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Pre-school attention deficit hyperactivity disorder: 12 weeks prospective study
Asian Journal of Psychiatry 48 (2020) 101903
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Pre-school attention deficit hyperactivity disorder: 12 weeks prospective study
T
Sivapriya Vaidyanathana, Tess Maria Rajanb, Venkatesh Chandrasekaranc,1, Preeti Kandasamya,* a
Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India Department of Child and Adolescent Psychiatry, National Institute of Mental Health and Neuro-Sciences, Bangalore, India c Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India b
A R T I C LE I N FO
A B S T R A C T
Keywords: Attention deficit hyperactivity disorder Preschool ADHD Pharmacotherapy
Introduction: Extant literature lack studies on behavioural training or pharmacotherapy in Indian preschool children. With adverse long term outcomes, effective, safe and affordable early interventions for ADHD are a priority. Aim of this prospective study is to report on short term outcome of preschool ADHD with specific focus on safety and tolerability of medications. Methods: Children with ADHD aged 2.5–6 years were assessed for severity and adverse events at baseline and follow-up using Conner’s abbreviated rating scale and Clinical Global Impression-Severity scale. Children with Autism spectrum disorder and those with social quotient less than 50 were excluded. Statistical Analysis included descriptive statistics and Repeated measures ANOVA. Results: Of 56 children recruited, 33.93 %(N = 19) were on behavioural interventions alone, 66.07 %(N = 37) were on a combination of medication and behavioural intervention. All children received treatment according to standard care. The most prescribed drug was clonidine (44.64%), then risperidone (28.7%), methylphenidate (10.7%) and atomoxetine (10.7%). Medication choice was determined by affordability, availability and comorbidity profile. Sedation occurred in 24 % of children on clonidine. Atomoxetine was not well tolerated in 2 children. Methylphenidate was well tolerated. Irrespective of medication choice, all children showed significant improvement at 12 weeks (p < 0.001). Conclusions: Choice of interventions is largely determined by availability and affordability. There is a need for structured parent behavioural training program deliverable in low resource setting. Anti-ADHD medications should be made available under the NMHP, RBSK program and all government settings in India, to address overprescription of antipsychotics in preschool ADHD.
1. Introduction Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with the presence of pervasive inattention and/or hyperactivity-impulsivity that interferes with functioning directly (Association AP, 2013). The long term outcomes of children with ADHD are multiple and in various psychosocial, educational and neuropsychological domains when compared to those without this disorder. There is a higher lifetime occurrence of antisocial, anxiety, mood and substance use disorder in these individuals (Biederman et al., 2010, 2012). The prevalence of ADHD, in India in primary school children is 11.32%. (Venkata and Panicker, 2013) In preschool children the
prevalence is at 12.2% (Suvarna and Kamath, 2009). Diagnostic stability of ADHD at this age is varied. One study found that about 74.5% retained the diagnosis of ADHD at the end of 3 years (Garg and Arun, 2013). To the contrary, other study noted that only 40% retained diagnosis at 3 months follow up (Srinivasaraghavan et al., 2013). The differences in these studies could be due to varying sample size, age, duration of follow up and, the difference in assessment tools. However, currently, there are no biomarkers for predicting the long term outcomes, although clinical parameters such as baseline severity, associated comorbidity such as conduct or oppositional defiant disorders and age of intervention contribute to long term outcome (Riddle et al., 2013; Jacob et al., 2016). This makes early diagnosis and intervention paramount in ADHD due to its long term implications in avoiding these
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Corresponding author. E-mail addresses: [email protected] (S. Vaidyanathan), [email protected] (T.M. Rajan), [email protected] (V. Chandrasekaran), [email protected], [email protected] (P. Kandasamy). 1 Department of Psychiatry and Paediatrics, JIPMER, Puducherry. https://doi.org/10.1016/j.ajp.2019.101903 Received 30 April 2019; Received in revised form 10 December 2019; Accepted 13 December 2019 1876-2018/ © 2019 Elsevier B.V. All rights reserved.
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deficits. Treatment for ADHD in this age group has several limitations. Behaviour therapy is recommended as first-line treatment for ADHD in children (Wolraich et al., 2019). Preschool children are ideal candidates for behavioural therapy considering the risk-benefit ratio with pharmacological interventions and its long term impact on their neurotransmitter systems. However, there is a lack of studies evaluating the efficacy of a structured behavioural parent training module for preschool children with ADHD in the Indian setting. While developed nations have parenting programs, studies on feasibility in implementing similar modules with due consideration to socio-cultural aspects and available health care resources are limited which makes pharmacological treatments a necessary treatment alternative. The FDA approved pharmacological management of ADHD includes methylphenidate, clonidine extended release and atomoxetine for children in the age group of over 6 years (Brown et al., 2018). However off-label use of stimulants, clonidine, atomoxetine, antipsychotics and other drugs are prescribed in preschool age-group though the occurrence of adverse effects with methylphenidate and atomoxetine was found to be more in the pre-school age group (Vitiello et al., 2015). Clonidine is often prescribed especially in children with sleep disturbances, there is however inadequate evidence for its safe use in this population (Prince et al., 1996). With the current context of the Rashtriya Bal Swasthya Karyakram (RBSK) introducing district early intervention centres and weekly child guidance clinic to facilitate early recognition and management of neurodevelopmental disorders, testing the efficacy and tolerability of affordable treatment options is a priority (Rashtriya Bal SwasthyaKaryakram, 2019; "Directorate General Of Health Services",n.d.) With this in the background, this study aimed to examine the clinical profile, short-term course and outcome, with specific focus on pharmacological interventions, its safety and tolerability in pre-school children with ADHD receiving standard care in a child guidance clinic in South India.
children on clonidine was checked. All the children received treatment according to the standard care offered which included pharmacotherapy, behavioural therapy or a combination of both. Behaviour therapy included parent training approaches used in preschool ADHD, generally referred to as behavioural parent training (BPT); typically apply principles learning and reinforcement to teach parents behavioural strategies to manage problem behaviours in young children (Charach et al., 2013). Components comprised of structuring of routine, improving parental communication and stress, attention enhancing tasks, differential reinforcement strategies and social stories by Dr SV (Anon, 2019). The choice of treatment modality was that of the treating team and was not influenced by the investigators. Of the 56 subjects recruited initially, 51 completed the follow-up and were included in the analysis. Reasons for drop out were unknown in n = 3 children, due to logistic difficulties in following up in n = 1child and pregnancy of mother in n = 1 child. 2.4. Statistical analysis All statistical analysis was carried out using SPSS version 19.0. Categorical variables are represented as frequencies and percentages. Continuous variables are represented as means and standard deviations. Comparisons done using Repeated measures ANOVA with time as a within subjects factor and group as in between subject factors. Bivariate correlation analysis using Pearson’s correlation was done to identify predictors of child-related outcome variables. 3. Results 3.1. Profile of children The socio-demographic profile and clinical profile of the children in both groups those who received only behavioural intervention and those who received combination treatment recruited in this study are depicted in Tables 1 and 2. There were no statistical significant differences in the 2 groups at baseline in sociodemographic data; however there was a statistically significant difference in baseline severity between the 2 groups with those on combination treatment having more severe ADHD. The predominant subtype of ADHD was the combined type; 71.4% of the children had a history of developmental delay. Table 3 shows intervention variables. Of the 56 children recruited, 66.07 %(N = 37) of children were on medication for ADHD and 33.93 %(N = 19) were only on behavioural interventions. Children received combination of behavioural intervention and pharmacotherapy whenever indicated. Indication for pharmacotherapy were baseline moderate or severe illness in 86.4%, failure of trial behaviour therapy (8.9%) and parental preference due to logistic difficulty in implementing structured behavioural interventions in 54.05%. Failed behavioural interventional trial was defined as intensive structured behavioural interventions for a minimum of 8 weeks duration (Pliszka, 2007).
