanzapine in four children and four adults (aged 5–42 years) with autism (N = 5) or pervasive developmental disorder not otherwise specified (PDD-NOS) (N = 3) and significant self-injurious or compulsive behaviors. Six of the seven subjects completing the trial were classified as responders based on the CGI-I scale, and improvements were observed in the symptoms of autism, hyperactivity, social relatedness, affectual reactions, sensory responses, language usage, self-injurious behavior, aggression, irritability, anxiety, and depression. No improvements were observed in repetitive behaviors. In the first placebo-controlled trial of olanzapine in the treatment of children and adolescents with PDD, there was 50 % responders on olanzapine versus 20 % on placebo according to Clinical Global Impressions- Improvement (CGI-I) (Hollander et al., 2006). Yoon et al. (2016) investigated the weight gain effect of the second generation antipsychotics (SGAs), subjects treated with olanzapine showed a statistically significant greater increase in BMI Z-score when compared with the other SGAs (Yoon et al., 2016). Owing to the increasing use of antipsychotic drugs in children and adolescents (Penfold et al., 2013), examining the side effects that adversely affect their efficacy and treatment has become important (Stentebjerg-Olesen et al., 2013). Besides, the clinicians sometimes are faced with drug-refractory aggression, self-injurious behavior, and severe tantrums in people with autism spectrum disorders. In such cases different medication alternatives should be considered (Adler et al., 2015). Although studies on the use of risperidone and aripiprazole in the treatment of ASD in children have been conducted (Ghanizadeh et al., 2014; McDougle et al., 2005), research on the use of olanzapine is limited. Therefore, this study aims to examine the use of olanzapine, risperidone and aripiprazole in autism spectrum disorders (ASD) in terms of their effects and side effects in ASD patients with irritability, lethargy, stereotypy, hyperactivity, and speech. 2. Methods 2.1. Participants and procedure The approval for the study was obtained from the Ethics Committee of the Ankara Yildirim Beyazit University Faculty of Medicine, Yenimahalle Training and Research Hospital with 2017/06 protocol number. Patients were included from those receiving treatment in the clinic of the Child and Adolescent Psychiatry Department of Ankara Yildirim Beyazit University between January 1, 2014, and August 31, 2017, retrospectively. The inclusion criteria for this study were, being diagnosed with ASD, having used olanzapine minimum for 8 weeks, using no concomitant medications, and having ABC and CGI scale scores in the hospital files. Between this time period, 309 cases were diagnosed as ASD according to DSM-5 and 168 of them were treated with antipsychotics. 34 of those cases were on olanzapine treatment but only 20 of them had no concomittant medications, were used olanzapine at least for 8 weeks and had the ABC and CGI scales in the hospital files (Fig. 1). The olanzapine doses were 2.5−10 mg/day. However, all of those cases had a previous psychopharmacologic agent use history before olanzapine initiated (Fig. 2). The chlorpromazine equivalences of the olanzapine doses were calculated as (50−200 mg/day chlorpromazine). This was equal to 1−4 mg risperidone and 3.75−15 mg aripiprazole. The inclusion criterion for a control group that were comprised of risperidone and aripiprazole using patients who were being treated at least 8 weeks with risperidone or aripiprazole between 50−200 mg/day chlorpromazine equivalent doses, being not using other psychotropic agents and being treated with equivalent chlorpromazine doses within the time period. If the scales that are used to assess effectiveness and tolerability of the antipsychotics were include missing data, the cases were excluded from the study. Between this time period 42 risperidone, 40 aripiprazole using patients fulfilled the inclusion criterion (Fig. 1). Thus analysis was conducted on 20 olanzapine- (2.5−10 mg/day), 42 risperidone- (1−4 mg/day), and 40 aripiprazole (3−15 mg/day) using patients (Woods, 2003). Primary outcome measure of the study was irritability, agitation, and crying subscale of Aberrant Behavior Checklist (ABC). ABC subscale score at baseline and on the eighth week were analyzed. The antipsychotic is accepted as effective if the ABC subscale scores decreased significantly in this study. The clinical global impression (CGI) scale was used to measure the clinical improvement of the cases. All the selected patients were monitored at the baseline and on the eighth week of the treatment. The side effects were evaluated 2

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Fig. 1. The number of autism spectrum disorder cases that are referred to clinic between January 1, 2014, and August 31, 2017 and the selection of the groups.

