International Journal of Psychiatry in Clinical Practice, 2008; 12(1): 48
54

ORIGINAL ARTICLE

Can we predict short-term side effects of methylphenidate immediate-release?

KORAY KARABEKIROGLU1, YANKI M. YAZGAN2 & CEYDA DEDEOGLU3 Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 11/21/14 For personal use only.

1

School of Medicine, Ondokuz Mayis University, Samsun, Turkey, 2School of Medicine, Marmara University, Istanbul, Turkey and Yale Child Study Center, New Haven, CT, USA, and 3Private Practice, Istanbul, Turkey

Abstract Objective. In children and adolescents who were prescribed immediate-release methylphenidate (MPH-IR) for the first time, we aimed to investigate the effect of gender, psychiatric co-morbidity and the baseline severity of clinical symptoms on the short-term side-effects of the medication. Method. In a clinical sample, over a period of 6 months, all MPH-naive patients with attention deficit hyperactivity disorder (ADHD) (N90; male, n 73; female, n 17) age: 9.092.2 years (5
16 years)) were included. Patients were prescribed MPH-IR 10
30 mg/day (17.694.95). The assessment included structured measurements, including the Turgay Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) (parents and teachers), Conners’ Teacher Rating Scale for ADHD-Short version (teachers). Parents also completed the ‘‘Barkley Stimulants’ Side Effects Rating Scale’’ (BSSERS) at baseline and on the third, seventh and 15th days of medication. Results. Repeated measures multiple ANOVA revealed an overall significant difference in BSSERS between the baseline measures and the 15th day (P B0.01). On the 15th day, only the ‘‘loss of appetite’’ item severity scores increased (P 0.001), whereas the scores of ‘‘irritability’’, ‘‘proneness to cry’’, ‘‘anxiety’’, ‘‘nail biting’’ and ‘‘euphoria’’ items decreased significantly. In post hoc analyses, when subjects whose side effects increased and did not increase were compared, chi-square tests revealed a significant difference (P 0.029) only for the presence of co-morbidity, and no difference for the gender, age, dosage of MPH, and the baseline severity of inattentiveness and/or hyperactivity. Discussion. The only significant increase during MPH treatment was for the ‘‘loss of appetite’’ item on BSSERS. Our results suggest that some of the BSSERS items may represent both the ADHD symptoms and the side effects. When overall BSSERS item severity is considered, having a co-morbid diagnosis may be predictive of more severe adverse effects.

Key Words: Methylphenidate, immediate-release, side-effects, adverse effects

Introduction The efficacy of the stimulant medications has long been recognized clinically in previous researches [1] and the short- and intermediate-term therapeutic efficacy of psychostimulants for treating children with attention deficit/hyperactivity disorder (ADHD) was well-established [2]. For decades, stimulant medication, particularly methylphenidate (MPH), is the most frequently recommended medical treatment for ADHD [3]. In several countries methylphenidate immediate-release (MPH-IR) is the only available formulation of MPH, and in others, it is still frequently used for attention deficit disorders. There is a considerable individual variability with respect to adverse effects and a family’s tolerance for a side effect is also influenced by their perception of the benefit derived from that medica-

tion [4]. The objective of this study is to investigate short-term side effects of MPH-IR and to find out predictive clinical and demographic characteristics of patients that predispose them to short-term side effects and consequent discontinuation of MPH-IR. Side effects are common and most notably being a ‘‘decrease in appetite’’, but also ‘‘stomach ache’’, ‘‘headache’’, ‘‘irritable mood’’ and ‘‘sleep difficulties’’ [5]. A meta-analysis [6] examined the efficacy and safety of short-acting MPH compared with placebo for attention-deficit disorder (ADD) in the individuals aged 18 years and less. It included 62 randomized trials that involved a total of 2897 participants with a primary diagnosis of ADD (e.g., with or without hyperactivity). This meta-analysis reported that most common side effects were ‘‘decreased appetite’’, ‘‘insomnia’’ and/or ‘‘stomach ache’’. In a double-blind, placebo-controlled trial