2. Materials and methods 2.1. Study setting and design The study was conducted in the child guidance clinic of a tertiary care centre in South India from December 2017 to December 2018. It was a prospective study. 2.2. Study participants A total of 64 children were screened of whom 56 were consecutively recruited after written informed consent. Children aged 2.5–6 years with a diagnosis of ADHD according to DSM 5, with a reliable informant were included and children with autism spectrum disorder and social quotient less than 50 were excluded. 2.3. Methodology
3.2. Pharmacological interventions The study was approved by Institute Ethics Committee. Primary caregivers, mostly the mothers, were interviewed using a semi-structured proforma for the socio-demographic profile; this was done in addition to diagnostic workup, comprehensive evaluation, and initiation of treatment as usual for ADHD by the primary treating team. ADHD symptom profile and severity assessment were done at baseline and at follow-up using Conner’s abbreviated rating scale, and Clinical Global Impression-severity scale (Busner and Targum, 2007; Ullmann et al., 1985). Re-assessment was done at 4,812 weeks follow up. The occurrence of any adverse event was documented using a checklist and through physical examination, weight monitoring and vitals monitoring including pulse rate, blood pressure, cardiovascular examination of
Of those who were on medication, most commonly prescribed drug was Clonidine (Table 3). The mean age of children receiving clonidine was 59.08 ± 15.3 months. Cardiology opinion, electrocardiogram and 2 dimensional ECHO was done for children less than 4 years age which included 12% of the recruited children (N = 3). In addition to baseline severity, presence of impulsivity posing danger to self, severe and prolonged tantrums and sleep disturbance were some of the clinical indicators which were considered before deciding on pharmacological intervention with informed decision of parents and cardiac clearance as part of standard care (Ming et al., 2011; Shier et al., 2012). 2
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Table 1 Socio-demographic details of the study population. Socio demographic parameters
Sex
Male Female
Employment status of primary care Homemaker giver Employed Years of schooling of Primary care giver Socioeconomic status Lower Middle Upper Domicile Rural Urban
Total participants (n = 56) Mean (Standard deviation)/ N (%)
Participants on combination therapy alone Mean (SD)/ N (%)
Participants on combination therapy alone Mean (SD)/ N (%)
Comparison Chi square/T (p value)
7(83.9) 9(16.1) 43(76.8) 13(23.3) 10.6 (4.84) 35(62.5) 16(28.6) 5(8.9) 30(53.6) 26(46.4)
32(86.4) 5(13.5) 28(75.67) 9(24.32) 10.24(4.34) 25(67.56) 11(29.72) 1(2.70) 23(62.16) 14(37.84)
15(78.94) 4(21.05) 15(78.94) 4(21.05) 11.31(5.76) 10(52.63) 5(26.31) 4(21.05) 7(36.84) 12(63.15)
ƛ2 = 0.53(0.47)
Clonidine was the primary choice of drug in 84%(N = 21) of children on treatment. The most common reason for choice was cost-effectiveness 68% (N = 17), followed by presence of seizure disorder which is a relative contraindication for methylphenidate in 20% (N = 5) and need for sedative property in 4%(N = 1). The minimum dose decided as per weight of clonidine was started at was 0.025 mg. The mean dose and adverse effects are shown in Table 4. Clonidine was up titrated over 12 weeks in 88% of the children. It was augmented with risperidone in 40 %(N = 10) of children. Most common adverse effect with clonidine was sedation. It occurred in 24 %(N = 6) of children receiving clonidine but it was persistent over 12 weeks in only one and resulted in the change of the drug due to excessive sedation. Most common dosing regimen was night time dosing followed by divided doses with the afternoon dose being given afterschool. This strategy was used to counter the sedative adverse effects in the other five children. Among children receiving other pharmacological agents, atomoxetine was not well tolerated in 2 children. However no significant adverse effects were noted among those receiving methylphenidate. The sample receiving these two medications was too small to make clinically meaningful inference. Care was taken to ensure baseline growth parameters before treatment initiation with methylphenidate as part of standard care.
ƛ2 = 1.8(0.76) t=-0.78(0.438) ƛ2 = 5.23(0.073)
ƛ2 = 3.24(0.0720
Table 3 Interventions for preschool ADHD.
Behaviour therapy alone Combined BT + pharmacotherapy Methylphenidate Clonidine Atomoxetine Risperidone alone Risperidone augmentation Total
Frequency
Percentage
19 37 6 25 6 3 13 56
33.9 66.1 10.7 44.64 10.7 5.4 23.2 100.0
ADHD- Attention deficit hyperactivity disorder. BT- Behaviour therapy.
3.3. Treatment efficacy Irrespective of the pharmacotherapy or behaviour therapy all the children improved form baseline to completion of interventions. as measured by Repeated measures Analysis of Variance (RMANOVA) Significant difference was found in reduction in ADHD symptom severity as measured by Conner’s abbreviated rating scale, at the end of 12 weeks of intervention (F = 63.4; p < 0.001) The improvement in severity score on CGI-S and Conner’s abbreviated rating
Table 2 Clinical profile of the children. Clinical profile of the children
Total participants (n = 56) Mean (SD)/ N (%)
Participants on combination therapy alone Mean (SD)/ N (%)
Participants on behaviour therapy alone Mean (SD)/ N (%)
Comparison Chi square/T (p value)
Age (in months) Family history of psychiatric illness Developmental delay Specific(Speech and language delay) Global Comorbidities Seizure disorder ODD Anxiety disorder SLD DSM5 Subtype of ADHDCombined, Inattentive, Hyperactive-Impulsive Baseline CGI-S Score Baseline Conner’s abbreviated rating scale
57.82 (15.12) 27(48.2) 27(48.2)
60.48(14.87) 21(56.7) 18(48.64)
52.63(14.60) 6(31.57) 9(47.3)
1.88(0.069) 3.19(0.17) ƛ2 = 0.17(0.91)
13(23.2) 11(19.64) 4(7.14) 2(3.57) 5(3.57) 31(55.4). 11(19.6), 14(25)
8(21.61) 8(21.6) 4(10.81) 1(2.7) 5(13.51) 20(54.05), 6(16.21), 11(29.72)
5(26.31) 3(15.79) 0(0) 1(5.2) 0(0) 11(57.9), 5(26.31), 3(15.78)
4.37(1.00) 20.92(4.01)
4.67(0.97) 21.89(4.18)
3.78(0.78) 19.05(2.95)
ADHD-Attention deficit hyperactivity disorder. CGI-S-Clinical global impression-Severity rating scale. DSM 5- Diagnostic and Statistical Manual of Mental Disorders Version 5. ODD-Oppostional defiant disorder. SLD-Specific learning deficits. 3
ƛ2 ƛ2 ƛ2 ƛ2 ƛ2
= = = = =
0.27(0.732) 2.21(0.28) 0.24(1) 2.81(0.16) 1.6(0.4)
t = 3.4(0.001) t = 2.6(0.01)
Asian Journal of Psychiatry 48 (2020) 101903
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Table 4 Pharmacotherapy in preschool ADHD- dose and adverse effects.
Dose range Average dose Reasons for prescribing
Adverse effects Strategies to cope with adverse effects
Clonidine
Risperidone
Atomoxetine
Methylphenidate
0.025-0.150mg 0.074 ± 0.03 mg Affordability (67.6%) Comorbid seizure disorder (18.91%) Sleep disturbances (5.40 %) Sedation(N = 6)
0.5-3mg 1.45 ± 0.90 Affordability (100%) Aggression (31.25%) Augmentation- (62.5%)
10-18mg 16.85 ± 3.02 Comorbid anxiety disorder(N = 2) Inattentive type ADHD(N = 4)
5-25mg 10.83 ± 7.35 –
Weight gain (N = 2) Sedation(N = 1) Dose reduction(N = 2) Divided dosing Afterschool dosing(N = 0) Night time dosing(N = 2)
Hyperbilirubinemia(N = 1) Worsening of symptoms(N = 1) Discontinuation(N = 1) Augmentation with Risperidone(N = 3)
Nil
Divided dosing(N = 2) Afterschool dose(N = 2) Dose reduction(N = 1) Change of drug(N = 1)
Nil
ADHD-Attention deficit hyperactivity disorder.