Fig. 2. Previous psychopharmacologic agent use history of the cases that are included in the study.

with the Udvalg für Kliniske Undersogelser (UKU) Side Effect Rating Scale. The psychiatric diagnoses of the cases were made by using the diagnostic and statistical manual of mental disorders (DSM-5) (APA, 2013). The intelligence quotients of the cases were evaluated by Wechsler Intelligence Scale for Children-Revised (WISC-R) or Ankara Developmental Screening Inventory according to their ages. 2.1.1. Power of the study To compute post-hoc achieved power of this study, we evaluated irritability, agitation, and crying subscale of ABC. By taking effect size as 0.25; Type-I error rate as 0.05; the achieved power of this study is 0.60 (λ = 6.38; F = 3.09). 3

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2.2. Data collection tools 2.2.1. ABC ABC is a five-factor scale with 58 items that are rated on a four-point scale ranging from 0 (“not at all a problem”) to 3 (“the problem is severe in degree”) (Aman, Singh, Stewart, & Field, 1985). The subscales of the ABC were designated as follows: (I) irritability, agitation, and crying, (II) lethargy and social withdrawal, (III) stereotypic behavior, (IV) hyperactivity and noncompliance, and (V) inappropriate speech. The coefficient alpha ranged from .86 to .94 across subscales (median = 0.91). The validity of the Turkish version of the scale was confirmed by Karabekiroglu and Aman (2009). 2.2.2. CGI The CGI index is a widely used three-item, observer-rated scale in psychiatry that measures the severity of illness (CGI-S), global improvement or change in symptoms (CGI-I), and therapeutic response (or efficacy) (Guy, 1976). The CGI-S is a seven-point scale. Based on the responses to a range of questions, it grades the severity of illness as (1) normal and not at all ill, (2) borderline mentally ill, (3) mildly ill, (4) moderately ill, (5) markedly ill, (6) severely ill, and (7) extremely ill. The CGI-I index is a seven-point scale, with 1 =very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = slightly worse, 6 = much worse, and 7 = very much worse (Guy, 1976). On the basis of these CGI-I scores, the clinician assesses how much a patient’s illness has improved or worsened relative to a baseline state. The treatment response ratings should consider both therapeutic efficacy and treatment-related adverse events, and they range from 0 (marked improvement and no side effects) to 4 (unchanged or worse and side effects outweighing the therapeutic effects). Each component of the CGI is rated separately, and the instrument does not yield a global score. 2.2.3. UKU side effect rating scale This scale assesses psychotropic treatment side effects and divides them into the “psychic, neurologic, autonomic, and other” categories. The extent of the side effect is scored between 0 and 3. A total of 48 individual side effects are evaluated with a semistructured interview. The scale can be used in different psychiatric problems, from psychosis to affective and neurotic disorders. The scale evaluates currently present side effects (Lingjaerde, Ahlfors, Bech, Dencker, & Elgen, 1987). 2.2.4. Wechsler intelligence scale for children-revised (WISC-R) (Wechsler, 1974): The Wechsler Intelligence Scale for Children (WISC) was revised (WISC-R) in 1974, and the scale is administered to children aged 6–16 years. The scale was adapted to Turkish by Savasir, Sezgin, and Erol (1993). The WISC-R consists of 10 core subtests and 2 supplemental subtests, which are organized into verbal scales (Information, Similarities, Arithmetic, Comprehension, Vocabulary, and Digit Span) and performance scales (Picture Completion, Picture Arrangement, Block Design, Object Assembly, Coding, and Mazes). The WISC-R provides scores for Verbal IQ, Performance IQ, and Full-Scale IQ as well as standard scores for these subtests. 2.2.5. Ankara developmental screening inventory This inventory is used for the evaluation of developmental aspects of children aged 0–6 years. It was tested for validity and reliability in Turkey (Savaşır, 1995). Speech development, cognitive skills, fine muscle development, gross muscle development, social development, and self-care skills are observed and scored. 2.3. Statistical analysis SPSS 20.0 was used to perform statistical analyses. The Kolmogrov–Smirnov test was performed to identify the distribution characteristics of the data. The ages of the cases were compared with One Way ANOVA test. Chi Suare test was performed to compare gender and comorbid psychiatric disorders between groups. Kruskal-Wallis test was performed to compare chlorpromazine equivalent doses of the antipsychotics. One-way ANOVA test was used to compare the baseline ABC subscale scores and ANCOVA tests used to compare groups in terms of 8th week ABC subscale scores that were normally distributed. Before performing ANCOVA tests, the homogeneity of the variances and regression curves are controled between subjects. All 8th week ABC subscale scores are controlled for the baseline measures in ANCOVA. The Kruskal–Wallis one-way ANOVA test was performed to compare baseline and the 8thweek ABC subscale scores between groups that were not normally distributed. To compare the subscale scores of the groups between the two measures, repeated measures ANOVA test was performed for the normally distributed data and the Friedman test for those that were not normally distributed. The side effects were compared by using the chi-square test. After comparing three groups in terms of side effects with Chi Square tests, pairwise comparisons were also run between groups. Degrees of freedom for pairwise comparisons was 1 (df = 1). A p < 0.05 was accepted as statistically significant. 3. Results The analyses were conducted on 42 risperidone-, 40 aripiprazole-, and 20 olanzapine-using patients with ASD. No statistical difference was found among the three groups in terms of age and gender (p = 0.4).The sociodemographic and clinical characteristics and the drug doses of the cases in the three treatment groups are presented in Table 1. According to the Table 1, there is no difference between groups in terms of gender, age, and any comorbid psychiatric disorders except schizophrenia spectrum and other psychotic 4

