Excerpts from the Raine Study Data ADHD Long Term Drug Effect Review

Note: all words in italics are direct quotes from the report

Highlights

Significance – The longitudinal and comprehensive nature of the Raine study provides a unique opportunity to examine the long-term outcomes associated with the use of stimulant medication during childhood.^[1] The 9 year data (ages 5 to 14) available from the Raine study is the only comprehensive educational, social, and health long term data source on the effect of stimulant medication available worldwide.

Permanent cardiovascular damage from medication – The most noteworthy finding in the study was the association between stimulant medication and diastolic blood pressure. Compared to not receiving medication the consistent use of stimulant medication was associated with a significantly higher diastolic blood pressure (of over 10mmHg) This effect did not appear to be solely attributable to any short-term effects of stimulant medication, as when comparing groups who were currently receiving medication, it was found that those who had consistently received medication at all time points had a significantly higher mean diastolic blood pressure than those who had not consistently received medication in the past (difference of 7mmHg).These findings indicate there may be a lasting longer-term effect of stimulant medication on diastolic blood pressure above and beyond the immediate short-term side-effects.^[2]

Significant long term impairment of educational performance from medication – 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).^[3]…The finding that stimulant medication-use increased the odds of below-age-level academic achievement by a factor of 10 times strongly suggests that medication may not result in any long-term academic gains (as rated by a classroom teacher). And, at worst, may result in poorer teacher-rated academic performance.^[4]

ADHD symptoms (inattention and hyperactivity) and depression marginally worse with long term use of medication - …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.^[5]

Whilst no statistically significant results were noted, a trend toward slightly higher depression scores was noted with the use of medication.^[6]

Why is this analysis so significant?

The longitudinal and comprehensive nature of the Raine study provides a unique opportunity to examine the long-term outcomes associated with the use of stimulant medication during childhood.^[7] The 9 year data (ages 5 to 14) available from the Raine study is the only comprehensive educational, social, and health long term data source on the effect of stimulant medication available worldwide.

Whilst there are thousands of mostly industry funded studies that claim to show ADHD stimulants are relatively safe and effective in the short term, “there is a paucity of evidence on the long term effects of psychostimulants on childen.”^[8] 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).^[9] Prior to the Raine Study review the longest relevant comprehensive study was the 3 year data from the Multimodal Treatment Study for Attention Deficit Hyperactivity Disorder (The MTA Study). ^[10] The MTA Study indicated the longer you look at the performance of ADHD medicated children the worse the results become.^[11] However, 3 years data can only at best be described as a medium term study.

Another advantage of the original Raine study data is that it reduces the risk of design bias as the original designers of the study had no idea the data would eventually be used to study ADHD. In addition the commissioning body, the Western Australian Ministerial Implementation Committee on ADHD (MICADHD), was a extremely diverse group. Opinions as to the safety and efficacy of stimulant medications within MICADHD are highly divergent. This lack of consensus should be seen as a strength of the study as it limited the potential for ‘publication bias’ where there is a collective decision to bury results that are not in keeping with the consensus position of participants.

What is the Raine Study and how is the data used to analyse the safety and effectiveness of ADHD stimulants?

The Western Australian Pregnancy Birth Cohort (Raine) Study is an ongoing longitudinal study following 2,868 children. The study began in 1989 as a pregnancy cohort of women enrolled at or before the 18th week of gestation from the public antenatal clinic at the principal obstetric hospital in Perth, Western Australia or nearby private practices. Since 1989, data has been collected from the participants (both the mother and her child) at regular intervals including when the child turned 1, 2, 3, 5, 8, 10, 14 and 17 years old.^[12]

Across the globe there are other similar long term, large scale, studies into children’s health and wellbeing, however, they are in locations with historically low rates of ADHD prescribing. The Raine Study is unique, in that it was conducted in a location which has had high rates of ADHD stimulant child prescribing. This unique potential data source was recognised by the Western Australian Ministerial Committee on ADHD (MICADHD) who commissioned a review of the Raine Study data in response to a 2004 Western Australian Parliamentary Inquiry that recommended “research into the safety and efficacy of the long run use of psychostimulant medication”.^[13],[14]

By age fourteen ‘of the 1785 adolescents in the sample, 131 (7.3%) had received a diagnosis of ADHD.’^[15] At age five none of the 131 had taken ADHD stimulants. The comparison of the groups at age five showed there were no statistically significant differences in symptom severity or health measures. The statistically significant differences that existed at age 14 occurred between age five and fourteen, after some of the children were medicated. To the extent that (non statistically significant differences) existed at age 5 these were ‘controlled for by using the ‘propensity for medication’ score, the symptom severity before commencement of medication treatment, and a number of sociodemographic measures.’^[16]

The data for the 131 ADHD diagnosed children was grouped for analysis in two different ways:

The first was by ‘Current Use of Medication’. At age fourteen, “21 (16.0%) were using medication… and had used it consistently since being diagnosed with ADHD; 40 (30.5%) were using medication.. but had not consistently used it in the past; 41 (31.3%) had used medication in the past be were not using it at age 14, and; 29 (22.1%) had not reported using stimulant medication.”^[17]

The second was by ‘Ever Use of Medication’. Of the 131 children, “21 (16.0%) reported the use of stimulant medication at all three follow-up points (8, 10, 14 years), 42 (32.1%) at two follow-up points, and 39 (29.8%) at one of the follow-up points. 29 (22.1%) reported no use of stimulant medication at any of the follow-up points.”^[18]

These two measures gave the capacity to analyse the differences attributable to differences resulting from 1- residual effects of medication, 2- current effects of medication, 3- effects of extended duration of medication.

What did the Analysis find?