¨ niversitesi, Kurupelit kampu¨su¨, Samsun, Correspondence: Koray Karabekiroglu, C ¸ ocuk ve Ergen Psikiyatrisi Poliklinig˘i, C ¸ ocuk Hastanesi. Ondokuz Mayis U Turkey. Tel.: 90 362 312 1919 3753. Fax: 90 216 341 3872. E-mail: [email protected], [email protected]

(Received 10 December 2006; accepted 2 May 2007) ISSN 1365-1501 print/ISSN 1471-1788 online # 2008 Taylor & Francis DOI: 10.1080/13651500701435954

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Predicting side effects of MPH-IR [7], they examined parent- and teacher-reported adverse effects in 82 children diagnosed with ADHD who received either a low (0.3 mg/kg) or high (0.5 mg/kg) dose of MPH twice daily. They found that both levels of medication resulted in mild levels of ‘‘decreased appetite’’, ‘‘insomnia’’, ‘‘anxiety’’, ‘‘irritability’’, and ‘‘emotional lability’’ in more than 50% of the sample. One-third of the sample reported ‘‘abdominal pains’’ and ‘‘headaches’’. These symptoms were also present in the placebo group to a lesser degree, which suggests that the symptoms may be characteristic of ADHD rather than side effects associated with stimulants. They concluded that MPH treatment for ADD exhibits a short-term safety profile. Other less frequently reported short-term side effects include ‘‘mood disturbance’’, ‘‘tics’’, ‘‘anxiety’’, ‘‘nightmares’’, and ‘‘social withdrawal’’ [8]. The reported short-term side effects of MPH-IR are usually mild and responsive to dose adjustment and often abate with continuous use. Most side effects and other unwanted symptoms are most likely to be evident within the first few days or weeks of therapy and can often be effectively managed without discontinuing an otherwise effective preparation [9]. Serious adverse events, such as hallucinations, are rare. Continuous use has been associated with slowing of physical growth, which is slight, transient and of unclear cause [10,11]. However, a recent study that investigated methylphenidate-induced aberrations in growth parameters and insulin-like growth factor (IGF)-I in children with ADHD found that MPH treatment had no sustained effects on growth parameters and IGF-I [12]. Some of the previous studies consider the impact of co-morbidity on the efficacy of MPH. However, studies that explore the impact of co-morbidity
other than tic disorders and Tourette syndrome
on the side effects profile of MPH-IR are still needed. In this study, in a clinical sample, in a period of 6 months, we aimed to investigate the effect of gender, psychiatric co-morbidity and baseline severity of clinical symptoms, such as inattention and hyperactivity, on short-term side effects of the MPH-IR monotherapy. As MPH-IR has a rapid onset of action and most side effects appear in shortterm, and in order not to avoid necessary medication for co-morbid conditions for a long period of time, this study addresses individual variabilities only for short-term side effects of MPH-IR. In this shortterm, side effects were assessed on the third, seventh and 15th days of MPH-IR monotherapy.

Method Setting and subjects In a clinical sample, in a period of 6 months, all MPH-naive patients with attention deficit hyperac-

49

tivity disorder (ADHD) (N 90; [male, n 73; female, n 17] age: 9.092.2 years (5
16 years)), whose parents accepted to participate in the study with an informed consent, were included. Mean Clinical Global Impression (CGI) for ADHD was 4.391.35 (2
7). Of the patients with ADHD, 70.5% had at least one co-morbid diagnosis, including learning disorders (26.7%), conduct disorder (16.7%), obsessive-compulsive disorder (16.3%), Tourette syndrome (TS) (10.1%), and depression (9.2%). Procedure All patients were assessed clinically and psychiatric clinical diagnosis was based on a comprehensive evaluation of the patients. The Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version-Turkish Version (K-SADS-PL-T) was used in a specilized child and adolescent psychiatry clinic. The assessment included structured measurements, including the Turgay Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) [13] (parents and teachers), and the Conners’ Teacher Rating Scale for ADHD-Short version (teachers) [14]. Parents also completed the ‘‘Barkley Stimulants’ Side Effects Rating Scale’’ (BSSERS) [7] at baseline and on the third, seventh and 15th days of the medication. Baseline measures also included clinical global impression (CGI) for ADHD, structured diagnostic interview based on DSM-IV (K-SADS-PL-T), socio-economic status index, and family history for psychiatric disorders. For a wash-out period, patients did not receive any medication for the last 15 days before initiating MPH-IR. MPH-IR monotherapy was administered according to the age and the school schedule, 2
3 times/day (2.390.51), with an average dose of 17.694.95 (10
30) mg/day. Measures Barkley Stimulants’ Side Effects Rating Scale (BSSERS) (parents) [7]. This scale (17 symptoms; 0absent, severity rated from 1 to 9) was developed by Barkley and it assesses the frequency and severity of 17 common side effects of each stimulant, each rated on a Likert-type scale. Turgay Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) (parents and teachers) [13]. This scale consists of 41 items (0absent, severity rated from 1 to 3). The items are mostly the DSM-IV criteria of disruptive behavior disorders. The Turkish translation and the validity study of T-DSM-IV-S were made by Ercan et al. [13].

