Table I.

Pediatric studies examining the effect of psychostimulants in patients (pts) with attention-deficit hyperactivity disorder (ADHD) [i.e. without a diagnosis of bipolar disorder (BD)]

Study, y	Objective and population	Method	Results	Conclusions	Limitations
Carlson and Kelly,[8] 1998	Determine response to treatment of mania with a stimulant (drug and dose unspecified) Inpatients aged 5–12 y with ADHD and manic (n = 29) and non-manic (n = 19) symptoms not meeting criteria for BD	p, 1-wk trial with PL followed by a 2-wk trial with stimulant Blind ratings from teacher and nurse	Children with mania symptoms had more severe illness Improved teacher and nurse ratings with stimulant treatment No greater AEs among pts with manic symptoms when treated with stimulants vs PL No worse outcomes after medication wore off between manic and non-manic children Depression and anxiety ratings did not improve for either group	Symptoms of mania were markers of more severe illness regardless of diagnosis. Exposure to stimulants did not negatively impact children with symptoms of mania. Both groups improved from treatment with stimulants	A diagnosis of BD was not formally assessed by structured clinical interview
Carlson et al.,[9] 2000a	Examine long-term effects of MPH exposure in boys at risk for BD, and examine if these subjects are at greater risk for adult mania spectrum disorders as a result of exposure to MPH 75 boys aged 4–12 y followed up between ages 21 and 23 y to assess adult diagnosis	rt, longitudinal, all subjects treated with MPH, diagnoses made at the time using DSM-II were ‘translated’ into DSM-IV ‘emulated’ diagnoses using blind raters reviewing the medical record Subjects were placed into high (n = 17; MAX) and low (n = 58; MIN) illness-severity categories	Duration, dosing, side effects, and response to medication in the MAX and MIN group were similar 13 were diagnosed with a mania spectrum disorder as an adult; an equal percentage of these were from the MAX and MIN groups There was no variance between MAX and MIN groups in the degree or quality of response to MPH Both groups showed a significant positive improvement in ADHD symptoms	Stimulant use in children with ADHD was not a risk factor or predictor of adult BD. No differential response to stimulants in boys with or at risk for childhood mania vs those without childhood mania. Stimulant use in children with co-morbidities who have or may be developing BD did not precipitate or exacerbate mania	Structured clinical interviews were not used to determine diagnoses. Follow-up was rt
Galanter et al.,[10] 2003	Examine how children with ADHD and some manic symptoms not meeting BD criteria respond to treatment with MPH Subset of 270 subjects aged 7–9 y from the MTA study[11] receiving 1 mo MPH titration	rt, 1-mo duration Two ‘mania proxies’ were constructed to retrospectively measure manic symptoms using CBCL[12] and DISC[13]	11.9% were manic by CBCL, 10.7% were manic by DISC, 2.6% were manic by both All subjects from both groups responded similarly to MPH Higher doses of MPH were inversely proportional to ratings of crabbiness and worry	Subjects with ADHD and manic symptoms responded well to MPH with no increase in AEs compared with subjects with ADHD and no manic symptoms. MPH treatment was associated with fewer mania symptoms	Short duration. MPH titration schedule did not reflect real- world escalation of dose. The original MTA study was not designed to examine ADHD and mania symptoms Proxy measures used were not validated for pediatric ADHD and mania
Tillman and Geller,[14] 2006a	Examine rate, risk, and predictors of switch from ADHD to PEA-BP-I through a 6-y follow-up assessment Youths aged 7–16 y with ADHD (n = 81) with CGAS[15] score <60 vs controls (n = 94) Subjects with a history of BD or MDD were excluded	p, baseline, 2-, 4- and 6-y follow-up ratings. Raters were blinded to diagnosis	28.5% of ADHD subjects developed PEA-BP-I or -II, 9.9% of ADHD subjects developed PEA-BP-II, 2.1% of healthy controls developed PEA-BP-I. 83.3% of switchers to PEA-BP-I were treated with stimulants, 98.1% of non-switchers to PEA- BP-I were treated with stimulants. No specific baseline manic-like symptoms among ADHD subjects were significant in predicting switch	PEA-BP-I is a validated diagnosis with unique symptoms not overlapping with other diagnoses. ADHD subjects on stimulants were less likely to switch to PEA-BP-I. Antidepressant exposure was not associated with developing BD. Three predictors of switch from ADHD to PEA-BP-I were lower baseline CGAS; father with recurrent MDD rather than a family history of BD; and treatment without a stimulant	Skewed for Caucasian ethnicity and high social economic status. High rate of stimulant treatment among all subjects

^aThis study is relevant to sections 2 and 6 of the main text.

AEs = adverse events; CBCL = Child Behavior Checklist; CGAS = Children’s Global Assessment Scale; DISC = Diagnostic Interview Schedule for Children; DSM-II = Diagnostic and Statistical Manual of Mental Disorders, 2nd edition; DSM-IV = DSM, 4th edition; MAX = maximum; MDD = major depressive disorder; MIN = minimum; MPH = methylphenidate; MTA = Multimodal Treatment of Children with ADHD; p = prospective; PEA-BP-I = pre-pubertal and early adolescent bipolar I disorder; PEA-BP-II = PEA-BP II disorder; PL = placebo; rt = retrospective.