Charles DeBattista, D.M.H., M.D.
Amphetamine, first discovered in 1887, and the subsequently developed stimulants have been used in clinical psychiatry with varying results. Beyond their use for attention-deficit/hyperactivity disorder (ADHD), stimulants have been used for symptomatic relief based on their effects on mood and hedonic drive. Research into the use of stimulants as adjunctive agents in the treatment of specific symptoms and syndromes has been increasing. Various common adjunctive psychotherapeutic uses for stimulants, such as depression, have not been well researched, whereas other indications, such as narcolepsy, are backed by considerable clinical data. In this chapter, I review the pharmacology of these medications and their indications (Tables 44–1 and 44–2).
Agent |
Schedule |
Approved for |
Medication type |
Abuse potential |
Amphetamine |
II |
ADHD, narcolepsy |
Anorexiant/stimulant |
Black box warning |
Lisdexamfetamine |
II |
ADHD |
Stimulant |
Black box warning |
Methylphenidate |
II |
ADHD, narcolepsy |
Anorexiant/stimulant (“Mild stimulant”) |
Black box warning |
Modafinil |
IV |
Excessive daytime sleepiness associated with narcolepsy, OSAHS, and SWSD |
Wakefulness-promoting agent |
Reinforcing |
Armodafinil |
IV |
Excessive daytime sleepiness associated with narcolepsy, OSAHS, and SWSD |
Wakefulness-promoting agent |
Reinforcing |
Note. ADHD=attention-deficit/hyperactivity disorder; FDA=U.S. Food and Drug Administration; OSAHS=obstructive sleep apnea/hypopnea syndrome; SWSD=shift-work sleep disorder. Source. Adapted from Physicians’ Desk Reference, 60th Edition. Montvale, NJ, Medical Economics Company, 2006. |
||||
Stimulant |
Time to effect |
Peak (hours) |
Duration (hours) |
Dosing |
Amphetamine preparations |
||||
Adderalla |
~1 hour |
3 |
6–9 |
bid |
Adderall XR |
1–2 hours |
7 |
6–10 |
qd (or bid) |
Dexedrine |
1 hour |
3 |
4–6 |
bid or tid |
Dexedrine Spansules |
1 hour |
4 |
6–10 |
qd or bid |
Desoxyn (methamphetamine) |
40 minutes |
1–3 |
4–24 |
qd, bid, or tid |
Vyvanse (lisdexamfetamine) |
~1 hour |
2 |
9 |
qd |
Methylphenidate preparations |
||||
Methylphenidate |
15–30 minutes |
1–2 |
4–5 |
bid or tid |
Focalin (dexmethylphenidate) |
15–30 minutes |
1–2 |
4–5 |
bid or tid |
Ritalin SR (tablet) |
1–2 hours |
5 |
8 |
qd or bid |
Concertab |
1–2 hours |
6–8 |
12 |
qd or bid |
Metadate-CDc |
1 hour |
Biphasic: 1–2 and 4–5 |
6–8 |
qd or bid |
Note. bid = twice daily; qd = once daily; tid = three times daily. aAmphetamine/dextroamphetamine, 1:3 ratio. bLaser hole in capsule allows passage of drug; osmotically active push layer expels drug. cRapid-release and continuous-release beads give biphasic response. |
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Structurally, amphetamine is phenylisopropylamine. Ultimate pharmacological action is determined by alterations to any of the three basic parts of the amphetamine molecule.
In terms of affecting clinical utility, substitution at the amine group is the most common alteration. Methamphetamine (both L and D isomers), which is characterized by an additional methyl group attached to the amine, making it a secondary substituted amine, is more potent than amphetamine. Usefully, one may think of the amine group as enhancing stimulant-like properties.
An intact isopropyl side chain appears to be needed in order to maintain the potency of amphetamine. For example, changing the propyl to an ethyl chain creates phenylethylamine, an endogenous neuroamine (a metabolite of the monoamine oxidase inhibitor [MAOI] phenelzine) that has mood- and energy-enhancing properties but less potency and a much shorter half-life than amphetamine (Janssen et al. 1999).
