The stimulants are among the most common medications used to treat ADHD across the lifespan. Stimulants have been shown to increase intrasynaptic concentrations of dopamine (DA) and norepinephrine (NE; for a review, see [28
]). Owing to the methodological limitations in studying NE reuptake (inhibition), more is known about DA. MPH primarily acts by blocking the reuptake of DA by binding to the DA transporter protein on the presynaptic membrane [30
], although postsynaptic activation of β-receptors may also be present [28
]. While AMPs diminish presynaptic reuptake of DA, they also are taken into the DA neuron and facilitate the release of DA from vesicles into the cytoplasm, prevent reuptake from the cytoplasm into the vesicles and are associated with the release of more DA from the presynaptic neuron [28
]. In addition, stimulants (AMP > MPH) increase levels of NE and 5-hydroxy-tryptamine (5-HT) in the interneuronal space.
Although it is clear that MPH and AMP have distinct pharmacodynamic properties and that clinically, patients often express a preference for one preparation over another, the reason(s) underlying this preference remain understudied. We understand their preference to be based on a combination of tolerability and efficacy. However, to date, we are not aware of any data that helps clinicians predict whether an individual patient will tolerate or respond to either MPH or AMP preferentially, and the usual clinical practice is to try one or both. Through differences in absorption through transdermal or gastrointestinal (GI) administration, prodrug metabolism, uptake into the CNS and distribution in the brain, even stimulants within the same class may differ in their effects on neurotransmission and, ultimately, efficacy [32
In comparison to the more than 300 controlled studies of stimulant efficacy in pediatric ADHD (for a review, see [36
]), there are at least 25 short-term controlled stimulant trials in adults with ADHD including 2804 subjects, and at least 15 longer-term stimulant trials including 1989 subjects ( & ) [32
]. The majority of recent larger stimulant studies were undertaken with commercial support.
Representative short-term controlled clinical studies of stimulants in adults with attention-deficit/hyperactivity disorder†.
Representative longer-term studies of stimulants in adults with attention-deficit/hyperactivity disorder†.
Although historically children and adolescents in controlled studies demonstrate a consistent response rate to stimulants of approximately 70% [39
], the response rate of adults with ADHD to stimulants has been variable. While in an open-label trial with dexmethylphenidate (d-MPH), the response rate in adults was reported to be 95% [75
], in controlled trials the response rates to stimulants in adults range from 25 [41
] to 78% [44
], with a short-term controlled weighted mean of 60% response rate and a longer-term weighted mean of 74% response rate. It is important to note that in trials of adults with ADHD, efficacy between AMP (n = 9 studies including 1118 subjects; weighted mean: 61% response rate vs 20% placebo) and MPH (n = 19 controlled short-term studies including 1913 subjects; weighted mean: 60% response rate vs 26% placebo) are similar. Moreover, adults with ADHD overall manifest a 26 and 34% response to placebo in short-term (n = 18) and longer-term (n = 7) controlled trials, respectively. Although the initial trials in adults with ADHD studied the safety, tolerability and efficacy of immediate or intermediate stimulant preparations (including at least 14 studies of the immediate or intermediate [e.g., MPH sustained release] release forms of MPH, and eight studies of immediate or intermediate release AMP [including mixed AMP salts]), recent work has focused on investigating the effects of the extended delivery preparations of MPH or AMP (including 17 trials of osmotic-release oral system [OROS] MPH, d-MPH extended release (ER), MPH ER, mixed amphetamine salts [MAS] ER and d-AMP ER). These recent trials are particularly reassuring as these are the stimulant preparations usually prescribed in clinical practice.
There are several factors that may account for the differences in response rate for these medications, including the criteria used to determine ADHD, varying stimulant doses, inclusion of psychopathology and differing methods of determining overall response. Dosing of AMP and MPH, for example, appears important in outcome: controlled investigations using higher immediate release (IR) MPH dosing (≥1.0 mg/kg/day) resulted in more robust outcomes [44
] than those using lower MPH dosing (<0.7 mg/kg/day) [41
]; likewise, data from studies with AMP suggest higher response rates with higher doses (48% response rate using 0.3 mg/kg/day [48
] vs 70% response rate using 0.9 mg/kg/day [47
]). Interestingly, an inconsistent dose response has been shown in recent large multisite dose ranging studies. For example, Medori et al.
failed to show a dose–response relationship when using 18–72 mg/day of OROS MPH [34
]. Spencer et al.
also reported that 20–40 mg/day of d-MPH ER resulted in an inconsistent dose–response relationship [32
]. Likewise, Adler et al.
using 30–70 mg/day of lisdexamfetamine dimesylate (LDX) found a similar response rate of between 57 and 62% across all doses [57
]. In applying these data to clinical practice, it is imperative for clinicians to recognize that research data are collected on a selected patient population and at a group level. Within a group, there is a wide range of doses to which individual patients may respond. In fact, some patients may respond to low or intermediate stimulant doses. In our clinical practice, like in a research study, we recommend the initiation of stimulant medication at a low dose and titrating upwards in a reasonable time course, usually at 1-week intervals. These intervals permit the patient and clinicians to gather enough data about the tolerability and effectiveness of the chosen medication in order to inform clinical decision making. It is equally important to recognize that some patients require a relatively higher dose in order to achieve a clinical response. The most important factor underlying the safe and proper titration of stimulant medications is the ongoing collaborative relationship between the clinician and patient.