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K. Karabekiroglu et al.

Conners’ Teacher Rating Scale for ADHD-Short version (CTRS) (teachers) [14]. This is another scale which mostly covers symptoms of disruptive behavior disorders. The items are rated by teachers from 1 to 4 on a Likert-type scale. The Turkish translation and the validity of CTRS were made by two studies [15,16]. Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version-Turkish Version (K-SADS-PL-T) [17,18]. K-SADS-PL-T is a structured diagnostic assessment schedule based on DSM-IV criteria of major psychiatric disorders. It is an effective instrument for diagnosing major childhood psychiatric disorders. The validity of K-SADS-PL-T was found to be excellent for elimination disorders, good for attention deficit and hyperactivity disorder and tic disorders, fair for affective disorders, anxiety disorders and oppositional defiant disorder. The interrater reliability was observed to be excellent for elimination disorders and tic disorders, good for attention deficit and hyperactivity disorder and anxiety disorders. The test
retest reliability was observed to be excellent for elimination disorders, tic disorders, attention deficit and hyperactivity disorder and anxiety disorders. Psychiatric Assessment Sociodemographic Form. This form included most sociodemographic, medical and developmental variables for childhood psychiatric assessment, such as complaint history, family relations, medical problems, cultural background, etc. Data analyses In order to avoid excluding the cases who discontinued MPH-IR because of the side-effects from the overall analysis, the missing data on BSSERS for patients who discontinued treatment because of side effects (n 8) were replaced with the highest severity point ‘‘9’’ for the reported side effects. The repeatedmeasures ANOVA was used to assess the significance of increase in side effect severity for each item, from day 0 to the third, seventh and 15th days. For each item, where the Friedman test revealed significance difference, the Wilcoxon test was computed for day 0 to day 3, day 0 to day 7, and day 0 to day 15. To assess the difference in severity of the side effects
as three different time periods (from day 0 to day 3, day 0 to day 7, and day 0 to day 15) were evaluated
P  0.05 is divided by 3 and P B0.016 was assumed to represent a significant difference. In the exploratory post hoc analyses, the group was divided into two, in terms of increase or decrease in side effect severity, as ‘‘affected’’ and ‘‘not-affected’’. The patients whose total side effect measure was higher in the 15th day with respect to basal measure, as well as the patients who discontinued medication because of side effect, were accepted as ‘‘affected’’ and the patients whose total side effect measure was lower or not different with respect to basal measure were

