An Update on the Pharmacotherapy of Attention-deficit/Hyperactivity Disorder in Adults

Timothy E Wilens; Nicholas R Morrison; Jefferson Prince

Expert Rev Neurother. 2011;11(10):1443-1465.

Expert Commentary

Attention-deficit/hyperactivity disorder is now viewed as a disorder capable of causing significant distress and/or impairment in a patient's life. In terms of treating ADHD in adults, pharmacotherapy is often responsible for reducing 'core' symptoms, as well as other concurrent psychiatric disorders. The extant literature suggests that agents comprised primarily of noradrenergic and/or dopaminergic formulations appear to be most beneficial to those adults diagnosed with ADHD. The data also suggest that agents approved by the FDA (some stimulants and ATX) are among the most effective agents for adults with ADHD.

The literature on medication therapy in adults with ADHD echoes many of the findings in pediatric groups with ADHD. However, trials involving ADHD in adults frequently generate findings with greater variability in outcome, and less information on dosing parameters and effectiveness of the various agents that are used. The stimulant medications continue to be the most rigorously investigated treatment with at least 40 studies in 4793 individuals (Table 1 & Table 2 and are considered first-line medications of choice for ADHD in adults. The effects of age, dosing, long-term adverse effects and stimulant use in subgroups with ADHD still remain unclear, despite a growing literature.

The nonstimulants, namely ATX, bupropion and TCAs, appear useful for stimulant naive patients, stimulant nonresponders or adults with concurrent psychiatric disorders.^[117] Whereas ATX appears to be more responsive in stimulant naive individuals,^[135] the anti-ADHD response to antidepressants appears to be independent of previous response status to stimulants.^[122] Although no adequately powered direct studies comparing stimulants and antidepressants have been completed, comparative data using robust dosing of these compounds in adults, coupled with studies in children, support that stimulants appear slightly more effective in reducing ADHD symptoms.^[177,178] While the response to the stimulants is immediate,^[40,44,63] ATX and the antidepressants have a delayed onset of full therapeutic action of up to 4 weeks, related both to the titration of the medication and the delay in the onset of action of the agent.^{[122,124,129,137,153,179,180]} Generally speaking, MAOIs have been shown to be only minimally useful in adults with ADHD.^[123] The α-adrenergic agents, wake-promoting agents and SAMe have yet to establish a critical role in the treatment of ADHD in adults.^[49] Cholinesterase inhibitors do not appear to be useful in ADHD.^[145] The amino acids appear to be only transiently helpful for ADHD^{[109,112,114]} and are not recommended.

There are few controlled studies that have investigated the treatment of ADHD and comorbidity in adults. This is due, in part, to the inclusion of largely currently noncomorbid individuals into the studies, the bulk of which are commercially funded. Notable exceptions include the multisite controlled study of Adler et al. of ATX for ADHD and social anxiety disorder in which both ADHD and anxiety were improved significantly with ATX compared with placebo.^[150] Weiss et al. similarly found that adults receiving paroxetine or d-AMP and paroxetine demonstrated greater improvement for mood and anxiety symptoms compared with adults receiving d-AMP or placebo alone.^[70] Co-occurring nicotine and substance abuse disorders are the most studied comorbidity with adult ADHD: there have been at least 13 controlled studies completed. While these studies generally only show negligible effects on ADHD or substance abuse, some noteworthy exceptions exist. In a study evaluating cigarette smokers, Winhusen et al. showed improved ADHD and no worsening or improvement in cigarette use.^[61] Wilens et al. reported improved ADHD and reduced heavy drinking episodes, but no overall impact on relapse in recently abstinent alcoholics.^[147] Of interest, none of the studies of ADHD and substance abuse report worsening of substance use or misuse of medication. Studies of comorbid mood and antisocial disorder have yet to be completed. Only small open studies have been completed on medically compromised adults and few have extended beyond 55 years of age. Investigators have recently reported increased rates of Axis II disorders in adults with ADHD. These investigators observed increased rates of both Cluster B (primarily borderline personality disorder) and Cluster C disorders compared with rates in control subjects without ADHD.^[181] Moreover, investigators recently reported that treatment with ATX under controlled conditions improved core symptoms of ADHD (attention and hyperactivity/impulsivity), as well as symptoms of emotional dysregulation.^[139]

Methodological differences between studies may account for some of the variance in outcome. The discrepancies in outcome are probably related to the incomplete characterization of study subjects, methodological disparities in assessing ADHD outcome and low medication dosing. Furthermore, it is noteworthy that there continues to be an inconsistent dose–response relationship of stimulants within studies that may be owing to the assignment of individuals to a dose group as opposed to the actual dose achieved. For instance, in studies with MAS ER, a clear dose–response relationship was established if the actual achieved dose was used compared with the assigned dose.^[69] Another area of intrigue is the varying placebo response in the various studies of medications for ADHD. Whereas initial studies reported relatively low response to placebo (e.g., typically <20%), more contemporary studies indicate placebo responses as high as 55%.^[71] While the etiology of an apparently increasing placebo response is unclear, investigators need to consider this important issue when determining the design and adequate sample size for future controlled clinical trials.