children primarily due to affordability, presence of comorbid seizure where methylphenidate is contraindicated or presence of sleep disturbances in the child were the other clinical reasons to choose clonidine. Clonidine appeared largely well tolerated and the most common adverse effect with clonidine was sedation as described in literature (Connor et al., 1999). Afterschool and night-time dosing strategies could address this in majority of children. There were no cardiac sideeffects in any of the children. However, nearly 40% of those on clonidine (N = 10) required augmentation with risperidone in the dose range 0.5−2 mg which needs attention. In literature search there was a dearth of data noted regarding study looking into the safety and tolerability of clonidine in the preschool age group. In study by Prince et al., 1996, 85% of children aged 4–12 years were treated with clonidine for ADHD associated with sleep disturbances and 31% had mild adverse effects (Prince et al., 1996). Studies show that alpha agonist medications accounted for 42% of the offlabel prescriptions for children ages 3–5 years, which was more than those written for methylphenidate formulations combined (41%) even though methylphenidate is the first-line medication recommended by the AAP guidelines for use in children starting at age 4 years. Clonidine and guanfacine both immediate and extended release combined accounted for 42.6%. It was also reported that clonidine immediate release tablets at 97.6% are prescribed more often than the extendedrelease tablets at 1.2% and patches at 1.2% (Panther et al., 2017). Guanfacine and extended release formulations of clonidine if available may be used as an alternative strategy to counter the sedation however these formulations are not available in the Indian context. Current evidence points towards a possible role of oxidative stress in pathogenesis of ADHD where in patients with ADHD have normal levels of antioxidant production, but that their response to oxidative stress is insufficient, leading to oxidative damage (Joseph et al., 2015). Neuroprotective effects of alpha 2 adrenorecepter agonists has been under investigation and with promising results, this could give clonidine an added edge over other treatment options (Ma et al., 2005). The AAP guidelines note efficacy, but limited supporting evidence for the extended-release formulation of the alpha agonist medications in children older than preschool-age, and do not support immediate release use for any age group and do not mention the use of other dosage forms such as the clonidine patch (Wolraich et al., 2019). Although these results are preliminary and observational, clonidine appears to be well tolerated, cost effective and helpful in ameliorating baseline severity in preschool ADHD, however need for risperidone augmentation in a significant number of children is a concern. Further randomised controlled studies and head-head comparison with methylphenidate and atomoxetine to explore its safety and efficacy for this population is warranted. In this study 28.7 % received antipsychotic risperidone population which is very high in comparison to the PATS study where it was only
There was also a significant difference in group effect in favour of the combination interventions on change in Conner’s abbreviated rating scale (F = 6.67, p = 0.013, ES (η2) = 0.124) although weak. The group requiring combination pharmacotherapy was too heterogeneous to compare individually and include in analysis. By the end of 12 weeks, 37.5 % of parents preferred behavioural intervention alone, 17.9 % only pharmacotherapy, 35.7% a combination of both. The various parent and child-related factors which predicted the outcome measure that is change in ADHD severity at the end of 12 weeks of intervention was assessed. Age of the child in months was found to have a negative correlation (r=-0.3, p = 0.035) with difference in severity of ADHD as measured by in Conner’s abbreviated rating scale. Baseline severity of ADHD(r = 0.10, p = 0. 46) and education in years of primary caregiver (r = 0.18, p = 0. 20) was not found was found to have correlation with improvement in symptoms severity. 4. Discussion This study was a prospective follow-up of preschool children diagnosed with ADHD. All medications used to treat ADHD are considered off-label for children younger than age 6 years according to most guidelines. There is limited literature regarding the prescribing of ADHD medications to preschool-aged children. About 84% of this sample was male which is in line with literature (Venkatesh et al., 2012; Jacob et al., 2016). Majority of children belonged to a lower socioeconomic background form rural areas with limited access to specialised mental health care facilities. This also had treatment implications in terms of choice of medication. In our study population, 71.4% had some form of developmental delay and 19.64% had seizure disorder. It was also found that children on pharmacotherapy had higher baseline severity of ADHD. These were other relevant clinical factors which also influenced the need for pharmacotherapy and drug of choice. (Khajehpiri et al., 2014) In our study, only 33.9% of children were on behavioural interventions alone and a majority received pharmacological interventions. Of those who were on medication, most commonly prescribed drug was clonidine at 44.7%, followed by risperidone at 28.7%. This is in contrast to data from other studies where in the most commonly prescribed pharmacotherapy was stimulant monotherapy. In Preschool ADHD Treatment Study (PATS) nearly 40% received receive stimulant monotherapy among pre-schoolers, antipsychotic medication was prescribed at 8.3–13.4% and a variety of other psychotropic, such as alpha2-agonists, antidepressants, and mood stabilizers were also prescribed (Vitiello et al., 2015). Side effects of clonidine include increased sedation that prevents the child from actively engaging in therapy and others such as hypotension and cardiac arrhythmias can be potentially serious (Connor et al., 1999). In our study clonidine was the primary choice of drug in 84% of 4
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combination interventions on change in severity of ADHD (F = 6.67, p = 0.013, ES (η2) = 0.124). In our study age of the child in months was found to have a negative correlation(r=-0.3, p = 0.035) and baseline severity of ADHD and education in of primary caregiver was not found was found to have correlation with improvement in symptoms severity. This was consistent with extant literature although other parameters such as comorbidity, parental psychopathology known to influence outcomes were not analysed in our study. (Biederman et al., 2012; Cherkasova et al., 2013).This also highlights the role of early interventions in improving symptom severity in ADHD. By the end of 12 weeks 37.5% of parents preferred only behaviour therapy while majority preferred pharmacotherapy in combination with behaviour therapy or pharmacotherapy alone in preschool ADHD children. Combined treatment was relatively common at 25% and concerns have been raised about psychotropic polypharmacy in children in light of the dearth of supporting controlled investigations. However, the current evidence-base for combined therapy in the treatment of ADHD is limited to the use of stimulants and alpha-2 agonists, and few studies have evaluated the efficacy and safety of other combinations such as methylphenidate and atomoxetine in children with partial response. (Shier et al., 2012) The cost of methylphenidate is about INR 10 for one 10 mg tablet, atomoxetine about INR 5 for one 10 mg tablet and clonidine is about INR 1 for one 0.1 mg tablet. (DrugsUpdate - News, 2019) In this study the average out-of-pocket expenditure for Clonidine was estimated to be 21–24 INR per month. In our setting, a proportion of children, who could not even afford this, have availed risperidone, which was the only available free drug in our setting. While few centres have taken efforts to provide these drugs, it is largely unavailable in government settings in South India. To our knowledge National mental health programme(NMHP) does not have anti-ADHD medication. Though first line, there are practical implications in making available methylphenidate as it a scheduled drug with risk of abuse. Clonidine and atomoxetine could be made available in NMHP, RBSK and other government setting to address the need of preschool and school going children with ADHD and prevent over-prescription of antipsychotics in them (Rashtriya Bal SwasthyaKaryakram, 2019; "Directorate General Of Health Services",n.d.). Implementing cost-effective behavioural as well as pharmacological interventions for ADHD and making it feasible for application in general mental health setting can facilitate widespread dissemination of evidence-based intervention to children in the rural areas who have limited access to specialized units. This is urgent in low resource developing countries.
