Table II.

Pediatric studies examining the effect of psychostimulants (and atomoxetine) in patients (pts) with bipolar disorder (BD)

Study, y	Objective and population	Method	Results	Conclusions	Limitations
Scheffer et al.,[16] 2005	Examine, in a 3-phase study, if the addition of MAS was a safe and effective treatment of ADHD symptoms compared with PL in youth aged 6–17 y with BD I (n = 31) or II (n = 9)	In phase 1, youth were treated with 8 wk of DVPX for resolution of manic symptoms. In phase 2, DVPX responders (n = 32) were then treated in a p, r, db, pc, 4-wk, co design for 2 wk with MAS 5 mg bid or PL, then 2-wk, co to the other group. In phase 3, youth (n = 23) completed a 12–wk, open-label, follow-up with DVPX and MAS Clinical evaluations occurred monthly The CGI[17] rating scale was the main outcome measure for assessing change from baseline ADHD symptoms	80% treated with DVPX alone had 50% reduction in YMRS[18] scores YMRS ratings were no different for either group CGI was greater for those taking MAS than with PL No carryover effect from co sequence One subject experienced mania with coadministration of MAS and DVPX. Symptoms resolved with discontinuation of MAS 50% of pts in the 12-wk, open-label follow-up required increased doses of MAS to maintain ADHD symptom control	DVPX was effective in treating mania, although ineffective in treating co-morbid ADHD. Adding MAS to DVPX was safe, tolerable and effective for symptoms of ADHD in BD youth. Treatment with MAS did not improve or worsen mania symptoms	Stabilization with DVPX was open-label. MAS dosing was conservative at 5 mg bid. A higher dose of MAS may have further reduced ADHD symptoms or may have resulted in more manic symptoms. Long-term outcome beyond 12 wk of follow-up unknown
Findling et al.[19] 2007	Examine short-term efficacy of MPH in euthymic youth with ADHD and BD 24 youth aged 5–17 y 16 youth completed the study Subjects met criteria for both ADHD and BD I or II, or NOS	p, r, db, pc, 4-wk, co. Every pt underwent randomly assigned dosing sequences composed of 1 wk each of PL; MPH 5 mg bid; MPH 10 mg bid; MPH 15 mg bid The best dose wk was determined (after unblinding) using a parent ADHD rating scale and report of AEs Mood stabilizers utilized included DVPX + lithium (n = 12); DVPX alone (n = 3); and lithium alone (n = 1)	Significant difference between PL and ‘best dose’ on ADHD scales. No significant difference between PL and ‘best dose’ on CDRS-R;[20] and YMRS No difference between dosing strengths	MPH may be a safe and effective treatment for co-morbid ADHD in youth treated with DVPX, lithium or DVPX + lithium. Adjunctive MPH treatment did not affect mood stability. MPH was superior to PL on the total score for parent completed ADHD-RS-IV rating scales. Higher doses of MPH were not more efficacious	Small sample size, short duration. MPH was immediate release with bid dosing; therefore, no information about effects of long-acting MPH is available. Clonidine in some pts may have confounded results
Chang et al.,[21] 2009	Examine if atomoxetine is effective for treating co- morbid ADHD in euthymic youth with BD I or II Youth aged 6–17 y (n = 12 enrolled; n = 10 completed) Euthymia was defined by 3 consecutive wk of no hypomania, mania, mixed or depressive episodes	8-wk open-label ITT analysis Atomoxetine mean final dose of 59.2 mg/d Evaluations were performed weekly Response = 25% reduction in ADHD-RS-IV,[22] remission = 40% reduction in ADHD-RS-IV symptoms Mood stabilizers utilized included typicals (n = 8), anticonvulsants (n = 9), and lithium (n = 2)	67% responders, 50% remitters, 92% with reduction in ADHD-RS- IV. No change in YMRS or CDRS. No subjects became manic or mixed, one discontinued in wk 4 because of hypomania, one discontinued in wk 2 because of persistent suicidal ideation	Atomoxetine is effective in treating ADHD in youth with BD receiving a mood stabilizer. Moderate effect size of 0.73	Open-label study, small sample size Unclear if symptomatic worsening (n = 2) coincided or correlated with administration of atomoxetine
Zeni et al.,[23] 2009	Examine if adjunctive treatment with MPH was safe and effective for treatment of ADHD symptoms compared with PL in euthymic youth with BD I or II treated with ARI Youth aged 8–17 y (n = 16 enrolled; n = 14 completed)	4-wk co trial: 2 wk with MPH or PL, then switch to the other group for 2 wk ARI dose range 5–20 mg/d, mean dose of 12.81 mg/d MPH was administered bid: first wk 15 mg total/d; second wk 35 mg total/d Weekly assessments using rating scales to measure changes in symptoms of ADHD and mood as well as overall clinical improvement	No significant difference in ADHD or mania symptoms when MPH was added. Significant decrease in depressive symptoms was noted according to secondary self-report. One subject discontinued because of onset of mixed mood state with manic features	MPH did not improve ADHD symptoms but did improve self-report of depressive symptoms. MPH added to a mood stabilizer may be helpful in treating depressive symptoms in BD	Small sample size. Challenges comparing results as this study used a mixed-effects model analysis unlike similar studies. Short duration

ADHD = attention-deficit hyperactivity disorder; ADHD-RS-IV = ADHD-rating scale-IV; AEs = adverse events; ARI = aripiprazole; bid = twice daily; CDRS = Children’s Depression Rating Scale; CDRS-R = CDRS-Revised; CGI = Clinical Global Improvement; co = crossover; db = double-blind; DVPX = divalproex semisodium; ITT = intent to treat; MAS = mixed amphetamine salts; MPH = methylphenidate; NOS = not otherwise specified; p = prospective; pc = placebo-controlled; PL = placebo; r = randomized; YMRS = Young Mania Rating Scale.