Table 1.
Representative short-term controlled clinical studies of stimulants in adults with attention-deficit/hyperactivity disorder†.
| Study (year) | n | Design | Medication | Duration (weeks) | Total dose mean and/or range | Outcome | Comments | Ref. |
|---|---|---|---|---|---|---|---|---|
| Wood et al. (1976) | 15 | Double-blind, placebo crossover | MPH | 4 | 27 mg/day | 73% response rate | Dx criteria not well defined; low doses of pemoline; mild side effects | [40] |
| Mattes et al. (1984) | 61 | Double-blind, placebo crossover | MPH | 6 | 48 mg/day | 25% response rate | Moderate rate of comorbidity; mild side effects | [41] |
| Wender et al. (1985) | 37 | Double-blind, placebo crossover | MPH | 5 | 43 mg/day | 57% response rate (11% placebo) | 68% dysthymia; 22% cyclothymia; mild side effects | [42] |
| Gualtieri et al. (1985) | 22 | Double-blind, placebo crossover | MPH | 2 | 42 mg/day | Mild–moderate response | No plasma level-response associations | [43] |
| Spencer et al. (1995) | 23 | Double-blind, placebo crossover | MPH | 7 | 1.0 mg/kg/day | 78% response rate, dose relationship (4% placebo) | No plasma level associations; no effect of gender or comorbidity | [44] |
| Iaboni et al. (1996) | 30 | Double-blind, placebo crossover | MPH | 4 | 30–45 mg/day | Moderate response | Improvement in neuropsychology and anxiety | [45] |
| Paterson et al. (1999) | 45 | Double-blind, parallel | d-AMP | 6 | 23 mg/day | 58% response rate | Weight loss only major adverse effect | [46] |
| Spencer et al. (2001) | 27 | Double-blind, placebo crossover | AMP salts | 7 | 54 mg/day 20–60 mg/day |
70% response rate, dose relationship (7% placebo) | No effect of comorbidity or gender on response; well tolerated | [47] |
| Taylor (2000); Taylor (2000) | 39 | Double-blind, placebo crossover | d-AMP | 7 | 22 mg/day | 48% response rate | Used as comparator in two studies of nonstimulants; respiratory >30% reduction in scales | [48,49] |
| Kooij et al. (2004) | 45 | Double-blind, randomized crossover | MPH | 3 | 0.5–1.0 mg/kg/day | 38–51% response rate (7–18% placebo) | European study; compare with US high rate of side effects for MPH and placebo | [50] |
| Carpentier et al. (2005) | 25 | Double-blind, placebo crossover | MPH | 8 | 15–45 mg/day | 58% response rate on CGI (32% placebo) | SUD study; positive response to Tx not significantly higher than placebo | [51] |
| Spencer et al. (2005) | 146 | Double-blind, placebo parallel | MPH | 6 | 1.1 mg/kg/day | 76% response rate (19% placebo) | Tx well tolerated despite higher dose | [52] |
| Biederman et al. (2006) | 141 | Double-blind, placebo parallel | OROS MPH | 6 | 81 mg/day | 66% response rate (39% placebo) | Slight SBP, DBP and HR increases with medication | [53] |
| Weisler et al. (2006) | 255 | Double-blind, placebo parallel | MAS ER | 4 | 20, 40 or 60 mg/day | 55% response rate on CGI (27% placebo) | MAS ER 60-mg group had greatest improvement on ADHD RS | [54] |
| Spencer et al. (2007) | 221 | Double-blind, fixed-dose, placebo parallel | d-MPH-ER | 5 | 20, 30 or 40 mg/day | 54–61% response rate on ADHD RS (34% placebo) | Inconsistent dose response | [32] |
| Reimherr et al. (2007) | 45 | Double-blind, placebo crossover | OROS MPH | 8 | 57 mg/day (treatment responder mean) 75 mg/day (treatment nonresponder mean) |