8.3% (Riddle et al., 2013). Common reasons for prescribing antipsychotic use were for impulsivity and aggression (31.25%) posing injury to self and others, and moreover it was the only free drug among the available treatment options in the hospital at the time the study was conducted. Risperidone has a specific paediatric indication approved by the Food and Drug Administration for the treatment of irritability in children with Autism, Schizophrenia and Bipolar Disorder. Finally, the average daily dose of risperidone (1.45 ± 0.90) was similar to that reported in a recent clinical trial of risperidone in children with ADHD aged 6–12 years (Vitiello et al., 2015). Over prescription of antipsychotic medication in this age group for lack of availability of other medication is a concern that needs to be addressed. Methylphenidate is the only ADHD medication recommended for use in children as young as 4 years by AAP guidelines. Studies have demonstrated that children aged 4–5 years are to receive a weightbased dose of 0.4-0.7 mg/kg/day of methylphenidate (Wigal et al., 2006). From this dosing guidance, most children under the age of 5 years should be receiving doses smaller than 25 mg per day, and our population average dose 10.83 ± 7.35 mg was well within these limits. The factors limiting the use of stimulants in this population apart from cost, availability and comorbid seizure disorder is that more children come from socioeconomically disadvantaged background which puts them at risk for compromised baseline growth parameters. Studies of preschool-aged children have revealed that 30% of the children will experience side effects when prescribed a stimulant to treat ADHD and 11% will choose to discontinue the medication. These included emotional outbursts, difficulty falling asleep, repetitive behaviours/ thoughts, appetite decrease, and irritability (Wigal et al., 2006). In this study population, among those receiving pharmacotherapy, only 10.8% were on atomoxetine. The average dose of it was 16.85 ± 3.02 mg. Common reasons for choice of atomoxetine were the presence of comorbid anxiety disorder (N = 2) and inattentive type ADHD (N = 4). (Shier et al., 2012) One child had hyperbilirubinemia and one had a worsening of symptoms of hyperactivity and impulsivity while on atomoxetine requiring a change of the drug. In one study, a high proportion (66.7%) of the pre-schoolers experienced side effects with atomoxetine. Side effects of defiance, tantrums, aggression, and irritability were most disconcerting to parents, and gastrointestinal complaints were the most commonly reported adverse effects, therefore restricting its use.(Ghuman et al., 2009) Regardless of pharmacotherapy, the study sample was on average moderately severe illness, as shown by CGI scores and Conner’s abbreviated rating scale severity (Figs. 1 and 2), with greater severity in the group on medication, all of whom improved with time. Since it was a naturalistic follow up the different drugs could not be compared for efficacy. However, there was a significant difference in favour of the
5. Strengths and limitations A number of important limitations must be taken into account in interpreting these data. Medication data on adherence were obtained exclusively from parental report; pill counts, or other measures of adherence was not assessed. Another limitation to assessing trajectories of pharmacotherapy is the short duration and the sample size of the study. Finally, the study was not powered enough to compare effectiveness of individual pharmacotherapy. Studies in future, with larger sample size and duration of follow up, randomised control trial designs can provide further insights.Despite the limitations, the study informs on the pharmacotherapy of children with ADHD in preschool age group. In summary, the findings of our study are1) About 66.07 %(N = 37) of children were on combined pharmacological and behavioural interventions for ADHD and 33.93 %(N = 19) were only on behavioural interventions. 2) Most prescribed drug was clonidine (44.64%), then risperidone (28.7%), methylphenidate (10.7%) and atomoxetine (10.7%). 3) Medication choice was determined by affordability and availability apart from clinical parameters such as comorbidity profile and
Fig. 1. Severity on Clinical Global Impression-Severity scale over 12 weeks. 5
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Fig. 2. Severity on Conner’s abbreviated rating scale over 12 weeks.
baseline growth indicators. Methylphenidate was well tolerated. Sedation occurred in nearly 1/4 of children on clonidine. Atomoxetine was not well tolerated in 2 children. Irrespective of medication choice, all children showed significant improvement at 12 weeks (p < 0.05).
deficit hyperactivity disorder in children and adolescents: a review for practitioners. Transl. Pediatr. 7, 36–47. https://doi.org/10.21037/tp.2017.08.02. Busner, J., Targum, S.D., 2007. The clinical global impressions scale. Psychiatry Edgmont (Edgmont) 4, 28–37. Charach, A., Carson, P., Fox, S., Ali, M.U., Beckett, J., Lim, C.G., 2013. Interventions for preschool children at high risk for ADHD: a comparative effectiveness review. Pediatrics 131, e1584–1604. https://doi.org/10.1542/peds.2012-0974. Cherkasova, M., Sulla, E.M., Dalena, K.L., Pondé, M.P., Hechtman, L., 2013. Developmental course of attention deficit hyperactivity disorder and its predictors. J. Can. Acad. Child Adolesc. Psychiatry 22, 47–54. Connor, D.F., Fletcher, K.E., Swanson, J.M., 1999. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 38, 1551–1559. https://doi.org/10.1097/00004583-199912000-00017. Wolraich, M.L., Hagan, J.F., Allan, C., Chan, E., et al., 2019. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics 144 (4). https://doi.org/10.1542/peds.20192528. (e20192528). DrugsUpdate - News, Information and Solutions for Indian Doctors [WWW Document], n. d. URL http://www.drugsupdate.com/ (accessed 4.26.19). Garg, J., Arun, P., 2013. A follow-up study of academic functioning and social adjustment in children with attention deficit hyperactivity disorder. Indian J. Psychol. Med. 35, 47–52. https://doi.org/10.4103/0253-7176.112201. Ghuman, J.K., Aman, M.G., Ghuman, H.S., Reichenbacher, T., Gelenberg, A., Wright, R., Rice, S., Fort, C., 2009. Prospective, naturalistic, pilot study of open-label atomoxetine treatment in preschool children with attention-deficit/hyperactivity disorder. J. Child Adolesc. Psychopharmacol. 19, 155–166. https://doi.org/10.1089/cap.2008. 054. Jacob, P., Srinath, S., Girimaji, S., Seshadri, S., Sagar, J.V., 2016. Co-morbidity in attention-deficit hyperactivity disorder: a clinical study from India. East Asian Arch. Psychiatry 26, 148–153. Joseph, N., Zhang-James, Y., Perl, A., Faraone, S.V., 2015. Oxidative stress and ADHD: a meta-analysis. J. Atten. Disord. 19, 915–924. https://doi.org/10.1177/ 1087054713510354. Khajehpiri, Z., Mahmoudi-Gharaei, J., Faghihi, T., Karimzadeh, I., Khalili, H., Mohammadi, M., 2014. Adverse reactions of Methylphenidate in children with attention deficit-hyperactivity disorder: report from a referral center. J. Res. Pharm. Pract. 3, 130–136. https://doi.org/10.4103/2279-042X.145389. Ma, D., Rajakumaraswamy, N., Maze, M., 2005. α2-Adrenoceptor agonists: shedding light on neuroprotection? Br. Med. Bull. 71, 77–92. https://doi.org/10.1093/bmb/ldh036. Ming, X., Mulvey, M., Mohanty, S., Patel, V., 2011. Safety and efficacy of clonidine and clonidine extended-release in the treatment of children and adolescents with attention deficit and hyperactivity disorders. Adolesc. Health Med. Ther. 2, 105–112. https://doi.org/10.2147/AHMT.S15672. Panther, S.G., Knotts, A.M., Odom-Maryon, T., Daratha, K., Woo, T., Klein, T.A., 2017. Off-label prescribing trends for ADHD medications in very young children. J. Pediatr. Pharmacol. Ther. JPPT Off. J. PPAG 22, 423–429. https://doi.org/10.5863/15516776-22.6.423. Pliszka, S., 2007. Practice parameter for the assessment and treatment of children and adolescents with Attention-Deficit/Hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 46 (7), 894–921. https://doi.org/10.1097/chi. 0b013e318054e724. Prince, J.B., Wilens, T.E., Biederman, J., Spencer, T.J., Wozniak, J.R., 1996. Clonidine for sleep disturbances associated with attention-deficit hyperactivity disorder: a systematic chart review of 62 cases. J. Am. Acad. Child Adolesc. Psychiatry 35, 599–605. https://doi.org/10.1097/00004583-199605000-00014. Rashtriya Bal SwasthyaKaryakram (RBSK) National Health Portal Of India [WWW Document], n.d. URL https://www.nhp.gov.in/rashtriya-bal-swasthyakaryakram(rbsk)_pg (accessed 11.30.19). Riddle, M.A., Yershova, K., Lazzaretto, D., Paykina, N., Yenokyan, G., Greenhill, L., Abikoff, H., Vitiello, B., Wigal, T., McCracken, J.T., Kollins, S.H., Murray, D.W., Wigal, S., Kastelic, E., McGough, J.J., dosReis, S., Bauzó-Rosario, A., Stehli, A., Posner, K., 2013. The preschool Attention-Deficit/Hyperactivity disorder treatment study (PATS) 6-year follow-up. J. Am. Acad. Child Adolesc. Psychiatry 52, 264–278. https://doi.org/10.1016/j.jaac.2012.12.007. e2. Shier, A.C., Reichenbacher, T., Ghuman, H.S., Ghuman, J.K., 2012. Pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: clinical strategies. J. Cent. Nerv. Syst. Dis. 5, 1–17. https://doi.org/10.4137/JCNSD. S6691.