accepted as ‘‘not-affected’’. The one-way analysis of variance and the chi-square tests were used to measure differences between two groups, in terms of sex, age, symptom severity, co-morbidity. In this post hoc analysis, P B0.05 was assumed as significant difference. SPSS 10.0 was used for all statistical calculations. Results Seventy-seven patients out of 90 (85.6%) maintained treatment beyond the 15th day. Five patients discontinued MPH-IR due to ‘‘noncompliance’’ and/or ‘‘lack of efficacy’’. Eight (8.9%) patients discontinued due to the side effects of MPH, which included ‘‘loss of appetite’’ in three patients, ‘‘exacerbation in tic severity’’ in two patients, ‘‘irritability’’ in two patients, and ‘‘proneness to cry’’ in one patient. One of the patients who discontinued MPH because of ‘‘loss of appetite’’, additionally had ‘‘withdrawal’’, the second had ‘‘delay of sleep onset’’, and the third had ‘‘stomach aches’’ as side effects. Seven out of these eight cases had one or two comorbid diagnosis: TS (N2), learning disorder (N 2), depression (N 2), obsessive-compulsive disorder (N 1) and conduct disorder (N 1). Figure 1 presents the percentages of subjects who exhibited increase, decrease or ‘‘no change’’ in the severity of each item from the baseline to the 15th day of MPH-IR medication. Overall changes in side effect severity in the first 15 days of treatment Repeated measures multiple analyses of variance revealed an overall significant difference on Barkley’s Side Effects Severity Scale points (P B0.01), that allowed oneway ANOVA tests for each side effect. Significant changes were found on the items of ‘‘loss of appetite’’, ‘‘irritability’’, ‘‘proneness to cry’’, ‘‘anxiety’’, ‘‘nail biting’’, and ‘‘euphoria’’ (Table I). Only the severity of the ‘‘loss of appetite’’ item increased, while the remaining five symptoms decreased significantly. Within group comparisons (‘‘affected’’ versus ‘‘non affected’’) The total sum of all items in BSSERS was calculated. The subjects with an increase in the sum, as well as subjects who discontinued medication because of side effect, were accepted as ‘‘affected’’ and the ones who showed decrease or no difference were accepted as ‘‘not-affected’’. When the ‘‘affected’’ and ‘‘not-affected’’ groups were compared, a chi-square revealed a significant difference, in terms of side effect severity of MPH-IR, only for the for the presence of a co-morbidity (P 0.029), but not for gender, age, dosage of MPH, CGI for ADHD,

Predicting side effects of MPH-IR

51

Change in Side Effects (Day0 to Day 15) 90 80 70 60 %

50 40 30 20 10 sl e lo ep ss on of se ap t pr e on irri tite en tab es ilit y s to c an ry x sa iety d he nes st ad s om a ac che ni hac g h h ta lk day tm e in g dre are s le ss am to ing ot w ith her s dr dra ow wa s l na ine il ss bi eu ting ph di ori zz a in es s tic s

0

de

la y

of

decreased not changed increased

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side effects

Figure 1. Percentages of subjects who exhibited increase, decrease or ‘‘no change’’ in severity of each item of Barkley Stimulants’ Side Effects Rating Scale (BSSERS) from baseline to the 15th day of MPH-IR medication.

severity of ‘‘inattention’’ and ‘‘impulsivity-hyperactivity’’ (Tables II and III). Discussion MPH is the medication that is almost universally prescribed for ADHD, making it the de facto ‘‘gold standard’’ [19]. On the other hand, being a ‘‘gold standard’’ does not exclude untoward effects. Any negative reaction to a stimulant may result in the patient or parent stopping the medication, even if it is beneficial [20]. Our clinical practice suggests that some of the reported side effects may already exist as a symptom before medication is initiated and/or diminish after MPH-IR usage. Symptoms of ADHD and reported side effects of MPH-IR may be similar (e.g., ‘‘irritability’’, ‘‘day dreaming’’, etc.) and must be differentiated carefully. In the first weeks of medication, compliance
which would be better

without adverse effects
may increase overall efficacy of MPH-IR. The results of this study reveal that the reported side effects of MPH-IR may exist before medication and even subside with short-term MPH-IR treatment (e.g., ‘‘anxiety’’, ‘‘proneness to cry’’). ‘‘Loss of appetite’’ is found to be the only item in BSSERS, whose severity significantly increased with shortterm MPH-IR treatment. Similarly, a previous study reported ‘‘appetite suppression’’ as the most common adverse effect associated with stimulant use [21]. Many children with ADHD have sleep-related problems even before they begin stimulant medication. Nevertheless, mild insomnia is another common, dose-related side effect [21
23]. The second highest, although nonsignificant increase in our sample was in the severity ‘‘delay of sleep onset’’ (35%). It is typically worse during the first few days on medication but may well persist throughout the

Table I. Average side effects severity scores on Barkley Stimulants’ Side Effects Rating Scale (BSSERS) Baseline and on the third, seventh and 15th days of MPH-IR medication. Side effects /symptoms (Barkley Stimulants’ Symptom severity Symptom severity Symptom severity Symptom severity Side Effects Rating Scale) Day 0 (1) Day 3 (2) Day 7 (3) Day 15 (4) Delay of sleep onset Loss of appetite Irritability Proneness to cry Anxiety Sadness Headache Stomachache Nightmares Day dreaming Talking less to others Withdrawal Drowsiness Nailbiting Euphoria Dizziness Tics