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Table 1 Sociodemographic and clinical characteristics of the cases in the three treatment group. Risperidone

Aripiprazole

Olanzapine

Fa or X2

p

33 7 11.55 ± 3.6 7.6 ± 3.9 101.6 ± 52.5

17 3 12.07 ± 3.3 5.0 ± 1.6 100 ± 32.4

1.135b

0.5

Age Dose Chlorpromazine equivalent dose

38 4 12.45 ± 3.6 1.8 ± 0.9 93.7 ± 44.9

0.787a

0.4

c

0.6

Comorbid DSM-5 Diagnosis Intellectual Disability ADHD Disruptive, Impulse control, and Conduct Disorders Depressive Disorders Enuresis Encopresis Anxiety Disorders Obsessive- compulsive and related disorders Schizophrenia spectrum and other psychotic disorders Stuttering

36 (85.7 %) 35 (83.3 %) 12 (28.6 %) 10 (23.8 %) 16 (38.1 %) 10 (23.8 %) 16 (38.1 %) 4(9.5 %) 0 (0 %) 2 (4.8 %)

33 (82.5 %) 33 (82.5 %) 18 (45.0 %) 12 (30.0 %) 14 (35.0 %) 11 (27.5 %) 18 (45.0 %) 3 (7.5 %) 0 (0 %) 0 (0 %)

19 (95.0 %) 16 (80.0 %) 5 (25.0 %) 14 (70.0 %) 10 (50.0 %) 8 (40.0 %) 8 (40.0 %) 4 (20.0 %) 2 (10.0 %) 0 (0 %)

5.9b 0.1b 3.4b 12.3b 1.2b 1.9b 0.7b 2.2b 8.3b 2.7b

0.4 0.9 0.1 0.002 0.5 0.3 0.6 0.3 0.01 0.2

4 (9.5 %) 2 (4.8 %) 20 (47.6 %) 16 (38.1 %)

6 (15.0 %) 1 (5.0 %) 1 (2.5 %) 0 19 (47.5 %) 4 (20.0 %) 14 (35.0 %) 15 (75.0 %) Risperidone - Aripiprazole Risperidone- Olanzapine Aripiprazole - Olanzapine

N/A N/A N/A 8.032 0.245 4.985 7.500

N/A N/A N/A 0.01 0.62 0.02 0.006

Gender

Male Female

The ID severity of the cases Normal IQ level Borderline intellectual functioning Mild ID Moderate-Severe ID Dual Comparisons for Moderate-Severe ID rates of the groups

0.9

a

The ages of the cases were compared with One Way ANOVA test. Chi Suare test was performed to compare gender, and comorbid psychiatric disorders between groups. c Kruskal-Wallis test was performed to compare chlorpromazine equivalent doses of the antipsychotics. ADHD: Attention Deficit and Hyperactivity Disorder, ID: Intellectual disability; IQ: Intellectual quotient. b

disorders, and depressive disorders. The olanzapine using cases had more frequent Schizophrenia spectrum and other psychotic disorders than risperidone (X2 = 4.46; df = 1; df = 1; p = 0.03) and aripiprazole (X2 = 4.03; df = 1; p = 0.04) using cases. Again the olanzapine using cases had more frequent depressive disorders than risperidone (X2 = 10.8; df = 1; p = 0.001) and aripiprazole (X2 = 8.6; p = 0.003) using cases. The number of moderate-severe ID cases in olanzapine using group were higher than the other two groups (X2 = 8.032; p = 0.01). 3.1. The history of previous psychopharmacologic medication use From the 42 risperidone using patients, 11 (26.2 %) of them had previous different antipsychotic use history (seven (16.6 %) of them used aripiprazole, two (4.7 %) of them quetiapine, two (4.7 %) of them chlorpromazine). Besides, 18 (42.8 %) of them got ADHD treatment, 10 (23.8 %) of them got valproic acid before risperidone treatment (Fig. 2, Table 2). Table 2 Previous psychopharmacologic agent use history of the cases that are included in the study. Risperidone (n=42) Previous psychopharmacologic agent use Dual Comparisons

Previous Different Antipsychotic Dual Comparisons

Previous Mood stabilizors Dual Comparisons

Previous SSRIs Previous ADHD drugs

Aripiprazole(n=40)