Substitutions on the phenyl group are associated with a decrease in amphetamine-like properties. Interestingly, reduction of the phenyl to a cyclohexyl ring reduces the potency, but not the efficacy, of amphetamine properties. Unlike changes at the amine or isopropyl level, additions to the aromatic ring substantially alter the effects of the compound. The most common changes at the aromatic ring are of the methoxy type and are associated with hallucinogenic properties.
In recent years there has been renewed interest in drugs that are pure stereoisomers, as opposed to racemic mixtures, especially with the release of dexmethylphenidate (the dextro isomer of methylphenidate) and escitalopram (the levo isomer of citalopram). In amphetamine isomers, it is true that the dextro form (i.e., dextro isomer, or dextroamphetamine) is almost twice as potent as the levo form (i.e., levo isomer, or levoamphetamine) in promoting wakefulness, but they are of equal potency in reducing cataplexy and rapid eye movement (REM) sleep (Nishino and Mignot 1997). The effect on dopamine reuptake is stereospecific; inhibition in rat brain, striatum, and hypothalamus has been found to be markedly different between the two isomers (Ferris and Tang 1979).
The clinical utility of stereospecificity is unclear. Urine levels of the levo isomer have been used to measure compliance in amphetamine-addicted patients prescribed dextroamphetamine for maintenance or detoxification; the logic is that the more levo isomer present in urine, the less compliance (George and Braithwaite 2000).
Perhaps the most clinically useful difference between amphetamine isomers involves their differential effects on reinforcement. Studies in rats have shown that the dextro isomer is four times more potent than the levo isomer in promoting lever pressing for intracranial stimulation (Hunt and Atrens 1992). However, that pure dextroamphetamine is better for the treatment of ADHD than, for example, the mixed salts of dextroamphetamine/amphetamine is neither obvious nor conclusively shown. In addition, the overall greater potency of the dextro form for central actions suggests that this form may have a higher potential for abuse.
Amphetamines are noncatecholamine, sympathomimetic amines with central nervous system (CNS) stimulant activity that causes catecholamine efflux and inhibits the reuptake of these neurotransmitters (see subsection “Mechanism of Action” later in this section).
Amphetamine is highly lipid soluble and reaches peak levels in approximately 2 hours. Because of this lipid solubility, amphetamine has rapid distribution into tissues and transit across the blood–brain barrier. The protein binding is highly variable, but the average volume of distribution (Vd) is 5 L/kg.
The half-life of amphetamine is approximately 16–30 hours. On average, 30% of amphetamine is excreted unchanged.
The classic mechanism of action of amphetamine involves rapid diffusion directly into neuron terminals; through dopamine and norepinephrine transporters, amphetamine enters vesicles, causing release of dopamine and norepinephrine. The release of these neurotransmitters into the synapse mediates some of the psychological and motoric effects of amphetamine, including euphoria, increased energy, and locomotor activation.
The side effects of amphetamines are predictable relative to their sympathomimetic pharmacology. The most common effects are nervousness, agitation, and decreased sleep. Serious adverse consequences have been observed with amphetamines and include arrhythmias, hyperpyrexia, rhabdomyolysis, and convulsions. Death, although uncommon, generally occurs only after the manifestation of one of these symptoms. Hallucinosis and psychosis are frequent complications of injected or inhaled amphetamines but are uncommon with oral intoxication.
Methamphetamine is more frequently associated with complications; because of its higher toxicity, it is not clear whether severe complications are dose dependent. For example, in a retrospective study of methamphetamine-related deaths in a large city, methamphetamine use was significantly associated with a higher risk of coronary artery disease, as well as a higher rate of subarachnoid hemorrhage, although it was of course impossible to determine whether the subjects were first-time users or chronic abusers (Karch et al. 1999). Of particular note in this study, however, was that blood levels of methamphetamine did not differ between the group in which methamphetamine was judged to be the cause of death and the group in which methamphetamine was detected but judged not to be related to the cause of death, suggesting that these toxicities are not necessarily dose dependent. Similarly, in one 5-year study, methamphetamine accounted for 43% of rhabdomyolysis cases in an emergency department setting.