2.42 3.10 5.16 4.06 3.27 2.89 1.12 1.52 1.24 2.67 1.17 2.51 1.03 2.11 2.91 .31 .81

2.70 3.88 3.73 2.79 1.74 1.77 .98 1.34 .61 1.50 1.35 1.60 1.03 1.85 2.16 .56 .86

2.44 3.86 3.78 2.71 1.92 1.89 .89 1.23 .64 1.52 1.07 1.44 1.05 1.65 1.93 .38 .74

2.54 4.24 3.74 2.87 1.85 2.00 .72 1.34 .69 1.78 1.21 1.75 1.01 1.51 1.81 .49 .69

Overall Significance 0.92 0.001 (
) 0.000 (¡) 0.001 (¡) 0.000 (¡) 0.067 0.71 0.90 0.019 0.082 0.89 0.26 0.42 0.009 (¡) 0.001 (¡) 0.36 0.72

Source of significance

1:2; 1:2; 1:2; 1:2;

1:4 1:3; 1:4 1:3 1:3; 1:4

1:4 1:2; 1:3; 1:4

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K. Karabekiroglu et al.

Table II. Comparison of side effect severity of MPH-IR between the ‘‘affected’’ and ‘‘not-affected’’ groups in terms of gender, age, dosage of MPH-IR, baseline CGI for ADHD, severity of ‘‘inattention’’ and ‘‘hyperactivity’’. Patients ‘‘affected’’ or ‘‘not affected’’ by side effects of MPH-IR ‘‘Not affected’’ N (%) Gender Boys Girls Total

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Age (years) mg/day Baseline CGI T-DSM-IV-S (DSM-IV- ADHD) I˙nattentive (parents) Impulsive-hyperactive (parents) Inattentive (teachers) Impulsive-hyperactive (teachers)

‘‘Affected’’ N (%)

38 (64.4) 8 (53.3) 46 (62.1)

21 (35.5) 7 (46.6) 28 (37.8)

(m9SD) 9.0492.29 18.0494.88 4.2791.38

(m9SD) 9.2592.23 18.0595.29 4.4291.30

16.7395.87 17.2495.83

17.3695.09 16.4895.40

16.9796.10 16.7197.74

19.0596.29 18.4597.06

Total N (%)

59 (100.0) 15 (100.0) 74 (100.0)

Patients with inappropriate or inconsistent data are excluded (e.g., patients whose scales had missing data, n16), *PB0.05. CGI, Clinical Global Impression; MPH-IR, methylphenidate immediate-release; T-DSM-IV-S, Turgay Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)-Based Child and Adolescent Behavior Disorders Screening and Rating Scale.

treatment period. The results of our study reveal that, in the first 15 days of medication relatively few cases discontinued MPH-IR because of side effects (7.7%). Stimulants have been associated with tics, and clinicians avoid trying MPH in individuals with tic disorder co-morbiditiy. Our findings, together with reports of infrequent de novo appearance or exacerbation of tics, and reports on improvement of tics with MPH in some cases [24] suggest that a diagnosis of tic disorder or TS should not be considered as an absolute contraindication of MPH in the treatment of ADHD with co-morbid tics. Co-morbidities, including tics, psychotic disturbances, and disorders associated with mood and anxiety, also must be considered because associated co-morbidities may predict nonoptimal response to stimulants [25]. Our results reveal that overall severity of the side effects and the side-effect related discontinuation of MPH-IR were found to be higher

in patients with a co-morbid psychiatric diagnosis, especially with Tourette syndome, depression and obsessive-compulsive disorder. This significant difference in side effects severity between patients with or without co-morbid psychiatric condition may be explained by several hypothesis: (1) the enduring symptoms of the co-morbid condition may be confused with side effects (e.g., ‘‘proneness to cry’’ in depression), (2) the symptoms of the co-morbid condition may exacerbate with MPH-IR (e.g., tics in the Tourette syndome), (3) due to its mechanism of action, for instance the effects on dopamine transporter protein, MPH-IR may cause more side effects in patients with special psychiatric traits (e.g., obssesive compulsive disorder) and states (e.g., depression). Depression is an uncommon but serious direct effect of stimulant medication. Most often the symptoms appear slowly only after several months on stimulants and following an initially favorable response [21]. One fourth of our sample