28 (66.6%) 38 (95%) Risperidone - Aripiprazole Risperidone- Olanzapine Aripiprazole - Olanzapine 11 (26.2%) 31 (77.5%) Risperidone - Aripiprazole Risperidone- Olanzapine Aripiprazole - Olanzapine 10 (23.8%) 10 (25%) Risperidone -Aripiprazole Risperidone-Olanzapine Aripiprazole-Olanzapine 10 (23.8%) 10 (25%) 18 (42.8%) 20 (50%)

Olanzapine(n=20)

χ2

p

20 (100%)

17.064 10.811 8.611 1.034 35.258 21.588 25.686 2.940 16.479 0.400 14.754 12.071 1.982 5.038

< 0.0001 0.004 0.003 0.309 < 0.0001 < 0.0001 < 0.0001 0.08 < 0.0001 0.527 < 0.0001 0.002 0.371 0.081

19 (95%)

15 (75%)

8 (40%) 4 (20%)

SSRIs: Selective serotonin reuptake inhibitors; ADHD: Attention deficit hyperactivity disorder. 5

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Table 3 Mean, standard deviation and difference of ABC subscale scores in the groups. Subscale

Group

Baseline

2 months

X2 or F (p)

Difference

Significance of difference X2 or F (p)

ABC-I

Risperidone Aripiprazole Olanzapine Risperidone Aripiprazole Olanzapine Risperidone Aripiprazole Olanzapine Risperidone Aripiprazole Olanzapine Risperidone Aripiprazole Olanzapine

39.4 ± 4.9 39.2 ± 5.8 39.7 ± 5.1 33.8 ± 9.7 32.7 ± 8.8 36.5 ± 11.3 11.9 ± 5.8 12.02 ± 4.8 13.6 ± 5.5 37.7 ± 9.0 37.0 ± 9.4 39.9 ± 8.6 4.2 ± 3.1 5.2 ± 3.4 5.1 ± 3.5

32.3 ± 6.0 30.8 ± 6.5 31.4 ± 7.8 29.2 ± 8.3 27.3 ± 8.7 30.9 ± 9.8 10.1 ± 5.2 10.4 ± 4.2 11.4 ± 4.7 30.0 ± 7.6 29.7 ± 7.2 31.7 ± 7.5 3.4 ± 2.8 4.1 ± 2.7 4.2 ± 3.1

216.6a (< 0.0001)

7.02 ± 4.9 8.32 ± 4.8 8.25 ± 5.8 4.6 ± 3.8 5.37 ± 5.4 5.65 ± 6.09 1.8 ± 1.6 1.6 ± 1.8 2.2 ± 2.0 7.7 ± 5.4 7.2 ± 5.3 8.2 ± 5.9 1 (0–7)* 1 (0–6)* 1 (0–3)*

0.7 c (0.5) Df = 2 0.2 d (0.8) Df = 2 2.2 d( 0.3) Df = 2 0.2 d (0.8) Df = 2 0.9 d (0.6) Df = 2

ABC-SW

ABC-SB

ABC-H

ABC-IS

101.5a (< 0.0001) 79.0 b (< 0.0001) 180.4a (< 0.0001) 60.0 b (< 0.0001)

ABC-I: Aberrant Behavior Checklist- irritability, agitation, and crying subscale, ABC-SW: Aberrant Behavior Checklist lethargy and social withdrawal subscale, ABC-SB: Aberrant Behavior Checklist-stereotypic behavior subscale, ABC-H: Aberrant Behavior Checklist- Hyperactivity and noncompliance, ABC-IS: Aberrant Behavior Checklist- inappropriate speech. Df: Degrees of freedom. a Repeated Measures ANOVA test was performed. b Friedman Test was performed. c One Way ANOVA test was performed. d Kruskall Wallis One-Way Analysis-of-Variance test was performed. Significance of difference: The difference between the each subscale’s first and second application of Aberrant Behavior Checklist. * Median scores are given.