There continues to be a paucity of longer-term data related to stimulants for ADHD. To date, there have been eight open (n = 1023 subjects) and seven controlled (n = 1136 subjects) studies of at least 12 weeks in duration (). The majority of longer-term studies are open studies that follow on to controlled shorter-term studies. Wender et al.
studied 78 subjects who were part of a controlled trial for 12 months and found that those who responded to MPH in the short term responded to longer-term treatment with improvement in ADHD [64
]. Weiss et al.
demonstrated continued improvement with dextroamphetamine (d-AMP) alone or in combination with paroxetine (64 and 44% response rates vs 16% placebo, respectively) over a 20-week study [70
]. Rösler et al.
showed that MPH ER significantly improved ADHD (61 vs 42% placebo) and related symptoms over the 24 weeks of the study [72
]. These limited data seem to suggest that the response to stimulants is sustained at the 24–72 week follow-up end points [79
Open-label studies have also shown the effectiveness of longer-term stimulants in adults with ADHD. In a 12-month study following a double-blind, placebo-controlled trial of initially 349 subjects receiving 30–70 mg/day of LDX, Weisler et al.
reported an 84% improvement of the intention to treat population on the Clinical Global Impression Improvement (CGI-I) at end point, and most adverse events were mild-to-moderate in severity [70
]. In a similar 6-month, open-label study following a randomized, placebo-controlled trial of OROS MPH, Marchant et al.
found that 85% of the 34 enrolled subjects demonstrated improvement on the CGI-I [77
]. Again in this study, adverse events were generally considered to be minimal [77
]. These aggregate data seem to support the longer-term effectiveness and tolerability of stimulants in adults.
Plasma levels of the stimulants [44
], as well as gender and psychiatric comorbidity [44
], have not been implicated in variable medication response in ADHD adults; however, exclusion criteria and limited sample sizes constrain generalizability of these findings. Similar findings between response rates and adverse effects have been reported between ER and IR stimulants. For instance, Spencer et al.
reported similar response rates and adverse effects using similar dosing of three-times daily IR MPH and once-daily ER OROS MPH [63
The side effects of the stimulants in ADHD adults have been reported to be generally mild to moderate, with dry mouth, insomnia, edginess, diminished appetite, weight loss, dysphoria, obsessiveness, tics and headaches observed most frequently. No cases of stimulant-related psychosis at therapeutic doses have been reported in adults during clinical trials.
There has been recent debate about the cardiovascular effects of stimulants across the lifespan [84
]. As a result of the greater prevalence of ADHD studies in children and adolescents, recent work has focused on cardiovascular trends in these populations [88
]. Despite the more limited work conducted on adults with ADHD, cardiovascular adverse effects of stimulant use in adults have been documented and are based on trials that indicate a consistent increase in systolic and diastolic blood pressures (3–5 mmHg) and heart rate (5 bpm). These statistically significant increases appear to be correlated to dose; however, the correlations do not appear to be strongly correlated with dose [75
]. Longer-term data on the cardiovascular effects of these medications in both children and adults suggest a lack of tolerance to the pressor and chronotropic effects of these medications [68
]. Little data are available outside of blood pressure and pulse effects [68
]. Schubiner and colleagues reported abnormalities in the autonomic nervous system in a pilot sample of 61 individuals treated with various forms of MPH and AMP [93
]. Although the significance of these findings is unknown, only 4% of the control group manifested abnormalities in the autonomic nervous system compared with 24% in the ADHD group. Hammerness et al.
recently reported prolonged heart rate recovery at 4 min in a small group of adults, but no other clinically significant changes in cardiac functioning or structure after up to 6 months of treatment with lisdexamfetamine [94
]. Wilens et al.
studied adults with treated hypertension openly treated with MAS ER up to 60 mg/day and found no recurrent hypertension or other cardiovascular adverse outcome during the 6-week study [95
No laboratory abnormalities have been reported in adults treated with stimulants, including complete blood counts, renal or liver function tests. Given the sympathomimetic properties of stimulants and potential effects on the cardiovascular system, evaluating symptoms referable to cardiovascular dysfunction (e.g., chest pain, palpitations and syncope) [87
], and the monitoring of blood pressure and pulse at baseline and during treatment are recommended.
Despite the potential abuse of the stimulants, there has been a remarkable lack of reports of stimulant abuse in controlled or retrospective studies of adults with ADHD [97
]. Of interest, more recent controlled studies of active substance abusers have failed to show worsening of substance abuse or misuse of the substances during the study [61
]. Although the subjects’ addiction did not improve in these studies, the investigators were able to demonstrate some limited improvement in ADHD symptoms. The long-term effects of stimulant exposure on later substance abuse in adults are inconsistent, with the bulk of studies showing either lower rates or no effects on substance abuse compared with matched groups of adults not treated with stimulants during their youth [100
]. Interestingly, differences in abuse liability appear to be noted, with ER manifesting lower likeability ratings compared with IR MPH-based stimulants [104
], as well as prodrug amphetamines (lisdexamfetamine) similarly having lower likeability than comparable doses of IR AMP [105
]. For MPH, it has been speculated that the rate of increase of the MPH levels in the brain and the level of saturation of DA transporter protein is related to the abuse liability of the stimulant [104
]. While the majority of individuals treated for ADHD use their medications appropriately [107
], survey studies have indicated that approximately 5% of college students have misused stimulants [108
] and that it is more common in competitive colleges, more often misused for their procognitive effects than euphoria, and more frequently occurs with immediate-compared with ER stimulant preparations.