Whereas the pathogenesis of ADHD remains under investigation, it would appear that catecholaminergic effects are necessary for clinical efficacy of anti-ADHD medications.^[28,182] AMP and MPH vary in their synaptic mechanisms of action,^[183] which translates into differing responses between classes of agents in individuals with ADHD.^[184,185] Alterations in DA and NE reuptake have also been reported with ATX, modafinil (in pediatric patients), α-agonists, TCAs and bupropion, which have also been shown to be effective for ADHD. The serotonergic antidepressants are not beneficial in terms of improving ADHD.^[70] Of interest, these findings add support to the older notion that the pathogenesis of ADHD appears to be mediated by dopaminergic and adrenergic systems, with little direct influence by the serotonergic systems.^[186]

Whereas early work demonstrated improvement in ADHD with nicotine or related agonists,^[169,170] more recent large (pediatric) multisite studies have failed to replicate significant improvements.^[171] Prohistaminergic agents, while appealing given the endogenous histamine effects on the attention arousal systems, have been disappointing.^[172]

Owing to lingering psychiatric and ADHD symptoms despite pharmacotherapy, as well as the sequela related to having a chronic disorder, ADHD adults frequently require a more comprehensive and integrated approach to treatment for their ADHD. For instance, the vast majority of studies have used 30% reductions in ADHD symptoms as a threshold for response, indicating that substantial symptomatic residua exist. Structured cognitive-based psychotherapies^[23] appear to be helpful, especially when used conjointly with pharmacotherapy, as observed in recent findings in both individual^[24] and group settings.^[25] For those adults diagnosed with ADHD who are taking steps to advance in their careers or academic pursuits, educational planning and restructuring of the school environment are worth consideration.

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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	58 mg/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 a 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 30–70 mg/day LDX	MPH, AMP, and LDX improved ADHD Sxs	AEs mild-to-moderate in severity

^†Up to 11 weeks.
Response rate refers to subject reported 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: Dexamphetamine; DBP: Diastolic blood pressure; d-MPH: Dexmethylphenidate; Dx: Diagnosis; ER: Extended release; HR: Heart rate; IR: Immediate release; LDX: Lisdexamfetamine dimesylate; MAS ER: Mixed amphetamine salt extended release; MAS: Mixed amphetamine salt; MLR: Multilayer release; MPH: Methylphenidate; OROS MPH: Osmotic release oral system methylphenidate; RS: Rating scale; SBP: Systolic blood pressure; SR: Sustained release; SUD: Sustained use disorder; Sx: Symptom; Tx: Treatment; WRAADDS: Wender–Reimherr Adult Attention-Deficit Disorder Scale.

