Table 3.
Representative clinical studies of nonstimulants in adults with attention-deficit/hyperactivity disorder.
| Study (year) | n | Design | Medication | Duration | Total dose mean and/or range | Outcome | Comments | Ref. |
|---|---|---|---|---|---|---|---|---|
| Wood et al. (1982) | 8 | Open | L-DOPA (+ carbidopa) | 3 weeks | 625 mg/day 62.5 mg/day |
No benefit | Side effects: nausea, sedation; low doses | [109] |
| Wender et al. (1983) | 22 | Open | Pargyline | 6 weeks | 30 mg/day 10–50 mg/day |
68% response rate | Delayed onset; brief behavioral action | [110] |
| Wender et al. (1985) | 11 | Open | Deprenyl | 6 weeks | 30 mg/day | 66% response rate | Amphetamine metabolite; two dropouts | [111] |
| Wood et al. (1985) | 19 | Double-blind, placebo crossover | Phenylalanine | 2 weeks | 587 mg/day | 46% response rate (15% placebo) | Transient mood improvement only | [112] |
| Mattes (1986) | 13 | Open | Propanolol | Mean: 9 weeks (3–50 weeks) | 528 mg/day 40–640 mg/day |
85% response rate | Part of ‘temper’ study | [113] |
| Reimherr et al. (1987) | 12 | Open | Tyrosine | 8 weeks | 50–150 mg/kg/day | 66% response rate | 14-day onset of action; tolerance developed; four dropouts | [114] |
| Shekim et al. (1989) | 18 | Open | Nomifensine maleate | 4 weeks | 50–300 mg/day | 94% response rate | Immediate response; one patient with allergic reaction | [115] |
| Shekim et al. (1990) | 8 | Open | S-adenosyl-L- methionine | 4 weeks | ≤2400 mg/day | 75% response rate | Mild adverse effects | [116] |
| Wender et al. (1990) | 19 | Open | BPR | 6–8 weeks | 359 mg/day 150–450 mg/day |
74% response rate | Five subjects could not tolerate lowest dose and dropped out; ten subjects with improvement at 1 year | [117] |
| Wilens et al. (1995) | 37 | Open, Retrospective | Desipramine Nortriptyline |
Mean: 50 weeks | 183 mg/day 92 mg/day |
68% response rate | Comorbidity unrelated to response; 60% on stimulants, 84% on concurrent meds; response sustained in 54% of patients | [118] |
| Adler et al. (1995) | 16 | Open | Venlafaxine | 8 weeks | 110 mg/day 25–225 mg/day |
83% response rate | Four subjects on other meds; four dropped out; 50% reduction in Sxs | [119] |
| Hedges et al. (1995) | 18 | Open | Venlafaxine | 8 weeks | 96 mg/day 50–150 mg/day |
50% response rate | Side effects led to 39% drop out rate; study divided into two groups, those who could tolerate medication and those who could not | [120] |
| Findling et al. (1996) | 10 | Open | Venlafaxine | 8 weeks | 150 mg/day (seven of nine) 75–150 mg/day |
70% response rate | Improved anxiety scores; one dropout | [121] |
| Wilens et al. (1996) | 43 | Double-blind, placebo parallel | Desipramine | 6 weeks | 147 mg/day | 68% response rate (0% placebo) | Comorbidity or levels not related to response | [122] |
| Ernst et al. (1996) | 24 | Double-blind, placebo parallel | Selegiline | 6 weeks | 20 mg/day, followed by 60 mg/day | Mild improvement; 60-mg dose better | High placebo response, mild side effects; three arms | [123] |
| Spencer et al. (1998) | 22 | Double-blind, placebo crossover | ATX | 7 weeks | 76 mg/day | 50% response rate (9% placebo) | Noradrenergic agent; Well tolerated | [124] |
| Wilens et al. (1999) | 32 | Double-blind, placebo crossover | ABT-418 | 7 weeks | 75 mg/day | 40% response rate (13% placebo) | Nicotinic analog; attentional symptoms improved preferentially | [125] |
| Taylor et al. (2000) | 22 | Double-blind, placebo crossover | Modafinil d-AMP |
7 weeks | 207 mg/day 22 mg/day |
48% response rate 48% response rate |
Improved neuropsychology with both Tx | [126] |
| Cephalon (2000) | 113 | Double-blind, placebo crossover | Modafinil | 7 weeks | 100 and 400 mg/day | No difference vs placebo | Cephalon report | [127] |
