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    QUEST - Stimulants

Author:
 M. Ojinga Harrison

Predictors of Adult Height and Weight in Boys Treated with Methylphenidate for Childhood Behavior Problems.

Chairman's Conference 

Kramer J, Loney J, Ponto L, Journal of the American Academy of Child and Adolescent Psychiatry April 2000; 39(4) 517-524

Category: Harm

Summary: Historic Cohort Sturdy involving 97 subjects who were treated with Methylphenidate (MTF) and compared to various control groups including sibling, classmates, and other boys with comparable behavior problems to determine the effects of Methylphenidate on adult height and weight. The subjects initially started methylphenidate therapy at ages ranging from 4-12 and were then followed-up at ages 21-23 and 28-32. Medication was discontinued in all patients by the second follow-up.

  1. Are the results of the study valid?
    1. Except for the exposure under study, were the compared groups similar to each other? Yes, comparison groups included brothers, classmates and other boys with comparable behavior problems.
    2. Were the outcomes and exposures measured in the same ways in both groups? Yes, height and weight were the used to measure the outcomes and the dose of medication and the length of time on medication were used as the exposure.
    3. Was the follow-up sufficiently long and complete? No. It was sufficiently long but incomplete because we don't know how long MTP had been stopped prior to follow-up at ages 21-23.
    4. Is the temporal relationship correct? Yes
    5. Is there a dose-response gradient? Yes, for weight only.
  2. What are the results?
    1. How strong is the association between exposure and outcome? There is no clear association between Methylphenidate (MPH) use and suppression of final adult height in the majority of subjects. Predictors of height variation in the subjects included height at referral, SES, age at referral (-), and nausea and vomiting as side effects. Predictive findings for weight include birth weight, age at referral, weight at referral, height at referral, SES and daily maintenance dose of MPH.
    2. How precise is the estimate of relative risk? We are unable to estimate because the study did not use dichotomous (present or absent) variables instead it used the average of continuous variables (length and weight). Therefore we are unable to calculate relative risk.
  3. Will the results help me in my patient care?
    1. Are the results applicable to my patient? The fact that only 52% of patients were still taking medication by age 13 (Adolescence follow-up) significantly limits the utility of this study. Especially since many patients taking MPH will continue the medication into high school and college. Since we do not know for sure when the other 52% of patients stopped the medication we can only say for certain that normal growth is achieved if medication is discontinued around age 13. This study is also limited by the fact that there were no minorities or women present.
    2. What is the magnitude of the risk? For the population described in the study the risk is insignificant. The study however suggests an association with initial vomiting as a medication side effect and decreased height. It also suggests an association with higher dose of medication (40mg) and decreased weight. These findings, however, need to be further studied.
    3. Should I attempt to stop the exposure? A risk- benefit determination should be made if the patient requires higher doses of medication or has vomiting as an initial medication side effect. Also recall the limited population on which this study was performed in particular the fact most patients had stopped the medication around age 13.
Bottom line: Methylphenidate does not cause changes in final adult height if discontinued by ages 13.

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DOES STIMULANT THERAPY OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER BEGAT LATER SUBSTANCE ABUSE?  

Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytical review of the literature. Wilens et al., 2003, Pediatrics 111:179-85

Premise: There is good evidence that pharmacological treatment of ADHD with stimulants (mainly methylphenidate and amphetamine) is highly effective. Many people, however, are concerned that treatment with these drugs may lead to higher incidence of later substance abuse.

Methods: Systematic review of all published longitudinal studies of ADHD children that measure prevalence of substance abuse during adolescence/adulthood. Random-effects meta­analysis (method of Carlin) was used to calculate the pooled estimate of all the odds ratios. This method weighs each study according to the number of subjects. To see if small-study bias was present, the method of Egger was used, i.e. regressing the standard normal deviate (SND) of the OR against the precision of the OR. In the absence of bias, these should run through the same origin. Small studies have low precision, large standard error, and therefore small SND, whereas large studies have higher precision, smaller standard deviations, and therefore large SND. Since these are naturalistic studies, baseline severity was also assessed (severe cases are more likely to be treated; severe cases may also be more susceptible to becoming substance abusers).

Validity: 1) Systematic review of RCT: no, 2) hand-searched journals: no, 3) bias towards positive trials taken into account: yes (but see below), 4) similar trend in all studies: no, 5) can they explain this heterogeneity: somewhat, 6) did they analyze individual data: yes

Results: 6 studies (5 prospective and 1 retrospective). 674 treated and 360 untreated subjects. Pooled OR was 1.9 for all substance abuse. NNT to prevent EtOHism was S and to prevent illicit­drug use, 16. There was a stronger protective effect in the studies with similar baseline severity; in fact, in the two studies that showed a deleterious effect of stimulant treatment, the non-treated group had more severe ADHD at baseline (per the authors; I did not look at individual studies). The method of Egger showed that no small-study bias could account for the effect.

Study

Rx+

Rx-

EtOH/+

EtOH/-

NNT/H

Drug/+

Drug/-

NNT/H

Lambert

93

81

44%

32%

8 (H)

25%

21%

25(H)

Biederman

145

45

21%

68%

2 (T)

16%

42%

4 (T)

Huss

98

21

33%

33%

--

32%

29%

33 (H)

Loney

182

37

27%

56%

3 (T)

17%

19%

50 (T)

Molina

53

73

4%

21%

6 (T)

 

28%

5 (T)

Barkley

data

not

available

for

me

to

look

at

Remarks: No randomized trials. Baseline severity was similar in studies that showed a protective effect, but there are many other factors. How good is the "method of Egger" to rule out small­study bias? The studies included in this paper were all about the same size (N range was 119-219)  -> is this method still applicable? What about non-English studies?

Bottom-line: Impossible to conclude that stimulant treatment protects against substance abuse. Likely that stimulant treatment does not cause a large increase in substance abuse. Therefore, harm-benefit ratio is probably in favor of benefit, since stimulants help ADHD kids function.

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ANTIDEPRESSANT OR STIMULANT - WHICH SHOULD BE FIRST-LINE TREATMENT FOR ADHD?

Bottom line: There are no head-to-head trials comparing these two agents. While this review suggests that they are equally effective, the validity of the comparison is weak.

 

Reference: Higgins, ES. A comparative analysis of antidepressants and stimulants for the treatment of adults with ADHD. Journal of Family Practice, 1999, 48(1), 15-20.

 

METHODS

Study sources-- medline

Design of studies included-- controlled and uncontrolled, retrospective and prospective, open label and double blind. Details unclear.

Inclusion/exclusion criteria-- Studies of combined treatment were excluded.

 

VALIDITY

Only one database was searched. Only English language. Few details of inclusion criteria. More weight given to placebo-controlled trials in the narrative, but no other assessment of study validity. Unclear which studies were placebo controlled and how repsonce was measured. No discussion of whether participant characteristics and population event rates were similar.

 

RESULTS:

No metanalysis was performed. Results are presented in tables and discussed narratively, but not combined. The range of responders to stimulants was 25-100%. Results in the placebo-controlled study were inconclusive. Childhood history of ADHD was associated with response in one study but not in another. The range of responders to anti-depressants 0-75%. Desipramine, buproprion, venlafaxine and tomxetine seemed equally effective. Fluoxetine and sertraline produced no response. Indirect comparison of two trials showed that groups treated with L.0 mg/kg/day MPH and 200mg /day desipramine had similar responses on ADHD scale.

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