From 40 aripiprazole using patients, 31 (77.5 %) of them had a previous different antipsychotic use history (28 (70 %) of them used risperidone, 2 (5 %) haloperidol and one (2.5 %) chlorpromazine used). Besides, 20 (50 %) of them got ADHD treatment, 10 (25 %) of them got valproic acid before aripiprazole treatment. From 20 olanzapine using patients, 19 (95 %) of them had a previous different antipsychotic use history (4 (20 %) of them had previous 3 (15 %) different antipsychotic use, 8 (40 %) of them used two (10 %) different antipsychotics, 7 (35 %) of them used one different antipsychotic). Besides, 4 (20 %) of them got ADHD treatment, 11 (55 %) of them got valproic acid and 1 (5 %) of them got carbamazepine treatment before risperidone treatment. Previous antipsychotic use characteristics of the groups are compared. There was a significance between groups (χ2 = 35.258; p < 0.0001). To understand the cause of the difference, comparisons between each individual pair of groups were also performed. The difference between risperidone and aripiprazole groups and risperidone and olanzapine groups was also significant (Table 2). The difference between aripiprazole and olanzapine was not significant. Previous mood stabilizers use characteristics of the groups are compared and the groups were significantly different. To understand the cause of the difference, comparisons between each individual pair of groups were also performed. Olanzapine using cases were significantly had higher mood stabilizator use than aripiprazole and risperidone using groups. 3.2. The effectiveness of the treatment Our results reveal that risperidone, aripiprazole, and olanzapine are effective in the treatment of irritability, hyperactivity, social withdrawal, stereotypy, and inappropriate speech in ASD. (Table 3) 3.3. The progress of irritability, agitation, and crying (ABC-I) No statistically significant difference was observed among the antipsychotic groups in terms of the baseline (F = 0.06, df = 2, p = 0.9) and eighth-week (F = 0.80, df = 2, p = 0.44) mean irritability, agitation, and crying subscale scores when ABC-I-baseline scores are controlled with ANCOVA test. The difference between the two irritability, agitation, and crying subscale measures did not significantly differ among the groups (F = 0.77, p = 0.5) (Table 3) The progress of the irritability, agitation, and crying subscale in eight weeks among the groups was compared by the Friedman test. The irritability scores of the groups statistically significantly decreased in eight weeks (F = 216.6; p < 0.0001) (Table 3). 3.4. The progress of lethargy and social withdrawal (ABC-SW) No statistically significant difference was found among the antipsychotic groups in terms of the baseline (F = 1.01, p = 0.4) and eighth-week (F = 0.46, df = 2, p = 0.63) mean lethargy and social withdrawal subscale scores when ABC-SW-baseline scores are 6

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compared with ANCOVA test. The difference between the two lethargy and social withdrawal subscale measures did not significantly differ among the groups (X2 = 0.28, p = 0.8) (Table 3). The progress of the lethargy and social withdrawal subscale in eight weeks among the groups was compared by the Friedman test. The lethargy and social withdrawal subscale score statistically significantly decreased in eight weeks (F = 101.5; p < 0.0001) (Table 3). 3.5. The progress of stereotypic behavior (ABC-SB) No statistically significant difference was observed among the antipsychotic groups in terms of the baseline (F = 0.07, p = 0.4) and eighth-week (F = 0.32, df = 2, p = 0.72) mean stereotypic behavior subscale scores when ABC-SB-baseline scores are compared with ANCOVA test. The difference between the two stereotypic behavior subscale measures did not significantly differ among the groups (X2 = 2.2, p = 0.3) (Table 3). The progress of stereotypic behavior in eight weeks among the groups was compared with a repeated measures ANOVA test. The stereotypic behavior subscale score statistically significantly decreased (X2 = 79.9; p < 0.0001) (Table 3). 3.6. The progress of hyperactivity and noncompliance (ABC-H) No statistically significant difference was found among the antipsychotic groups in terms of the baseline (X2 = 2.457, df = 2, p = 0.29) and eighth-week (X2 = 1.315, df = 2, p = 0.51) mean hyperactivity and noncompliance subscale scores. The difference between the two hyperactivity and noncompliance subscale measures did not significantly differ among the groups (X2 = 0.21, p = 0.8) (Table 3). The progress of the hyperactivity, noncompliance subscale in eight weeks among the groups was compared by the Friedman test. The hyperactivity and noncompliance subscale score statistically significantly decreased (F = 180.4; p < 0.0001) (Table 3). 3.7. The progress of inappropriate speech (ABC-IS) No statistically significant difference was found among the antipsychotic groups in terms of the baseline (F = 1.22, df = 2, p = 0.3) and eighth-week (F = 0.87, df = 2, p = 0.42) mean inappropriate speech subscale scores when ABC-IS-baseline scores are compared with ANCOVA test. The difference between the two inappropriate speech subscale measures did not significantly differ among the groups (X2 = 0.99, p = 0.6) (Table 3). The progress of the inappropriate speech subscale in eight weeks among the groups was compared by the Friedman test. The inappropriate speech subscale score statistically significantly decreased (X2 = 60.0; p < 0.0001) (Table 3). 3.8. Clinical improvement The Kruskal–Wallis test was performed to analyze the clinical improvement among the groups. The improvement of the cases on the eighth week was not statistically different among the groups (X2 = 4.549, p = 0.103). The mean CGI-I score was 2.9 ± 0.5 for risperidone, 2.9 ± 0.6 for aripiprazole, and3.3 ± 0.9 for olanzapine. 3.9. Side effects of the antipsychotics The side effects of the antipsychotics were evaluated by the UKU Side Effect Rating Scale. The side effects of the antipsychotics were compared among the three groups (Table 4). Sleepiness/sedation increased the duration of sleep and weight gain were the most common side effects. The comparisons of the side effects in the UKU Side Effect Rating Scale among the three groups are presented in Table 4. 4. Discussion This study compares the effectiveness and tolerability of risperidone, aripiprazole, and olanzapine in children with ASD. The first finding of our study indicates that risperidone, aripiprazole, and olanzapine are effective in reducing irritability, hyperactivity, social withdrawal, stereotypy, and inappropriate speech in children and adolescents with ASD. However, no statistically significant difference was found in efficacy among the ASD groups using risperidone, aripiprazole, and olanzapine. All three antipsychotics significantly decreased all of the ABC subscale scores, and no statistical difference was observed in the CGI-I scores for each antipsychotic. Aside from problems in social interaction and communication, comorbid irritability aggression, tantrums, deliberate self-injury, mood disturbance, and hyperactivity severely impair functioning in autistic patients. These outward-oriented problems disturb the children's family and school setting adaptation (Leskovec, Rowles, & Findling, 2008; Volkmar et al., 1999). For this reason, antipsychotic drugs are frequently used in treatment. Reducing the externalizing behavioral problems in ASD patients may increase family satisfaction and their ability to cope with the disorder. Risperidone is effective in treating behavioral symptoms associated with ASD in children and adolescents (Lemmon, Gregas, & Jeste, 2010; McDougle et al., 2005). Similarly, aripiprazole was efficacious, generally safe, and well tolerated in the treatment of 7