6. Conclusion The study attempted to inform on the pharmacotherapy received as part of standard care among preschool children with ADHD in a tertiary care setting and its efficacy. Data indicate that most children who are diagnosed with ADHD in preschool continue to receive medication. There is, however, considerable heterogeneity in the pharmacotherapy across countries and cost-effectiveness seem to be major factor in determining choice of medication in low income countries. There is pressing need for more studies on the safety and tolerability of medications and on efficacy of structured behavioural parent training program in the preschool age group in our setting. Efforts to address unavailability of anti-ADHD medication under NMHP, RBSK and other government hospitals are a pressing need. Financial disclosure We hereby declare no financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work. We hereby declare no potential competing interests including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. Hence, declarations of interest are none. Declaration of Competing Interest None. Acknowledgements We hereby declare no acknowledgements as well as no source of funding. Conflict of Interest is also declared as none. References Information leaflets | Jawaharlal Institute of Postgraduate Medical Education & Research [WWW Document], n.d. URL http://www.jipmer.edu.in/hospital-services/childpsychiatry/information-leaflets (accessed 5.27.19). Association AP, 2013. Diagnostic and Statistical Manual of Mental Disorders. 5th Revised Ed. American Psychiatric Publishing, Washington, DC 991 p. Biederman, J., Petty, C.R., Monuteaux, M.C., Fried, R., Byrne, D., Mirto, T., Spencer, T., Wilens, T.E., Faraone, S.V., 2010. Adult psychiatric outcomes of girls with attention deficit hyperactivity disorder: 11-Year follow-up in a longitudinal case-control study. Am. J. Psychiatry 167, 409–417. https://doi.org/10.1176/appi.ajp.2009.09050736. Biederman, J., Petty, C.R., Woodworth, K.Y., Lomedico, A., Hyder, L.L., Faraone, S.V., 2012. Adult outcome of attention-deficit/hyperactivity disorder: a controlled 16-year follow-up study. J. Clin. Psychiatry 73, 941–950. https://doi.org/10.4088/JCP. 11m07529. Brown, K.A., Samuel, S., Patel, D.R., 2018. Pharmacologic management of attention
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Psychol. Med. 34, 34–38. https://doi.org/10.4103/0253-7176.96155. Vitiello, B., Lazzaretto, D., Yershova, K., Abikoff, H., Paykina, N., McCracken, J.T., McGough, J.J., Kollins, S.H., Greenhill, L.L., Wigal, S., Wigal, T., Riddle, M.A., 2015. Pharmacotherapy of the preschool ADHD treatment study (PATS) children growing up. J. Am. Acad. Child Adolesc. Psychiatry 54, 550–556. https://doi.org/10.1016/j. jaac.2015.04.004. Wigal, T., Greenhill, L., Chuang, S., McGough, J., Vitiello, B., Skrobala, A., Swanson, J., Wigal, S., Abikoff, H., Kollins, S., McCracken, J., Riddle, M., Posner, K., Ghuman, J., Davies, M., Thorp, B., Stehli, A., 2006. Safety and tolerability of methylphenidate in preschool children with ADHD. J. Am. Acad. Child Adolesc. Psychiatry 45, 1294–1303. https://doi.org/10.1097/01.chi.0000235082.63156.27. https://dghs.gov.in/content/1350_3_NationalMentalHealthProgramme.aspx.
Srinivasaraghavan, R., Mahadevan, S., Kattimani, S., 2013. Impact of comorbidity on three month follow-up outcome of children with ADHD in a child guidance clinic: preliminary report. Indian J. Psychol. Med. 35, 346–351. https://doi.org/10.4103/ 0253-7176.122223. Suvarna, B.S., Kamath, A., 2009. Prevalence of attention deficit disorder among preschool age children. Nepal Med. Coll. J. NMCJ 11, 1–4. Ullmann, R.K., Sleator, E.K., Sprague, R.L., 1985. A change of mind: the Conners abbreviated rating scales reconsidered. J. Abnorm. Child Psychol. 13, 553–565. Venkata, J.A., Panicker, A.S., 2013. Prevalence of attention deficit hyperactivity disorder in primary school children. Indian J. Psychiatry 55, 338–342. https://doi.org/10. 4103/0019-5545.120544. Venkatesh, C., Ravikumar, T., Andal, A., Virudhagirinathan, B.S., 2012. Attention-deficit/ Hyperactivity disorder in children: clinical profile and Co-morbidity. Indian J.
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Pre-school attention deficit hyperactivity disorder: 12 weeks prospective study
T
Sivapriya Vaidyanathana, Tess Maria Rajanb, Venkatesh Chandrasekaranc,1, Preeti Kandasamya,* a
Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India Department of Child and Adolescent Psychiatry, National Institute of Mental Health and Neuro-Sciences, Bangalore, India c Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India b
A R T I C LE I N FO
A B S T R A C T
Keywords: Attention deficit hyperactivity disorder Preschool ADHD Pharmacotherapy
Introduction: Extant literature lack studies on behavioural training or pharmacotherapy in Indian preschool children. With adverse long term outcomes, effective, safe and affordable early interventions for ADHD are a priority. Aim of this prospective study is to report on short term outcome of preschool ADHD with specific focus on safety and tolerability of medications. Methods: Children with ADHD aged 2.5–6 years were assessed for severity and adverse events at baseline and follow-up using Conner’s abbreviated rating scale and Clinical Global Impression-Severity scale. Children with Autism spectrum disorder and those with social quotient less than 50 were excluded. Statistical Analysis included descriptive statistics and Repeated measures ANOVA. Results: Of 56 children recruited, 33.93 %(N = 19) were on behavioural interventions alone, 66.07 %(N = 37) were on a combination of medication and behavioural intervention. All children received treatment according to standard care. The most prescribed drug was clonidine (44.64%), then risperidone (28.7%), methylphenidate (10.7%) and atomoxetine (10.7%). Medication choice was determined by affordability, availability and comorbidity profile. Sedation occurred in 24 % of children on clonidine. Atomoxetine was not well tolerated in 2 children. Methylphenidate was well tolerated. Irrespective of medication choice, all children showed significant improvement at 12 weeks (p < 0.001). Conclusions: Choice of interventions is largely determined by availability and affordability. There is a need for structured parent behavioural training program deliverable in low resource setting. Anti-ADHD medications should be made available under the NMHP, RBSK program and all government settings in India, to address overprescription of antipsychotics in preschool ADHD.
1. Introduction Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with the presence of pervasive inattention and/or hyperactivity-impulsivity that interferes with functioning directly (Association AP, 2013). The long term outcomes of children with ADHD are multiple and in various psychosocial, educational and neuropsychological domains when compared to those without this disorder. There is a higher lifetime occurrence of antisocial, anxiety, mood and substance use disorder in these individuals (Biederman et al., 2010, 2012). The prevalence of ADHD, in India in primary school children is 11.32%. (Venkata and Panicker, 2013) In preschool children the
prevalence is at 12.2% (Suvarna and Kamath, 2009). Diagnostic stability of ADHD at this age is varied. One study found that about 74.5% retained the diagnosis of ADHD at the end of 3 years (Garg and Arun, 2013). To the contrary, other study noted that only 40% retained diagnosis at 3 months follow up (Srinivasaraghavan et al., 2013). The differences in these studies could be due to varying sample size, age, duration of follow up and, the difference in assessment tools. However, currently, there are no biomarkers for predicting the long term outcomes, although clinical parameters such as baseline severity, associated comorbidity such as conduct or oppositional defiant disorders and age of intervention contribute to long term outcome (Riddle et al., 2013; Jacob et al., 2016). This makes early diagnosis and intervention paramount in ADHD due to its long term implications in avoiding these
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Corresponding author. E-mail addresses: [email protected] (S. Vaidyanathan), [email protected] (T.M. Rajan), [email protected] (V. Chandrasekaran), [email protected], [email protected] (P. Kandasamy). 1 Department of Psychiatry and Paediatrics, JIPMER, Puducherry. https://doi.org/10.1016/j.ajp.2019.101903 Received 30 April 2019; Received in revised form 10 December 2019; Accepted 13 December 2019 1876-2018/ © 2019 Elsevier B.V. All rights reserved.
