Raine ADHD Study: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children This research study is a collaboration between the Ministerial Implementation Committee for Attention Deficit Hyperactivity Disorder in Western Australia (MICADHD) and the Telethon Institute for Child Health Research (TICHR), with funding provided by the Western Australian Department of Health (DOH) Principal Researchers Grant Smith Collaboration for Applied Research and Evaluation Telethon Institute for Child Health Research Dr Brad Jongeling Paediatrician DOH and MICADHD member Dr Petra Hartmann Paediatrician DOH Craig Russell Specialist Clinical Psychologist DOH & Executive Officer MICADHD Professor Lou Landau Paediatrician & Principal Medical Advisor DOH Chair MICADHD 2 Acknowledgements The authors wish to acknowledge their gratitude to the 2868 families who have participated in the Raine Study. Without the dedication of these families, research such as this could not be conducted. The authors also wish to thank the Raine Study team within the Telethon Institute for Child Health Research. The team’s advice on measures, suggestions for analyses, and continued acquiescence to our additional data requests have greatly contributed to the current project. The authors would also like to acknowledge the involvement of members from the Collaboration for Applied Research and Evaluation at the Telethon Institute for Child Health Research, particularly Tanyana Jackiewicz, who have provided input during all phases of the current research project. Special thanks also go to The Ministerial Implementation Committee for Attention Deficit Hyperactivity Disorder in Western Australia. The combination of research-related and clinical advice provided by this group has been invaluable. Many thanks also go to the Department of Health, who provided the funding to conduct this important research. 3 Contents Acknowledgements....................................................................................................................3 Contents....................................................................................................................................4 1. Executive Summary...............................................................................................................5 1.1 Background.....................................................................................................................5 1.2 Summary of results.........................................................................................................5 ADHD Diagnosis and Outcomes......................................................................................5 Outcomes Associated with Medication-Use for Children Diagnosed with ADHD.............5 Social/Emotional and School-Based outcomes................................................................5 School-Based outcomes...................................................................................................6 Height and Weight............................................................................................................6 Cardiovascular Function...................................................................................................6 Change in Key ADHD Symptoms.....................................................................................7 1.3 Conclusions.....................................................................................................................7 1.4 Limitations.......................................................................................................................8 2. Stimulant Medication in the treatment of ADHD....................................................................9 2.1 Introduction......................................................................................................................9 3. Raine Study and Sample.....................................................................................................14 3.1 Sample..........................................................................................................................14 3.2 Measures.......................................................................................................................15 4. Part A: Analytical Methods..................................................................................................21 4.1 Controlling for potential systematic differences between medication groups...............22 5. Results: ADHD and use of stimulant medication.................................................................24 5.1 Diagnosis of ADHD and demographic makeup of sample............................................24 5.2 Use of Stimulant Medication in Children Diagnosed with ADHD..................................25 6. Results: Social and Emotional Outcomes...........................................................................26 6.1 Depression....................................................................................................................26 6.2 Self Perception..............................................................................................................27 6.3 Social Functioning.........................................................................................................27 6.4 Summary.......................................................................................................................28 7. Results: School-Related Outcomes.....................................................................................30 7.1 Academic Performance.................................................................................................31 7.2 Absenteeism..................................................................................................................31 7.3 Enjoyment of School.....................................................................................................32 7.4 Summary.......................................................................................................................33 8. Results: Physical Side Effects.............................................................................................35 8.1 Height............................................................................................................................36 8.2 Weight...........................................................................................................................37 8.3 Limitations with weight and height analyses.................................................................40 8.4 Heart Function...............................................................................................................41 8.4.1 Blood Pressure - Systolic.......................................................................................41 