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Table 4 The comparison of the side effects between risperidone, aripiprazole and olanzapine using groups. Side effects

Risperidone n = 70 (%)

Aripiprazole N = 40 (%)

Olanzapine N = 20 (%)

X2*

p

Sleepiness /Sedation Increased Duration of Sleep Weight gain Asthenia/ Lassitude Constipation Concentration Difficulties Tension/ Inner Unrest Emotional Indifference Disturbance of Micturition Depression Failing Memory Tremor Hypokinesia Akinesia Akathisia Dystonia Rigidity Headache Increased Salivation Nausea/ Vomiting Orthostatic Dizziness Rash Pruritus Reduced Salivation

4(9.5 %) 4 (9.5 %) 8 (19.0 %) 2 (4.8 %) 3 (7.1 %) 1(2.4 %) 1 (2.4 %) 0 (0.0 %) 0 (5.7 %) 1 (2.4 %) 1 (5.7 %) 0 (0.0 %) 0 (0.0 %) 1 (2.4 %) 0 (0.0 %) 0 (0.0 %) 1 (2.4 %) 0 (0.0 %) 0 (0.0 %) 1 (2.4 %) 0 (0.0 %) 0 (0.0 %) 1 (2.4 %)

17 (42.5 %) 16 (40.0 %) 15 (37.5 %) 10 (25.0 %) 4 (10.0 %) 1 (2.5 %) 10 (25.0 %) 0 (0.0 %) 7 (17.5 %) 3 (7.5 %) 1(2.5 %) 2 (5.0 %) 2 (5.0 %) 1 (2.5 %) 2 (5.0 %) 2 (5.0 %) 5 (12.5 %) 0 (0.0 %) 2 (5.0 %) 0 (0.0 %) 0 (0.0 %) 0 (0.0 %) 0 (0.0 %)

15 (75.0 %) 13 (65.0 %) 11 (55.0 %) 9 (45.0 %) 4 (20.0 %) 5 (25.0 %) 3 (15.0 %) 6 (30.0 %) 3 (15.0 %) 3(15.0 %) 1 (5.0 %) 1 (5.0 %) 3 (10.0 %) 3 (10.0 %) 1 (5.0 %) 1 (5.0 %) 1 (5.0 %) 1 (5.0 %) 0 (0.0 %) 1 (5.0 %) 1 (5.0 %) 1 (5.0 %) 0 (0.0 %)

26.9 20.8 8.4 14.2 2.3 12.8 8.8 26.1 7.8 3.4 0.6 2.1 3.8 2.4 2.1 2.1 3.4 4.1 3.1 1.8 4.1 4.1 1.4

< 0.0001a,b,c < 0.0001a,b,c 0.01b,c 0.001a,b,c 0.3 0.002b,c 0.01a,b < 0.0001b,c 0.02 0.2 0.7 0.3 0.1 0.3 0.3 0.3 0.2 0.1 0.2 0.4 0.1 0.1 0.4

p: The significance level of comparison of three antipsychotics with Chi-Square test. a Statistical significance is between risperidone and aripiprazole. b Statistical significance is between risperidone and olanzapine. c Statistical significance is between aripiprazole and olanzapine.