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deficits. Treatment for ADHD in this age group has several limitations. Behaviour therapy is recommended as first-line treatment for ADHD in children (Wolraich et al., 2019). Preschool children are ideal candidates for behavioural therapy considering the risk-benefit ratio with pharmacological interventions and its long term impact on their neurotransmitter systems. However, there is a lack of studies evaluating the efficacy of a structured behavioural parent training module for preschool children with ADHD in the Indian setting. While developed nations have parenting programs, studies on feasibility in implementing similar modules with due consideration to socio-cultural aspects and available health care resources are limited which makes pharmacological treatments a necessary treatment alternative. The FDA approved pharmacological management of ADHD includes methylphenidate, clonidine extended release and atomoxetine for children in the age group of over 6 years (Brown et al., 2018). However off-label use of stimulants, clonidine, atomoxetine, antipsychotics and other drugs are prescribed in preschool age-group though the occurrence of adverse effects with methylphenidate and atomoxetine was found to be more in the pre-school age group (Vitiello et al., 2015). Clonidine is often prescribed especially in children with sleep disturbances, there is however inadequate evidence for its safe use in this population (Prince et al., 1996). With the current context of the Rashtriya Bal Swasthya Karyakram (RBSK) introducing district early intervention centres and weekly child guidance clinic to facilitate early recognition and management of neurodevelopmental disorders, testing the efficacy and tolerability of affordable treatment options is a priority (Rashtriya Bal SwasthyaKaryakram, 2019; "Directorate General Of Health Services",n.d.) With this in the background, this study aimed to examine the clinical profile, short-term course and outcome, with specific focus on pharmacological interventions, its safety and tolerability in pre-school children with ADHD receiving standard care in a child guidance clinic in South India.
children on clonidine was checked. All the children received treatment according to the standard care offered which included pharmacotherapy, behavioural therapy or a combination of both. Behaviour therapy included parent training approaches used in preschool ADHD, generally referred to as behavioural parent training (BPT); typically apply principles learning and reinforcement to teach parents behavioural strategies to manage problem behaviours in young children (Charach et al., 2013). Components comprised of structuring of routine, improving parental communication and stress, attention enhancing tasks, differential reinforcement strategies and social stories by Dr SV (Anon, 2019). The choice of treatment modality was that of the treating team and was not influenced by the investigators. Of the 56 subjects recruited initially, 51 completed the follow-up and were included in the analysis. Reasons for drop out were unknown in n = 3 children, due to logistic difficulties in following up in n = 1child and pregnancy of mother in n = 1 child. 2.4. Statistical analysis All statistical analysis was carried out using SPSS version 19.0. Categorical variables are represented as frequencies and percentages. Continuous variables are represented as means and standard deviations. Comparisons done using Repeated measures ANOVA with time as a within subjects factor and group as in between subject factors. Bivariate correlation analysis using Pearson’s correlation was done to identify predictors of child-related outcome variables. 3. Results 3.1. Profile of children The socio-demographic profile and clinical profile of the children in both groups those who received only behavioural intervention and those who received combination treatment recruited in this study are depicted in Tables 1 and 2. There were no statistical significant differences in the 2 groups at baseline in sociodemographic data; however there was a statistically significant difference in baseline severity between the 2 groups with those on combination treatment having more severe ADHD. The predominant subtype of ADHD was the combined type; 71.4% of the children had a history of developmental delay. Table 3 shows intervention variables. Of the 56 children recruited, 66.07 %(N = 37) of children were on medication for ADHD and 33.93 %(N = 19) were only on behavioural interventions. Children received combination of behavioural intervention and pharmacotherapy whenever indicated. Indication for pharmacotherapy were baseline moderate or severe illness in 86.4%, failure of trial behaviour therapy (8.9%) and parental preference due to logistic difficulty in implementing structured behavioural interventions in 54.05%. Failed behavioural interventional trial was defined as intensive structured behavioural interventions for a minimum of 8 weeks duration (Pliszka, 2007).
2. Materials and methods 2.1. Study setting and design The study was conducted in the child guidance clinic of a tertiary care centre in South India from December 2017 to December 2018. It was a prospective study. 2.2. Study participants A total of 64 children were screened of whom 56 were consecutively recruited after written informed consent. Children aged 2.5–6 years with a diagnosis of ADHD according to DSM 5, with a reliable informant were included and children with autism spectrum disorder and social quotient less than 50 were excluded. 2.3. Methodology
3.2. Pharmacological interventions The study was approved by Institute Ethics Committee. Primary caregivers, mostly the mothers, were interviewed using a semi-structured proforma for the socio-demographic profile; this was done in addition to diagnostic workup, comprehensive evaluation, and initiation of treatment as usual for ADHD by the primary treating team. ADHD symptom profile and severity assessment were done at baseline and at follow-up using Conner’s abbreviated rating scale, and Clinical Global Impression-severity scale (Busner and Targum, 2007; Ullmann et al., 1985). Re-assessment was done at 4,812 weeks follow up. The occurrence of any adverse event was documented using a checklist and through physical examination, weight monitoring and vitals monitoring including pulse rate, blood pressure, cardiovascular examination of
Of those who were on medication, most commonly prescribed drug was Clonidine (Table 3). The mean age of children receiving clonidine was 59.08 ± 15.3 months. Cardiology opinion, electrocardiogram and 2 dimensional ECHO was done for children less than 4 years age which included 12% of the recruited children (N = 3). In addition to baseline severity, presence of impulsivity posing danger to self, severe and prolonged tantrums and sleep disturbance were some of the clinical indicators which were considered before deciding on pharmacological intervention with informed decision of parents and cardiac clearance as part of standard care (Ming et al., 2011; Shier et al., 2012). 2
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Table 1 Socio-demographic details of the study population. Socio demographic parameters
Sex
Male Female
Employment status of primary care Homemaker giver Employed Years of schooling of Primary care giver Socioeconomic status Lower Middle Upper Domicile Rural Urban
Total participants (n = 56) Mean (Standard deviation)/ N (%)
Participants on combination therapy alone Mean (SD)/ N (%)
Participants on combination therapy alone Mean (SD)/ N (%)
Comparison Chi square/T (p value)
7(83.9) 9(16.1) 43(76.8) 13(23.3) 10.6 (4.84) 35(62.5) 16(28.6) 5(8.9) 30(53.6) 26(46.4)
32(86.4) 5(13.5) 28(75.67) 9(24.32) 10.24(4.34) 25(67.56) 11(29.72) 1(2.70) 23(62.16) 14(37.84)
15(78.94) 4(21.05) 15(78.94) 4(21.05) 11.31(5.76) 10(52.63) 5(26.31) 4(21.05) 7(36.84) 12(63.15)
ƛ2 = 0.53(0.47)
Clonidine was the primary choice of drug in 84%(N = 21) of children on treatment. The most common reason for choice was cost-effectiveness 68% (N = 17), followed by presence of seizure disorder which is a relative contraindication for methylphenidate in 20% (N = 5) and need for sedative property in 4%(N = 1). The minimum dose decided as per weight of clonidine was started at was 0.025 mg. The mean dose and adverse effects are shown in Table 4. Clonidine was up titrated over 12 weeks in 88% of the children. It was augmented with risperidone in 40 %(N = 10) of children. Most common adverse effect with clonidine was sedation. It occurred in 24 %(N = 6) of children receiving clonidine but it was persistent over 12 weeks in only one and resulted in the change of the drug due to excessive sedation. Most common dosing regimen was night time dosing followed by divided doses with the afternoon dose being given afterschool. This strategy was used to counter the sedative adverse effects in the other five children. Among children receiving other pharmacological agents, atomoxetine was not well tolerated in 2 children. However no significant adverse effects were noted among those receiving methylphenidate. The sample receiving these two medications was too small to make clinically meaningful inference. Care was taken to ensure baseline growth parameters before treatment initiation with methylphenidate as part of standard care.
ƛ2 = 1.8(0.76) t=-0.78(0.438) ƛ2 = 5.23(0.073)
ƛ2 = 3.24(0.0720
Table 3 Interventions for preschool ADHD.
Behaviour therapy alone Combined BT + pharmacotherapy Methylphenidate Clonidine Atomoxetine Risperidone alone Risperidone augmentation Total
Frequency
Percentage
19 37 6 25 6 3 13 56
33.9 66.1 10.7 44.64 10.7 5.4 23.2 100.0
ADHD- Attention deficit hyperactivity disorder. BT- Behaviour therapy.