| Taylor et al. (2001) | 17 | Double-blind, placebo crossover | Guanfacine d-AMP |
7 weeks | 1 mg/day 0.25–2 mg/day 10 mg/day 2.5–20 mg/day |
Both Tx improved vs placebo | Well tolerated; neuropsychology improved | [128] |
| Wilens et al. (2001) | 40 | Double-blind, placebo parallel | BPR SR | 6 weeks | 362 mg/day 100–400 mg/day |
52% response rate (11% placebo) | Delayed onset of action; well tolerated | [129] |
| Upadhyaya et al. (2001) | 10 | Open | Venlafaxine | 12 weeks | 75–300mg/day | Significant improvement in ADHD and alcohol craving and frequency | SUD study; four out of ten subjects completed 12 weeks | [130] |
| Kuperman et al. (2001) | 30 | Double-blind, placebo parallel | BPR SR MPH |
7 weeks | Maximum 300 mg/day Maximum 0.9 mg/kg/day |
64% response rate BPR 50% response rate MPH (27% placebo) |
Not statistically significant vs placebo; n = 8–11/group | [131] |
| Wilens et al. (2001) | 32 | Open | BPR SR | 6 weeks | 385 mg/day | 41% response rate | Substance abusers; mild effect on substance abuse | [132] |
| Levin et al. (2002) | 11 | Single-blind | BPR | 12 weeks | 400 mg/day 250–400 mg/day |
47% response rate | Cocaine abusers; reduced cocaine use | [133] |
| Wilens et al. (2003) | 36 | Open | BPR SR | 6 weeks | 370 mg/day 200–400 mg/day |
70% response rate by CGI | Bipolar adults with ADHD; no manic activation | [134] |
| Michelson et al. (2003); Simpson et al. (2004) | 536 | Double-blind, placebo parallel | ATX | 10 weeks | 60, 90 or 120 mg/day | 58% response rate | Combination of two, separate multisite studies; improved functioning and less disability | [135, 136] |
| Adler et al. (2005); Adler et al. (2008); Marchant et al. (2011) | 384 | Open | ATX | Mean: 40 weeks | 99 mg/day | Decrease on CAARS 33% | Continuation of Michelson et al. [135]; safety and efficacy established in adults with ADHD | [137–139] |
| Wilens et al. (2005) | 162 | Double-blind, placebo parallel | BPR ER | 8 weeks | 393 mg/day | 53% response rate on ADHD-RS (31% placebo) | Medicine provided benefit throughout day vs placebo; no serious or unexpected AEs | [140] |
| Wilens et al. (2005) | 6 adults | Open | Donepezil | 12 weeks | 9 mg/day 2.5–10 mg/day |
55% improvement on CGI | Not well tolerated | [141] |
| Reimherr et al. (2005) | 47 | Double-blind, placebo parallel | BPR SR | 6 weeks | 298 mg/day 100–400 mg/day |
41% response rate on CGI (22% placebo) | Not statistically significant vs placebo | [142] |
| Adler et al. (2006) | 218 | Double-blind, multicenter | ATX | 80 mg once daily versus 40 mg twice daily | Both treatments efficacious, twice daily treatment had greater effect | Changes in dosing are not associated with greater AEs or safety risks | [143] | |
| Wilens et al. (2006) | 11 | Double-blind, placebo crossover | ABT-089 | 8 weeks | 4, 8 and 40 mg/day | ABT-089 was more effective than placebo on CAARS and CGI | Nicotinic partial agonist; no safety or side effect profiles were observed; study interrupted | [144] |
| Biederman et al. (2006) | 28 | Double-blind, placebo parallel | Galantamine | 12 weeks | 20 mg/day 8–24 mg/day |
22% response rate on CGI (11% placebo) | Study did not support the use of galantamine; no statistically or clinically significant greater reduction in ADHD symptoms | [145] |
| Levin et al. (2006) | 98 | Double-blind, placebo parallel (32 MPH, 33 BPR, 33 placebo) | MPH SR BPR SR |
12 weeks | 10–80 mg/day 100–400 mg/day |
34% MPH and 49% BPR response rates on AARS (46% placebo) | SUD study; MPH & BPR did not provide a clear advantage over placebo | [99] |