Table 2. Representative longer-term studies of stimulants in adults with attention-deficit/hyperactivity disorder^†.
Study (year)	n	Design	Medication	Duration	Total dose mean and/or range	Outcome	Comments	Ref.
Levin et al. (1998)	12	Open	MPH SR	12 weeks	68 mg/day 40–80 mg/day	Improved ADHD and cocaine use	Cocaine abusers, eight out of 12 completed; no abuse of MPH	[65]
Horrigan et al. (2000)	24	Open	AMP salts	16 weeks	11 mg/day	54% response rate on CGI	Low doses used; retrospectively analyzed	[66]
Schubiner et al. (2002)	48	Double-blind, placebo parallel	MPH	12 weeks	79 mg/day 30–90 mg/day	77% response rate on global improvement scale (21% placebo)	Comorbid cocaine dependence; CBT for both arms	[67]
Weisler et al. (2005); Biederman et al. (2005)	223	Open	MAS ER	≤24 months	20, 40 and 60 mg/day	ADHD RS improved for all (p < 0.001)	AEs were mild to moderate, minimal cardiovascular effects; extension of double-blind study	[68,69]
Weiss et al. (2006)	98	Double-blind, placebo factorial	Paroxetine and/or d-AMP	20 weeks	Paroxetine (10, 20, 30 and 40 mg/day) d-AMP (5,10, 15 and 20 mg/day)	64% response rate to d-AMP, 44% response rate to paroxetine/d-AMP, 17% response rate to paroxetine (16% placebo)	Patients who received both d-AMP and paroxetine had more severe AEs, but did not show greater improvement overall than patients treated with one medication	[70]
Levin et al. (2007)	106	Double-blind, placebo parallel	MPH	14 weeks	40 mg/day 10–60 mg/day	47% response rate on AARS (55% placebo)	SUD study; toxicology revealed decreased probability of cocaine in urine for MPH vs placebo (p = 0.001)	[71]
Spencer et al. (2008)	274	Double-blind, placebo parallel	Triple bead AMP salts (MAS)	5 weeks (Phase I); 2 weeks (Phase II); 7 weeks (Phase III)	13, 25, 38, 50, 63 or 75 mg/day after dose optimization	52% response rate on CGI (21% placebo)	Mild-to-moderate AEs of insomnia, dry mouth, decreased appetite, headache, weight loss; improved quality of life >12-h duration	[33]
Rösler et al. (2009)	359	Double blind, placebo parallel	MPH ER	6 months	41 mg/day	61% response rate (42% placebo)	Relatively low doses used; increased heart rate among MPH ER group	[72]
Weisler et al. (2009); Ginsberg et al. (2011)	349	Open	LDX	12 months	30, 50 or 70 mg/day	84% improvement on CGI	Most AEs were mild to moderate in severity	[73,74]
Adler et al. (2009)	170^‡	Open	d-MPH ER	6 months	20–40 mg/day	95% response rate on CGI	Open-label extension of Spencer et al. [32]	[75]
Bejerot et al. (2010)	133	Open	MPH d-AMP	6–9-month follow-up	49 mg/day 18–90 mg/day 28 mg/day 15–70 mg/day	80% response rate	66 of 133 discontinued (38% of which before the 6–9-month time point)	[76]
Marchant et al. (2010)	34	Open	OROS MPH	6 months	60 mg/day	85% response rate on CGI	Followed double-blind crossover phase; all 34 included for safety phase	[77]
Wender et al. (2010)	78	Open	MPH	12 months	60 mg/day 30–100 mg/day	94% response rate on CGI	Participants who improved on MPH IR double-blind phase entered the 12-month, open-label trial	[64]
Konstenius et al. (2010)	24	Double-blind, placebo parallel	OROS MPH	13 weeks	18–72 mg/day	84% retention in treatment completers (59% placebo)	Both groups reduced ADHD Sxs; no difference found between groups in craving for AMP	[78]
Biederman et al. (2010)	227	Three-phase, double-blind, placebo parallel	OROS MPH	6 weeks (Phase I); 24 weeks (Phase II); 4 weeks (Phase III)	78 mg/day OROS MPH at Phase I end point (mean)	62% response rate on CGI and AISRS (37% placebo)	Results include Phase I end point response rates only	[79]
Total
n = 15	n = 1989 12–359 (range)	Double blind: 7 Open: 8	MPH: 10 AMP: 5 LDX: 1	12 weeks – 12 months	10–100 mg/day MPH 5–75 mg/day AMP 30–70 mg/day LDX	Long term efficacy of MPH and AMP documented	AEs mild-to-moderate in severity

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.
^†At least 12 weeks.
^‡Subjects not included in total n.
AARS: Adult Attention-Deficit/Hyperactivity Disorder Rating Scale; ADHD: Attention-deficit/hyperactivity disorder; AE: Adverse event; AISRS: ADHD Investigator Symptom Report Scale; AMP: Amphetamine; CBT: Cognitive–behavioral therapy; CGI: Clinical Global Impression; d-AMP: Dexamphetamine; d-MPH: Dexmethylphenidate; Dx: Diagnosis; ER: Extended release; IR: Immediate release; LDX: Lisdexamfetamine dimesylate; MAS: Mixed amphetamine salt; MAS ER: Mixed amphetamine salt extended release; MPH: Methylphenidate; OROS MPH: Osmotic-release oral system methylphenidate; RS: Rating scale; SR: Sustained release; SUD: Substance use disorder.

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; ER: Extended release; L-DOPA: L-3,4-dihydroxyphenylalanine; MPH: Methylphenidate; NOS: Not otherwise specified; RS: Rating scale; SR: Sustained release; SUD: Substance use disorder; Sx: Symptom; Tx: Treatment.

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