3.3. Treatment efficacy Irrespective of the pharmacotherapy or behaviour therapy all the children improved form baseline to completion of interventions. as measured by Repeated measures Analysis of Variance (RMANOVA) Significant difference was found in reduction in ADHD symptom severity as measured by Conner’s abbreviated rating scale, at the end of 12 weeks of intervention (F = 63.4; p < 0.001) The improvement in severity score on CGI-S and Conner’s abbreviated rating
Table 2 Clinical profile of the children. Clinical profile of the children
Total participants (n = 56) Mean (SD)/ N (%)
Participants on combination therapy alone Mean (SD)/ N (%)
Participants on behaviour therapy alone Mean (SD)/ N (%)
Comparison Chi square/T (p value)
Age (in months) Family history of psychiatric illness Developmental delay Specific(Speech and language delay) Global Comorbidities Seizure disorder ODD Anxiety disorder SLD DSM5 Subtype of ADHDCombined, Inattentive, Hyperactive-Impulsive Baseline CGI-S Score Baseline Conner’s abbreviated rating scale
57.82 (15.12) 27(48.2) 27(48.2)
60.48(14.87) 21(56.7) 18(48.64)
52.63(14.60) 6(31.57) 9(47.3)
1.88(0.069) 3.19(0.17) ƛ2 = 0.17(0.91)
13(23.2) 11(19.64) 4(7.14) 2(3.57) 5(3.57) 31(55.4). 11(19.6), 14(25)
8(21.61) 8(21.6) 4(10.81) 1(2.7) 5(13.51) 20(54.05), 6(16.21), 11(29.72)
5(26.31) 3(15.79) 0(0) 1(5.2) 0(0) 11(57.9), 5(26.31), 3(15.78)
4.37(1.00) 20.92(4.01)
4.67(0.97) 21.89(4.18)
3.78(0.78) 19.05(2.95)
ADHD-Attention deficit hyperactivity disorder. CGI-S-Clinical global impression-Severity rating scale. DSM 5- Diagnostic and Statistical Manual of Mental Disorders Version 5. ODD-Oppostional defiant disorder. SLD-Specific learning deficits. 3
ƛ2 ƛ2 ƛ2 ƛ2 ƛ2
= = = = =
0.27(0.732) 2.21(0.28) 0.24(1) 2.81(0.16) 1.6(0.4)
t = 3.4(0.001) t = 2.6(0.01)
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Table 4 Pharmacotherapy in preschool ADHD- dose and adverse effects.
Dose range Average dose Reasons for prescribing
Adverse effects Strategies to cope with adverse effects
Clonidine
Risperidone
Atomoxetine
Methylphenidate
0.025-0.150mg 0.074 ± 0.03 mg Affordability (67.6%) Comorbid seizure disorder (18.91%) Sleep disturbances (5.40 %) Sedation(N = 6)
0.5-3mg 1.45 ± 0.90 Affordability (100%) Aggression (31.25%) Augmentation- (62.5%)
10-18mg 16.85 ± 3.02 Comorbid anxiety disorder(N = 2) Inattentive type ADHD(N = 4)
5-25mg 10.83 ± 7.35 –
Weight gain (N = 2) Sedation(N = 1) Dose reduction(N = 2) Divided dosing Afterschool dosing(N = 0) Night time dosing(N = 2)
Hyperbilirubinemia(N = 1) Worsening of symptoms(N = 1) Discontinuation(N = 1) Augmentation with Risperidone(N = 3)
Nil
Divided dosing(N = 2) Afterschool dose(N = 2) Dose reduction(N = 1) Change of drug(N = 1)
Nil
ADHD-Attention deficit hyperactivity disorder.
children primarily due to affordability, presence of comorbid seizure where methylphenidate is contraindicated or presence of sleep disturbances in the child were the other clinical reasons to choose clonidine. Clonidine appeared largely well tolerated and the most common adverse effect with clonidine was sedation as described in literature (Connor et al., 1999). Afterschool and night-time dosing strategies could address this in majority of children. There were no cardiac sideeffects in any of the children. However, nearly 40% of those on clonidine (N = 10) required augmentation with risperidone in the dose range 0.5−2 mg which needs attention. In literature search there was a dearth of data noted regarding study looking into the safety and tolerability of clonidine in the preschool age group. In study by Prince et al., 1996, 85% of children aged 4–12 years were treated with clonidine for ADHD associated with sleep disturbances and 31% had mild adverse effects (Prince et al., 1996). Studies show that alpha agonist medications accounted for 42% of the offlabel prescriptions for children ages 3–5 years, which was more than those written for methylphenidate formulations combined (41%) even though methylphenidate is the first-line medication recommended by the AAP guidelines for use in children starting at age 4 years. Clonidine and guanfacine both immediate and extended release combined accounted for 42.6%. It was also reported that clonidine immediate release tablets at 97.6% are prescribed more often than the extendedrelease tablets at 1.2% and patches at 1.2% (Panther et al., 2017). Guanfacine and extended release formulations of clonidine if available may be used as an alternative strategy to counter the sedation however these formulations are not available in the Indian context. Current evidence points towards a possible role of oxidative stress in pathogenesis of ADHD where in patients with ADHD have normal levels of antioxidant production, but that their response to oxidative stress is insufficient, leading to oxidative damage (Joseph et al., 2015). Neuroprotective effects of alpha 2 adrenorecepter agonists has been under investigation and with promising results, this could give clonidine an added edge over other treatment options (Ma et al., 2005). The AAP guidelines note efficacy, but limited supporting evidence for the extended-release formulation of the alpha agonist medications in children older than preschool-age, and do not support immediate release use for any age group and do not mention the use of other dosage forms such as the clonidine patch (Wolraich et al., 2019). Although these results are preliminary and observational, clonidine appears to be well tolerated, cost effective and helpful in ameliorating baseline severity in preschool ADHD, however need for risperidone augmentation in a significant number of children is a concern. Further randomised controlled studies and head-head comparison with methylphenidate and atomoxetine to explore its safety and efficacy for this population is warranted. In this study 28.7 % received antipsychotic risperidone population which is very high in comparison to the PATS study where it was only
There was also a significant difference in group effect in favour of the combination interventions on change in Conner’s abbreviated rating scale (F = 6.67, p = 0.013, ES (η2) = 0.124) although weak. The group requiring combination pharmacotherapy was too heterogeneous to compare individually and include in analysis. By the end of 12 weeks, 37.5 % of parents preferred behavioural intervention alone, 17.9 % only pharmacotherapy, 35.7% a combination of both. The various parent and child-related factors which predicted the outcome measure that is change in ADHD severity at the end of 12 weeks of intervention was assessed. Age of the child in months was found to have a negative correlation (r=-0.3, p = 0.035) with difference in severity of ADHD as measured by in Conner’s abbreviated rating scale. Baseline severity of ADHD(r = 0.10, p = 0. 46) and education in years of primary caregiver (r = 0.18, p = 0. 20) was not found was found to have correlation with improvement in symptoms severity. 4. Discussion This study was a prospective follow-up of preschool children diagnosed with ADHD. All medications used to treat ADHD are considered off-label for children younger than age 6 years according to most guidelines. There is limited literature regarding the prescribing of ADHD medications to preschool-aged children. About 84% of this sample was male which is in line with literature (Venkatesh et al., 2012; Jacob et al., 2016). Majority of children belonged to a lower socioeconomic background form rural areas with limited access to specialised mental health care facilities. This also had treatment implications in terms of choice of medication. In our study population, 71.4% had some form of developmental delay and 19.64% had seizure disorder. It was also found that children on pharmacotherapy had higher baseline severity of ADHD. These were other relevant clinical factors which also influenced the need for pharmacotherapy and drug of choice. (Khajehpiri et al., 2014) In our study, only 33.9% of children were on behavioural interventions alone and a majority received pharmacological interventions. Of those who were on medication, most commonly prescribed drug was clonidine at 44.7%, followed by risperidone at 28.7%. This is in contrast to data from other studies where in the most commonly prescribed pharmacotherapy was stimulant monotherapy. In Preschool ADHD Treatment Study (PATS) nearly 40% received receive stimulant monotherapy among pre-schoolers, antipsychotic medication was prescribed at 8.3–13.4% and a variety of other psychotropic, such as alpha2-agonists, antidepressants, and mood stabilizers were also prescribed (Vitiello et al., 2015). Side effects of clonidine include increased sedation that prevents the child from actively engaging in therapy and others such as hypotension and cardiac arrhythmias can be potentially serious (Connor et al., 1999). In our study clonidine was the primary choice of drug in 84% of 4
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combination interventions on change in severity of ADHD (F = 6.67, p = 0.013, ES (η2) = 0.124). In our study age of the child in months was found to have a negative correlation(r=-0.3, p = 0.035) and baseline severity of ADHD and education in of primary caregiver was not found was found to have correlation with improvement in symptoms severity. This was consistent with extant literature although other parameters such as comorbidity, parental psychopathology known to influence outcomes were not analysed in our study. (Biederman et al., 2012; Cherkasova et al., 2013).This also highlights the role of early interventions in improving symptom severity in ADHD. By the end of 12 weeks 37.5% of parents preferred only behaviour therapy while majority preferred pharmacotherapy in combination with behaviour therapy or pharmacotherapy alone in preschool ADHD children. Combined treatment was relatively common at 25% and concerns have been raised about psychotropic polypharmacy in children in light of the dearth of supporting controlled investigations. However, the current evidence-base for combined therapy in the treatment of ADHD is limited to the use of stimulants and alpha-2 agonists, and few studies have evaluated the efficacy and safety of other combinations such as methylphenidate and atomoxetine in children with partial response. (Shier et al., 2012) The cost of methylphenidate is about INR 10 for one 10 mg tablet, atomoxetine about INR 5 for one 10 mg tablet and clonidine is about INR 1 for one 0.1 mg tablet. (DrugsUpdate - News, 2019) In this study the average out-of-pocket expenditure for Clonidine was estimated to be 21–24 INR per month. In our setting, a proportion of children, who could not even afford this, have availed risperidone, which was the only available free drug in our setting. While few centres have taken efforts to provide these drugs, it is largely unavailable in government settings in South India. To our knowledge National mental health programme(NMHP) does not have anti-ADHD medication. Though first line, there are practical implications in making available methylphenidate as it a scheduled drug with risk of abuse. Clonidine and atomoxetine could be made available in NMHP, RBSK and other government setting to address the need of preschool and school going children with ADHD and prevent over-prescription of antipsychotics in them (Rashtriya Bal SwasthyaKaryakram, 2019; "Directorate General Of Health Services",n.d.). Implementing cost-effective behavioural as well as pharmacological interventions for ADHD and making it feasible for application in general mental health setting can facilitate widespread dissemination of evidence-based intervention to children in the rural areas who have limited access to specialized units. This is urgent in low resource developing countries.