The 9 year data from the Raine Study confirmed the trend evident from the 3 year data from the MTA study; that is, in the long term ADHD drugs are of no benefit and cause harm.^[19]

The major findings were:

Educational Achievement

‘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).’^[20] This findinding undermines the very basis of ADHD child stimulant prescribing as‘it is hypothesised that this (the treatment of ADHD with stimulants) makes children more available for learning and allows children to learn skills and concepts which are necessary to function well within a classroom in the future. Thus, children who have received stimulant medication at any time point should observe some long-term school-related benefits as a result’ (Carlson & Bunner, 1993).^[21]

Therefore ‘it would be expected that any stimulant medication-use would reduce short-term attentional and behavioural problems for the period in which it was used, thus allowing a child to learn the necessary information on which new information can be built upon in the future (Carlson & Bunner, 1993). The finding that stimulant medication-use increased the odds of below-age-level academic achievement by a factor of 10 times is in direct contrast to this hypothesis; indicating that ‘any’ use of stimulant medication is not associated with improved academic performance.’^[22]

…’The finding that stimulant medication-use increased the odds of below-age-level academic achievement by a factor of 10 times strongly suggests that medication may not result in any long-term academic gains (as rated by a classroom teacher). And, at worst, may result in poorer teacher-rated academic performance.’

Cardiovascular Function

Diastolic Blood Pressure

The most noteworthy finding in the study was the association between stimulant medication and diastolic blood pressure. Compared to not receiving medication the consistent use of stimulant medication was associated with a significantly higher diastolic blood pressure (of over 10mmHg) This effect did not appear to be solely attributable to any short-term effects of stimulant medication, as when comparing groups who were currently receiving medication, it was found that those who had consistently received medication at all time points had a significantly higher mean diastolic blood pressure than those who had not consistently received medication in the past (difference of 7mmHg).These findings indicate there may be a lasting longer-term effect of stimulant medication on diastolic blood pressure above and beyond the immediate short-term side-effects.^[23]

An elevation in diastolic blood pressure of 7 to 10mmHg does not necessarily represent a movement outside of the ‘normal’ range. This was mirrored by the fact that none of the children in the ADHD-diagnosed sample recorded a diastolic blood pressure that fell above the cut-off for the 95^th percentile (i.e. 79mmHg). However it should be noted that a meta-analysis examining cardiovascular function in adults found that elevated diastolic blood pressure, even falling within the ‘normal range’, significantly increases the risk of stroke and coronary heart disease. Prolonged elevation in diastolic blood pressure of 7.5 to 10mmHg was associated with 46% to 56% more stroke and 29% to 37% more coronary heart disease (MacMahon et al., 1990). However, whether similar long-term effects are associated with elevated blood pressure during childhood has not yet been studied.^[24]

Table 12. Estimated marginal means for diastolic blood pressure by current stimulant medication use (adjusting for gender, propensity, CBCL-E, CBCL-A, mother’s age, family structure, family income).^[25]

Resting Heart Rate

Whilst the results were not statistically significant, it is worth noting that there is a non-significant trend toward a higher resting heart rate in children who had consistently received medication (as compared to all other stimulant medication-use categories).^[26]

Systolic Blood Pressure

The pattern for Systolic Blood Pressure was similar to that for Diastolic Blood Pressure although increases in Diastolic Pressure are considered to be more important as they are more directly associated with adverse outcomes like heart attacks and strokes.

Table 11. Estimated marginal means for systolic blood pressure by current stimulant medication use (adjusting for gender, propensity, CBCL-E, CBCL-A, mother’s age, family structure, family income).^[27]

Change in Key ADHD Symptoms

‘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.^[28]

Emotional Outcomes (Depression)

Whilst no statistically significant results were noted, a trend toward slightly higher depression scores was noted with the use of medication.^[29]

[1] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p14

[2] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p56

[3] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p5

[4] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): pp34-35

[5] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p6

[6] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p5

[7] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p14

[8] Finding 13 Western Australia Legislative Assembly, Attention Deficit Hyperactivity Disorder in Western Australia, Education and Health Standing Committee, Report No. 8, (2004): p42

[9] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p10

[10] KC Wells, WE Pelham, et al, ‘Psychosocial treatment strategies in the MTA study: rationale, methods, and critical issues in design and implementation’, (abstract), Journal of Abnormal Child Psychology, 28; 6 (2000) Available here. (accessed 7 February 2008)

[11] Peter S Jensen, L. Eugene Arnold, James M. Swanson et al, “3-Year Follow-up of the NIMH MTA Study”, Journal of the American Academy of Child & Adolescent Psychiatry, Vol 46: 8; August 2007: pp989-1002

[12] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p14

[13] Education and Health Standing Committee: Annual Report 2003-2004, Legislative Assembly, Parliament of Western Australia, Perth, October 2004 recommendation 2, page 42

[14] Western Australian Ministerial Implementation Committee for Attention Deficit Hyperactivity Disorder, Raine Attention Deficit Hyperactivity Disorder Study, September 2009

[15] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p25

[16] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p56

[17] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p26

[18] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p26

[19]The MTA’s co-author University of Buffalo, Professor William Pelham, was describing the MTA’s 3 year results analyzing the benefits of stimulant medication when he said “There were no beneficial effects – none. In the short run (medication) will help the child behave better, in the long run it won’t. And that information should be made very clear to parents.” Allegra Stratton, ‘Questions raised about drugs as treatment for ADHD sufferers’, The Guardian, November 12th, 2007. Available here. (accessed 26 March 2008)

[20] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p5

[21] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p31

[22] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p34

[23] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p56

[24] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p48

[25] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p44

[26] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p46

[27] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p43

[28] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p6

[29] Draft: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Perth, Telethon Institute for Child Health Research (January 2010): p5