54% response rate on CGI (22% placebo) | Total ADHD RS score decrease of 41% (vs 14% placebo) | [55] |
| Jain et al. (2007) | 39 | Double-blind, placebo crossover | MLR MPH | 5–11 | 58mg/day (mean) MLR MPH 65 mg/day (mean) placebo |
49% response rate on CGI (23% placebo) | MLR MPH minimal side effects; short trial | [56] |
| Adler et al. (2008); Weber et al. (2009) | 420 | Double-blind, placebo parallel (2:2:2:1) | LDX | 4 | 30, 50 or 70 mg/day | Response rate on CGI: 57, 62 and 61% (29% placebo) | Incidence of AEs highest in first week of LDX treatment | [57,58] |
| Medori et al. (2008) | 401 | Double-blind, placebo parallel | Prolonged- release OROS MPH | 5 | 18, 36 or 72 mg/day | Responders were 51, 49 and 60% (27% placebo) | AE rates 75, 76 and 82% vs 66% in placebo; most common decreased appetite and headache | [34] |
| Chronis-Tuscano et al. (2008) | 23 | Double-blind, placebo-controlled | OROS MPH | 7 | 36, 54, 72 or 90 mg/day (mean 84 mg/day) | Significant reduction in CGI scores at all doses | Few AEs | [59] |
| Adler et al. (2009) | 226 | Double-blind, placebo parallel | OROS MPH | 7 | 68 mg/day OROS MPH (mean) 87 mg/day placebo (mean) |
37% response rate on CGI and AISRS (21% placebo) | Mild-to-moderate AE rate, 85% MPH vs 64% placebo; OROS MPH overall effective and well tolerated in dose escalation | [60] |
| Winhusen et al. (2010) | 255 | Double-blind, placebo parallel | OROS MPH | 11 | 18–72 mg/day | 71% response rate on CGI (44% placebo) | Cigarette smoking abstinence not significantly different between groups | [61] |
| Wigal et al. (2010) | 105 | Randomized, double-blind, crossover | LDX | 2 | 30, 50, or 70 mg/day | 77% response on CGI (23% placebo) | After open-label dose optimization (4 weeks), subjects entered 2-week crossover phase | [62] |
| Spencer et al. (2010) | 53 | Single-blind, parallel | OROS MPH or IR MPH | 6 | 77 mg/day IR MPH (mean) 80 mg/day OROS MPH (mean) |
OROS once a day was as efficacious as IR MPH three times per day in adults | OROS well tolerated and similar safety indices as IR; increased adherence with OROS | [63] |
| Wender et al. (2010) | 105 | Double-blind, placebo crossover | MPH | 2 | 45 mg/day 10–60 mg/day |
74% experienced at least 50% reduction on WRAADDS Sx score (22% placebo) | Participants who improved on MPH IR entered the 12-month, open-label trial | [64] |
| Total | ||||||||
| 25 | n = 2804 15–420 (range) |
Single: 1 Double: 24 |
MPH: 19 AMP: 4 LDX: 2 |
2–11 | 10–90 mg/day MPH 20–60 mg/day AMP 30–70mg/day LDX |
MPH, AMP, and LDX improved ADHD Sxs | AEs mild-to-moderate in severity | |
†
Up to 11 weeks.
Response rate refers to subject reporting much-to-very-much improved (i.e., by CGI) or with clinically significant reduction in symptoms on ADHD rating scales.
ADHD: Attention-deficit/hyperactivity disorder; AE: Adverse event; AISRS: ADHD Investigator Symptom Report Scale; AMP: Amphetamine; CGI: Clinical Global Impression; d-AMP: blood pressure; d-MPH: Dexmethylphenidate; Dx: Diagnosis; ER: Extended release; HR: Heart rate; IR: Immediate release; LDX: Lisdexamfetamine dimesylate; MAS ER: Mixed amphetamine MAS: Mixed amphetamine salt; MLR: Multilayer release; MPH: Methylphenidate; OROS MPH: Osmotic-release oral system methylphenidate; RS: Rating scale; SBP: Systolic blood pressure; SUD: Substance use disorder; Sx: Symptom; Tx: Treatment; WRAADDS: Wender Reimherr Adult Attention-Deficit Disorder Scale.