8.4.2 Blood Pressure - Diastolic.....................................................................................42 8.4.3 Resting Heart Rate................................................................................................43 8.5 Summary.......................................................................................................................44 9. Changes in key ADHD symptoms in comparison to peers.................................................46 9.1 Externalising Behaviour................................................................................................46 9.2 Attention Problems........................................................................................................47 9.3 Summary.......................................................................................................................49 10. Key Findings/Overview......................................................................................................50 11. Limitations..........................................................................................................................53 12. Conclusions/Recommendations........................................................................................55 13. References........................................................................................................................56 Appendix A. Creation of propensity score...............................................................................59 Appendix B. Unadjusted means and proportions for outcome measures...............................60 4 1. Executive Summary 1.1 Background The short term-benefits of methylphenidate and dexamphetamine in the management of Attention Deficit Hyperactivity Disorder (ADHD) symptoms are well described throughout the literature. Similarly, the short-term side-effects of these stimulant medications are well- documented. However, the long-term benefits and side-effects have been less well studied. This project uses longitudinal data collected as part of the Western Australian Pregnancy Birth Cohort to examine the long-term social, emotional, school-based, growth, and cardiovascular outcomes associated with the use of stimulant medication in the treatment of ADHD. These outcomes are measured at the age of 14-years. 1.2 Summary of results ADHD Diagnosis and Outcomes • Children with a diagnosis of ADHD as reported by parents (regardless of medication use), perform significantly worse at age 14 years on measures of depression, self perception, social functioning, academic performance, school enjoyment and attention than those without a diagnosis. • This is consistent with previous research and suggests that children diagnosed with ADHD have an underlying condition that impacts negatively on a range of long-term life skills. Outcomes Associated with Medication-Use for Children Diagnosed with ADHD Social/Emotional and School-Based outcomes • No significant differences based on medication-use were noted for the following measures taken at 14 years of age: depression, self-perception, and social- functioning. • Whilst no statistically significant results were noted, a trend toward slightly higher depression scores was noted with the use of medication. • A trend toward slightly lower self-esteem and social functioning was also noted with medication use at one time point or two time points. However, consistent medication- use at all time points, including at 14 years, trended toward slightly improved self- perception and social functioning. 5 • It should be emphasised that where these trends were noted, the effect sizes were small and were not statistically significant School-Based outcomes • In children with ADHD, ever receiving stimulant medication was found to increase the odds of being identified as performing below age-level by a classroom teacher by a factor of 10.5 times (compared to never receiving stimulant medication). • Absenteeism and school enjoyment were not found to be significantly predicted by stimulant medication-use. • It should be noted that analyses examining academic performance and absenteeism were limited due to low sample size and the lack of ability to examine differences based on the level of exposure to medication. Height and Weight • Height: There was no significant difference in average height or weight (at 14 years of age) when comparing children who were consistently on medication to those who were never on medication. • Non-significant trends indicated very little difference in growth measures between the ‘consistently medicated’ and ‘never medicated’ groups. • This is inconsistent with previous research; however it is likely that the small sample sizes in the stimulant exposure categories may have prevented significant results from being identified. Cardiovascular Function • Systolic Blood Pressure: no significant difference based on stimulant medication use was noted. • Diastolic Blood Pressure: children who had consistently received stimulant medication at all time points had significantly greater diastolic blood pressure than children who had never received medication (10.79 mmHg higher). • Children who had consistently received stimulant medication at all time points (including when cardiovascular health was measured) also had a significantly greater diastolic blood pressure than children who were currently receiving medication but had not in the past (7.05 mmHg higher). o These findings suggest that an elevation in diastolic blood pressure may not be due solely to the immediate short-term effects of stimulant medication on cardiovascular function. 6 • Resting Heart Rate: no significant difference based on stimulant medication use was noted. However a non-significant trend of higher resting heart rate in children receiving stimulant medication at all time points in the study was noted. Change in Key ADHD Symptoms • On average, externalising behaviour and attentional problems did not appear to improve or worsen significantly between the ages of 5 and 14 in children with ADHD, regardless of medication use. • Where an effect was noted, this was in the direction of symptoms worsening with the use of ADHD medication (however, this effect was small and not statistically significant). • The results seem to indicate that there is little long-term benefit of stimulant medication in the core symptoms of ADHD. This is not unexpected, as medication is used for the temporary management of core ADHD symptoms rather than as a cure. • Some concern may be raised over the apparent lack of effect with regard to children ‘currently’ on medication, as it would be expected that some short-term reduction in symptoms would be observed. However, the lack of a short-term effect may be explained by the fact that parents completed the assessments of core symptoms. Given that medication is taken mostly during school hours, the ‘onboard’ effects of medication may not be apparent to parents. 