children and adolescents with irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled studies (Marcus et al., 2009). In Marcus et al.’s study the baseline ABC-I scores were lower than our cases (Baseline ABC-I scores of Marcus et al.’s study (2009) approximately 28; for our study approximately 39). Because of the presence of severe cases in our study, the change in ABC-I scores is lower than their study. This may be due to the higher baseline ABC-I scores. In further studies, higher antipsychotic doses could be examined to determine if there is a greater effect. Recently, aripiprazole and risperidone appeared to have similar benefits in terms of efficacy and tolerability, although the two drugs had slight differences (Ghanizadeh et al., 2014). A few studies assessed the efficacy of olanzapine in small groups of ASD patients (Fido & Al-Saad, 2008; Hollander et al., 2006; Potenza et al., 1999)). In 2006, Hollander et al. reported an eight-week, double-blind, randomized, placebo-controlled trial in 11 children with any PDD and a CGI-S score of at least four (moderate) treated with flexibly dosed olanzapine (mean 10 mg/day). Eight of the 11 patients (four olanzapine and four placebo) completed the trial, and 50 % (3/6) of the subjects in the olanzapine group was labeled treatment responders (CGI-I = 1 or 2) vs. 20 % (1/5) of those receiving placebo. The small sample size limited the statistical power of the trial, and the authors noted that any beneficial effect of olanzapine was only suggested. A 13-week, open-label trial of olanzapine (mean dose 7.5 mg/day) in 40 youths (mean age 12.2 years; age range 7–17 years) with autistic disorder demonstrated a 30 % response rate (N = 12/40) as defined by at least 25 % reduction in the ABC-I score and at least a one-point improvement on the CGI-S score (Fido & Al-Saad, 2008). Note that the CGI criterion for the response rate was less strict than that in most studies on atypical antipsychotics in PDD populations. Significant reductions were also observed in the ABC subscale scores for lethargy, stereotypy, hyperactivity, and inappropriate speech. The second finding of our study is about the previous psychopharmacologic agent use. The entire olanzapine using group had a history of previous psychopharmacologic agent use and 95 % of them were using another antipsychotic before olanzapine initiated. Previous different antipsychotic using ratio was 77.5 % for aripiprazole using group and 26.2 % for risperidone using group. Risperidone is the most preferred antipsychotic agent in children and adolescents (Scahill, Oesterheld, & Martin, 2007). Besides, risperidone was the first drug to be approved for use in ASD and is still the best established psychopharmacological option for the treatment of irritability and behavioral problems in ASD (Dinnissen, Dietrich, van den Hoofdakker, & Hoekstra, 2015). The other cause of the difference between groups in terms of previous other antipsychotic use may be the severity of the cases. The number of moderate or severe ID cases was higher in olanzapine using group than the other two groups. The severity of the ID may make the cases more resistant to the treatment. In the more resistant ASD cases olanzapine had been preferred in this study. In our study, olanzapine was preferred to treat psychotic symptoms that accompany ASD. In a metaanalysis study comparing olanzapine and risperidone in psychotic children and adolescents, there was no difference in efficacy between olanzapine and risperidone for the treatment of children and adolescents with psychosis. However, it showed the olanzapine superiority for total Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores (Xia, Li, Liu, Hao, & Zhang, 2018). In order to reach a definite conclusion about the treatment options of the ASD cases with psychotic symptoms, larger sample studies are needed.