Table III. Co-morbidity rates in the ‘‘affected’’ and the ‘‘not-affected’’ groups. Patients ‘‘affected’’ or ‘‘not affected’’ by side effects of MPH-IR ‘‘Not affected’’ (n46)

‘‘Affected’’ (n28)

Total (n 90)

(%)

(%)

(%)

P

Co-morbid diagnosis Conduct disorder Chronic tic disorder Tourette Syndrome OCD PDD-NOS Learning disorder Depression

13.3

23.1

16.7

0.05

23.9 4.3 15.2 8.7 23.9 13.0

18.5 14.8 14.8 3.7 33.3 3.6

23.3 10.5 16.3 8.1 26.7 9.2

0.05 0.05 0.05 0.05 0.05 0.05

Total*

60.9

85.2

70.9

B0.05

Patients with inappropriate or inconsistent data are excluded (e.g., patients whose scales had missing data, n 16), *PB0.05. OCD, obsessive-compulsive disorder; PDD-NOS, pervasive developmental disorder
not otherwise specified.

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Predicting side effects of MPH-IR experienced an increase in ‘‘sadness’’ on the 15th day of treatment. On the other hand, in a placebo-controlled study of children treated with two doses of medication, approximately one third of the sample experienced mood lability, tearfulness, or irritability when the medication was wearing off [26]. The adverse effects which appear during the last minutes of predicted effective time period of MPH-IR, in other terms, rebound effects of MPH-IR should be differentiated from absolute side effects. As all parents were warned about the time period when rebound effects may appear, our study may be assumed valid for absolute short-term side effects of MPH-IR. Limitations As MPH-IR has a rapid onset of action and most side effects appear in short-term, and in order not to avoid necessary medication for co-morbid conditions for a long period of time, this study addresses individual variabilities only for short-term sideeffects of MPH-IR monotherapy. This study does not investigate possible side-effects of MPH-IR which may appear in the longer duration of medication. While the sample size was not large enough, the effect of co-morbidity on the severity of side effects could not be assessed for each co-morbid diagnosis group separately (e.g., Tourette syndrome). In order to distinguish rebound effects from absolute side effects, the parents are warned to report any side effect observed in 3
4 h after medication. However, this study design may not properly exclude rebound effects such as ‘‘irritability’’ or ‘‘hyperactivity’’. Conclusion The results indicate that some items of the BSSERS could themselves be symptoms, but not side effects, and decrease in severity by the MPH-IR medication. Therefore, baseline measurement of the severity of possible side effects and/or symptoms should be obtained before medication. In the short-term, MPH-IR can be considered as a safe medication for ADHD. When the overall BSSERS item severity is considered, our findings suggest having a comorbid diagnosis predicts more untoward effects. Co-morbid cases should be more closely monitored for side effects and these untoward effects mey benefit from concurrent medication for the comorbid psychiatric condition. Key points . The efficacy of stimulant medications has long been recognized clinically in previous researches and the short- and intermediate-term

therapeutic efficacy of psychostimulants for treating children with attention deficit/hyperactivity disorder (ADHD) is well-established . In this study, in children and adolescents who were prescribed immediate-release methylphenidate (MPH) for the first time, we aimed to investigate the effect of gender, psychiatric comorbidity and baseline severity of clinical symptoms on short term side effects of the medication . The only significant increase during MPH treatment was for the ‘‘loss of appetite’’ item on ‘‘Barkley Stimulants’ Side Effects Rating Scale’’ (BSSERS) . When subjects whose side effects increased and did not increase were compared, there was a significant difference only for the presence of comorbidity, and no difference for gender, age, dosage of MPH, baseline severity of inattentiveness and/or hyperactivity were found. Thus, having a comorbid diagnosis may be predictive of more severe adverse effects Statement of interest/Acknowledgements This research had a naturalistic design. Therefore, a limited financial support, which was supplied by the authors, was needed.

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