8.3% (Riddle et al., 2013). Common reasons for prescribing antipsychotic use were for impulsivity and aggression (31.25%) posing injury to self and others, and moreover it was the only free drug among the available treatment options in the hospital at the time the study was conducted. Risperidone has a specific paediatric indication approved by the Food and Drug Administration for the treatment of irritability in children with Autism, Schizophrenia and Bipolar Disorder. Finally, the average daily dose of risperidone (1.45 ± 0.90) was similar to that reported in a recent clinical trial of risperidone in children with ADHD aged 6–12 years (Vitiello et al., 2015). Over prescription of antipsychotic medication in this age group for lack of availability of other medication is a concern that needs to be addressed. Methylphenidate is the only ADHD medication recommended for use in children as young as 4 years by AAP guidelines. Studies have demonstrated that children aged 4–5 years are to receive a weightbased dose of 0.4-0.7 mg/kg/day of methylphenidate (Wigal et al., 2006). From this dosing guidance, most children under the age of 5 years should be receiving doses smaller than 25 mg per day, and our population average dose 10.83 ± 7.35 mg was well within these limits. The factors limiting the use of stimulants in this population apart from cost, availability and comorbid seizure disorder is that more children come from socioeconomically disadvantaged background which puts them at risk for compromised baseline growth parameters. Studies of preschool-aged children have revealed that 30% of the children will experience side effects when prescribed a stimulant to treat ADHD and 11% will choose to discontinue the medication. These included emotional outbursts, difficulty falling asleep, repetitive behaviours/ thoughts, appetite decrease, and irritability (Wigal et al., 2006). In this study population, among those receiving pharmacotherapy, only 10.8% were on atomoxetine. The average dose of it was 16.85 ± 3.02 mg. Common reasons for choice of atomoxetine were the presence of comorbid anxiety disorder (N = 2) and inattentive type ADHD (N = 4). (Shier et al., 2012) One child had hyperbilirubinemia and one had a worsening of symptoms of hyperactivity and impulsivity while on atomoxetine requiring a change of the drug. In one study, a high proportion (66.7%) of the pre-schoolers experienced side effects with atomoxetine. Side effects of defiance, tantrums, aggression, and irritability were most disconcerting to parents, and gastrointestinal complaints were the most commonly reported adverse effects, therefore restricting its use.(Ghuman et al., 2009) Regardless of pharmacotherapy, the study sample was on average moderately severe illness, as shown by CGI scores and Conner’s abbreviated rating scale severity (Figs. 1 and 2), with greater severity in the group on medication, all of whom improved with time. Since it was a naturalistic follow up the different drugs could not be compared for efficacy. However, there was a significant difference in favour of the
5. Strengths and limitations A number of important limitations must be taken into account in interpreting these data. Medication data on adherence were obtained exclusively from parental report; pill counts, or other measures of adherence was not assessed. Another limitation to assessing trajectories of pharmacotherapy is the short duration and the sample size of the study. Finally, the study was not powered enough to compare effectiveness of individual pharmacotherapy. Studies in future, with larger sample size and duration of follow up, randomised control trial designs can provide further insights.Despite the limitations, the study informs on the pharmacotherapy of children with ADHD in preschool age group. In summary, the findings of our study are1) About 66.07 %(N = 37) of children were on combined pharmacological and behavioural interventions for ADHD and 33.93 %(N = 19) were only on behavioural interventions. 2) Most prescribed drug was clonidine (44.64%), then risperidone (28.7%), methylphenidate (10.7%) and atomoxetine (10.7%). 3) Medication choice was determined by affordability and availability apart from clinical parameters such as comorbidity profile and
Fig. 1. Severity on Clinical Global Impression-Severity scale over 12 weeks. 5
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Fig. 2. Severity on Conner’s abbreviated rating scale over 12 weeks.
baseline growth indicators. Methylphenidate was well tolerated. Sedation occurred in nearly 1/4 of children on clonidine. Atomoxetine was not well tolerated in 2 children. Irrespective of medication choice, all children showed significant improvement at 12 weeks (p < 0.05).
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6. Conclusion The study attempted to inform on the pharmacotherapy received as part of standard care among preschool children with ADHD in a tertiary care setting and its efficacy. Data indicate that most children who are diagnosed with ADHD in preschool continue to receive medication. There is, however, considerable heterogeneity in the pharmacotherapy across countries and cost-effectiveness seem to be major factor in determining choice of medication in low income countries. There is pressing need for more studies on the safety and tolerability of medications and on efficacy of structured behavioural parent training program in the preschool age group in our setting. Efforts to address unavailability of anti-ADHD medication under NMHP, RBSK and other government hospitals are a pressing need. Financial disclosure We hereby declare no financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work. We hereby declare no potential competing interests including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. Hence, declarations of interest are none. Declaration of Competing Interest None. Acknowledgements We hereby declare no acknowledgements as well as no source of funding. Conflict of Interest is also declared as none. References Information leaflets | Jawaharlal Institute of Postgraduate Medical Education & Research [WWW Document], n.d. URL http://www.jipmer.edu.in/hospital-services/childpsychiatry/information-leaflets (accessed 5.27.19). Association AP, 2013. Diagnostic and Statistical Manual of Mental Disorders. 5th Revised Ed. American Psychiatric Publishing, Washington, DC 991 p. Biederman, J., Petty, C.R., Monuteaux, M.C., Fried, R., Byrne, D., Mirto, T., Spencer, T., Wilens, T.E., Faraone, S.V., 2010. Adult psychiatric outcomes of girls with attention deficit hyperactivity disorder: 11-Year follow-up in a longitudinal case-control study. Am. J. Psychiatry 167, 409–417. https://doi.org/10.1176/appi.ajp.2009.09050736. Biederman, J., Petty, C.R., Woodworth, K.Y., Lomedico, A., Hyder, L.L., Faraone, S.V., 2012. Adult outcome of attention-deficit/hyperactivity disorder: a controlled 16-year follow-up study. J. Clin. Psychiatry 73, 941–950. https://doi.org/10.4088/JCP. 11m07529. Brown, K.A., Samuel, S., Patel, D.R., 2018. Pharmacologic management of attention
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