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The third finding of our study is related to side effect. Sleepiness/sedation increased the duration of sleep and weight gain was the most common side effects of the three antipsychotics. These side effects were more frequent with olanzapine than with the other antipsychotics in our study. In our study, sedation and concentration were most frequently seen with olanzapine. According to clinical trials, olanzapine is associated with a high incidence of weight gain and sedation in PDD patients (Chavez, Chavez-Brown, Sopko, & Rey, 2007). Sedation was reported in three of seven subjects using olanzapine (Potenza et al., 1999). Mild, transient sedation was common in the groups using olanzapine and haloperidol (Malone, Cater, Sheikh, Choudhury, & Delaney, 2001). Mild sedation was common in Hollander et al. (2006). Mild, transient sedation that resolved by the end of week 13 was experienced in 12.5 % of the subjects (Fido & Al-Saad, 2008).For this reason, olanzapine should be used with caution in children with autism who go to school or special education. Olanzapine (55.0 %) was the antipsychotic that was mostly associated with the side effect of weight gain. No statistically significant difference was found in weight gain between risperidone (19.0 %) and aripiprazole (37.5 %) in autistic children. Weight gain due to the use of atypical antipsychotics in children is a common side effect (Correll et al., 2009). In Wink et al.’s (2014) study, on ASD children and adolescents, a significant increase in BMI was seen in both groups that are using risperidone or aripiprazole. However, there was no significant difference in BMI change when the two treatment groups were compared. Furthermore, antipsychotic-induced weight gain is associated with a high risk for diabetes mellitus, cardiovascular diseases, and overall mortality (Fontaine et al., 2001). Comparing the safety and efficacy of risperidone and aripiprazole for two months, Ghanizadeh et al. (2014) found increased appetite to be the most common side effect of both antipsychotics (34.5 % with aripiprazole vs. 40.0 % with risperidone). However, they did not observe a significant difference in terms of weight gain in the second month of the study. Potenza et al. (1999) found that increased appetite and significant weight gain occurred with olanzapine in six of the seven subjects, and it led to the discontinuation of the drugs in two subjects. In Malone et al.’s study (2001), olanzapine and haloperidol were compared, the anger/uncooperativeness and hyperactivity factors significantly improved in ASD patients with olanzapine but not with haloperidol. Greater weight gain was observed with olanzapine than with haloperidol (+9 vs. + 3.2 lbs. in six weeks), and all patients receiving olanzapine gained at least 5 lbs. Similar to other studies, significant weight gain with olanzapine was noted with the participants in Hollander et al.’s study (2006), and they gained a mean of 7.5 lbs. in eight weeks (placebo, +1.5 lbs.). Patients with ASD who received SGA, especially olanzapine, should be carefully monitored for metabolic syndrome (weight gain/obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hyperglycemia/ hyperinsulinism, and hypertension). Constipation due to SGA was quite common in our study. The incidence of constipation due to the use of SGA in ASD patients was found to be 20 % in olanzapine, 10 % in aripiprazole, and 7.1 % in risperidone, respectively. Constipation is a rarely studied but common side effect (De Hert et al., 2011). In Frenchman’s (2005) study on adults with different psychiatric diagnoses, the rate of constipation in olanzapine using groups was 6.8 %, and no constipation was reported for the group treated with risperidone. The constipation rate was 5.1 % in a study that evaluated the efficacy and safety of aripiprazole versus placebo in preventing the relapse of irritability symptoms associated with ASD in pediatric patients (Findling et al., 2014). Owing to the frequent occurrence of constipation, it is considered a side effect that should be inquired about with the family. In our study, no significant difference was found in the neurological side effects between three antipsychotics. Carbon et al. (2015) reported the frequency of atypical antipsychotic-induced extrapyramidal side effect (EPS) in children and adolescents using antipsychotics as 4.41 % for risperidone, 4.55 % for aripiprazole, 9.5 % for quetiapine, 15.52 % for olanzapine, and 26.67 % for ziprasidone. No EPS were reported for olanzapine in the studies of Potenza et al. (1999) and Hollander et al. (2006). Three of the 25 olanzapine-using subjects reported EPS, including rigidity, salivation, tremor, and gait rigidity, which resolved when the dose was lowered in Kemner et al.’s study (2002). There was no statistical difference in the present study between three groups in terms of EPS Our study has many limitations. The most important one is the retrospective design of the study, and the groups were not randomized. The small sample sizes and the lack of a placebo group is another limitation. Randomized placebo-controlled studies are needed in this issue. Biochemical data, such as serum prolactin levels, lipid profiles, and liver function, were not regularly monitored in the assessment of the side effects. The basal body mass index data of all cases could not be obtained, thus, we could not analyze this data in this study. Another limitation is the lack of the use of standardized structured diagnostic instruments (e.g., the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule). Our results revealed that risperidone, aripiprazole, and olanzapine were effective in the treatment of ASD patients with irritability, hyperactivity, social withdrawal, stereotypy, and inappropriate speech. In children with ASD, SGAs are generally safe drugs with good tolerability. There was no statistical difference between three groups in terms of extrapyramidal side effects. Sedation, increased the duration of sleep, and weight gain were the most common side effects of the three antipsychotics. These side effects were more frequent with olanzapine. Olanzapine was associated with a higher incidence of sedation than other antipsychotics. Consequently, risperidone and aripiprazole are first-line treatments in children and adolescents with ASD who have irritability, hyperactivity, and aggression (Lemmon et al., 2010; Marcus et al., 2009; McDougle et al., 2005) and our results are supporting this knowledge. The side effects should be considered when choosing an antipsychotic drug for ASD. However, the higher rates of drug history and history of psychotic symptoms of the olanzapine using participants might be expected, since olanzapine does not have a history of FDA approval for autism. Therefore it may be being reserved for cases resistant to other FDA approved antipsychotics or where there is another diagnosis, which is in indication for olanzapine, such as psychotic symptoms. Authors contributions STH and MFC designed the study, STH, MFC, MK, CPS collected the data, STH, MFC, MK and CPS entered the data to SPSS, STH 9

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and MFC analysed the data. STH wrote the first draft and all the authors read and contributed the final version of the manuscript. Selcen Yüksel, assoc.prof.,MD was also contributed the some parts of statistical analyze of the data. Declaration of Competing Interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.rasd.2020. 101520. References Aripiprazole: (Abilify) U.S. Full Prescribing Information (2009). Princeton, NJ: Bristol-Myers Squibb and Rockville MD: Otsuka America Pharmaceutical, Inc. Adler, B. A., Wink, L. K., Early, M., Shaffer, R., Minshawi, N., McDougle, C. J., et al. (2015). Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: A chart review study. Autism, 19(1), 102–106. 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