1.3 Conclusions The strength of the current study lies in its ability to provide a unique long-term view of a wide range of outcomes and their associations with the use of stimulant medication in the treatment of ADHD. Whilst limitations of the study prevent any strong causal relationships from being identified, some interesting results were observed that indicate rigorous research into the area is strongly warranted. • The lack of significant improvements in long-term social, emotional and academic functioning associated with the use of stimulant medication suggests a purpose- designed, longitudinal research study should be conducted to better understand the suspected long-term social, emotional and educational benefits of stimulant medication in the treatment of ADHD. • The results also indicated that between the age of 8 and 14 years there may be an effect of stimulant medication on diastolic blood pressure above and beyond the well- established immediate short-term effects on cardiovascular function. The finding that consistent use of medication was associated with an average elevation 10mmHg at 14-years of age indicates that the long-term cardiovascular implications of stimulant 7 medication-use need to take a high priority when determining directions for future research. 1.4 Limitations There are a number of limitations associated with the current study that should be taken into account when interpreting the results: • The relatively low sample size in the stimulant-use comparison groups may have reduced the chance of finding real differences where they may have existed. • Whilst a number of steps were taken to reduce the possible biases between the comparison groups, particularly with regard to symptom severity, it is still possible that these may not be adequately controlled for, threatening the validity of some multivariable models. • Measures used to document ADHD symptoms (CBCL 1991) may have been inadequate to document severity (though previous research has documented it to be useful in differentiating ADHD from non-ADHD cases). The version of the Achenbach scales used does not document ICD10/DSM IV criteria. • Due to sample size issues, dextroamphetamine and methylphenidate use were combined into one composite group: ‘stimulant use’. This prevented the effects of the different medications on the various outcomes to be identified. • Dosage and adherence to medication was not measured as part of the study. Medication usage at each of the time points was determined by the mother reporting that the medication had been used in the 6 months prior to completing the questionnaire. • ADHD diagnosis by a medical professional was reported by the child’s parent and was not validated using diagnostic tools. • The subtypes of ADHD were not able to be analysed separately (due to sample size). 8 2. Stimulant Medication in the treatment of ADHD 2.1 Introduction ADHD Attention Deficit/Hyperactivity Disorder (ADHD) a disorder is typified by hyperactivity, impulsivity and/or attention difficulties that significantly impact upon social, academic, and/or occupational functioning (America Psychiatric Association, 2000). Children with ADHD have been identified as being at greater risk of experiencing poor academic performance, problems with social integration, and emotional difficulties during childhood and adolescence (Barkley, 1997; Edbom, Granlund, Lichtenstein, & Larsson, 2008; Gewirtz, Stanton-Chapman, & Reeve, 2009; Malhi & Singhi, 2001; Powers, Marks, Miller, Newcorn, & Halperin, 2008). The disorder also has long-term implications for development into adulthood, with ADHD being associated with greater risk for outcomes such as drug/alcohol abuse, poor relationship quality and imprisonment (Eakin et al., 2004; Rosler, Retz, Yaqoobi, Burg, & Retz-Junginger, 2009). Prevalence ADHD is currently the most commonly diagnosed psychiatric disorder in children. A recent review of the literature indicated that internationally, approximately 5.3% of children under the age of 18 years are diagnosed with ADHD (Polanczyk, de Lima, Horta, Biederman, & Rohde, 2007). More locally, the proportion of Australian children meeting the diagnosis requirements for ADHD has been estimated at approximately 8% (AIHW, 2003). Treatment The current treatment of choice for ADHD in Western Australia (and worldwide in general) is the prescription of stimulant medication, either alone or in conjunction with cognitive/behavioural treatments (Taylor, O'Donoghue, & Houghton, 2006). The two most commonly prescribed stimulants in WA are dextroamphetamine sulphide (dexamphetamine) and methylphenidate (short and long acting). The 2008 annual report released by the WA Stimulant Regulatory Scheme indicated that approximately 1.26% of all children in the state had received either dexamphetamine or methylphenidate in the treatment of ADHD during that year (Department of Health, 2008). Given the significant rate of stimulant prescription in WA children, is it important to know whether this form of treatment is effective and safe for children with ADHD. Effectiveness of stimulant medication in treatment of ADHD 9 Short-term to medium-term There have been many randomised controlled trials indicating the effectiveness of both dexamphetamine and methylphenidate in the short-term treatment of core ADHD symptoms. The majority of these studies span between 2 weeks and approximately 6 months. Whilst the body of research is too large to cover comprehensively in this report, a number of reviews and meta-analyses summarising the results of the literature-base have been identified. These reviews and meta-analyses indicate that the use of both dexamphetamine and methylphenidate result in the clinically meaningful short-term reduction in the key symptoms of ADHD: attention, hyperactivity and impulsivity (Greenhill, Halperin, & Abikoff, 1999; Leonard, McCartan, White, & King, 2004; Schachter, Pham, King, Langford, & Moher, 2001; Van der Oord, Prins, Oosterlaan, & Emmelkamp, 2008). Whilst the greater part of the literature provides consistent evidence for the effects of stimulant medication in the management of ADHD symptoms, it is noted that a strong ‘publication bias’ (i.e. the likelihood of positive findings being published over ‘null’ findings) is present within the ADHD treatment literature (Schachter et al., 2001). This may result in meta- analyses overestimating the effect of medication on certain domains. However despite this concern, the size of the body of research, along with the broadly consistent findings, has resulted in a general consensus amongst medical researchers that methylphenidate and dexamphetamine are effective in managing the short-term symptoms of ADHD. 10