| Wilens et al. (2008) | 126 | Double-blind, placebo parallel | NS2359 | 8 weeks | 0.5 mg/day | 33% response rate on ADHD-RS (27% placebo) | Triple amine-reuptake inhibitor; no serious AEs; some attentional improvement on neuropsychological testing | [146] |
| Wilens et al. (2008) | 147 | Double-blind, placebo parallel | ATX | 12 weeks | 90 mg/day 25–100 mg/day |
Improved ADHD; ATX reduced cumulative heavy drinking days 26% vs placebo | SUD study; no serious AEs or specific drug–drug reactions related to current alcohol use; no effect on relapse rate vs placebo | [147] |
| Levin et al. (2009) | 20 | Open | ATX | 12 weeks | 80 mg/day 20–100 mg/day |
50% response rate on AARS | Cocaine abusers; little to no effect on cocaine abuse | [148] |
| Johnson et al. (2009) | 20 | Open | ATX | 10 weeks–1 year | 85 mg/day 40–100 mg/day |
50% response rate on CGI | Side effects led to 95% drop-out rate by 10 weeks; only one patient continued treatment for 1 year | [149] |
| Adler et al. (2009) | 442 | Double-blind, placebo parallel | ATX | 14 weeks | 83 mg/day 40–100 mg/day |
ATX monotherapy improved ADHD Sx and comorbid social anxiety disorder | Rates of insomnia, nausea, dry mouth and dizziness were higher with ATX than with placebo | [150] |
| Adler et al. (2009) | 501 | Double-blind, placebo parallel | ATX | 6 months | 85 mg/day 25–100 mg/day |
Once-daily morning- dosed ATX was efficacious when measured 10 weeks and 6 months after initiating Tx | AEs similar to previous trials | [151] |
| Wilens et al. (2010) | 32 | Open | BPR SR | 6 weeks | 100–400 mg/day | 66% response rate on ADHD RS | SUD study; 19 out of 32 completed 6-week protocol; no clinically significant reductions observed in self-report of SUD or CGI SUD scores | [152] |
| Surman et al. (2010) | 45 | Open | ATX | 6 weeks | 79 mg/day 50–120 mg/day |
64% response rate on CGI and AISRS | ADHD-NOS population, similar outcome vs full ADHD; no serious AEs | [153] |
| Adler et al. (2010) | 18 | Open | ATX | 10 weeks | 25–120 mg/day | Improvement in ADHD, reduced cravings | SUD study; 12 out of 18 completed | [154] |
| McRae-Clark et al. (2010) | 38 | Double-blind, placebo-controlled | ATX | 12 weeks | 25–100 mg/day | Improvement in ADHD, not marijuana use | SUD study; 16 out of 38 completed | [155] |
| Takahashi et al. (2011) | 45 | Open | ATX | 8 weeks | 114 mg/day 40–120 mg/day |
Statistically significant changes in CAARS and CGI scores | No serious AEs were reported | [156] |
| Young et al. (2011) | 502 | Double-blind, placebo-controlled | ATX | 24 weeks | 90 mg/day 40–100 mg/day |
68% response rate (42% placebo) | AEs overall and for on-label or slow titration ATX were similar and consistent with previous adult ATX studies | [157] |
| Total | ||||||||
| n = 47 | 4069 6–536 (range) |
Double: 23 Single: 1 Open: 23 |
BPR:10 ATX:14 Others: 23 |
2 weeks–1 year | BPR: 100–450 mg/day ATX: 25–320 mg/day |
Variable response | Some delay in therapeutic response – may be related to titration schedule. Response rates typically less than stimulants | |
Response rate refers to subject reporting much-to-very-much improved (i.e., by CGI) or clinically significant reduction in symptoms on ADHD rating scales.
AARS: Adult Attention-Deficit/Hyperactivity Disorder Rating Scale; ADHD: Attention-deficit/hyperactivity disorder; AE: Adverse event; AISRS: Adult Attention-Deficit/Hyperactivity Disorder Investigator Symptom
Rating Scale; ATX: Atomoxetine; BPR: Bupropion; CAARS: Conner’s adult ADHD rating scale; CGI: Clinical Global Impression; d-AMP: Dextroamphetamine; Dx: Diagnosis; L-DOPA: L-3,4- ER: Extended dihydroxyphenylalanine; MPH: Methylphenidate; NOS: Not otherwise specified; RS: Rating scale; SR: Sustained release; SUD: Substance use disorder; Sx: Symptom; Tx: Treatment.