Methamphetamine is more neurotoxic than amphetamine; it can cause destruction of dopaminergic neurons in the basal ganglia and thus is widely thought to increase the likelihood of future parkinsonism (Guilarte 2001). Although it is commonly believed that MDMA (3,4-methylenedioxy-N-methamphetamine; “Ecstasy”) is toxic primarily to serotonergic neurons (Sprague et al. 1998), evidence shows that it is also toxic to dopaminergic neurons (Ricaurte et al. 2002).
Seizures are fairly common in amphetamine abuse scenarios, especially with the more potent methamphetamine and hallucinogenic analogs.
Stimulant psychosis—often referred to as paranoid psychosis—is also common in amphetamine abuse scenarios because of the overwhelming presentation of the eponymous symptom. Visual hallucinations are also disproportionately common with amphetamine psychosis. Psychosis is often seen together with stereotypy. In humans, stereotypy can take many forms but usually is expressed as pacing, searching, or examining minute details.
A comprehensive review found that drug interactions with amphetamine were mostly pharmacodynamic in nature (Markowitz and Patrick 2001); however, because a small portion of amphetamine metabolism occurs via the cytochrome P450 (CYP) 2D6 isoenzyme, those drugs that inhibit 2D6 metabolism can, theoretically, have the effect of increasing the plasma level of amphetamine.
Lisdexamfetamine dimesylate, a prodrug that on absorption is metabolized to dextroamphetamine and L-lysine, was approved in 2007 for the treatment of ADHD. Food does not affect absorption of lisdexamfetamine, but acidification of the urine results in more rapid clearance.
Two small studies in children found good efficacy and tolerability for lisdexamfetamine in the treatment of ADHD. A 4-week randomized, double-blind, forced-dose, parallel-group study compared lisdexamfetamine 30, 50, or 70 mg/day with placebo in children (ages 6–12 years) with ADHD (Biederman et al. 2007b). Efficacy, as measured by scores on the ADHD Rating Scale—Version IV (ADHD-RS-IV), the Conners Parent Rating Scale (CPR), and the Clinical Global Impression–Improvement (CGI-I) scale, was statistically superior to that of placebo for all dosages tested. A randomized, double-blind, placebo-controlled crossover study compared lisdexamfetamine with placebo and extended-release mixed amphetamine salts (Adderall XR) in 52 children (ages 6–12 years) with ADHD in an analog classroom setting (Biederman et al. 2007a). The study found comparable efficacy and safety for the active medications and superiority over placebo as measured by scores on the CGI-I scale and the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)–Deportment subscale.
In 420 adults, a 4-week forced-dose (30, 50, or 70 mg/day) study found lisdexamfetamine to have significantly greater efficacy over placebo as measured by ADHD-RS scores. Human liability studies have also found lower abuse-related drug-liking scores compared with immediate-release D-amphetamine at equivalent dosages (Najib 2009).
In 2014, lisdexamfetamine was approved for the treatment of binge-eating disorder in adults. The registration trials involved more than 700 patients with moderate to severe binge-eating disorder. In a Phase II trial, subjects were randomly assigned to 30, 50, or 70 mg/day lisdexamfetamine or placebo for 3 weeks and maintained at this dosage for an additional 8 weeks. Compared with placebo, the 50-mg/day and 70-mg/day dosages were more effective in reducing the total number of binge-eating days, were more likely to result in a a remission of symptoms, and produced greater global improvement (McElroy et al. 2015a). Subsequent to that study, two Phase III trials have evaluated the efficacy and safety of lisdexamfetamine (target dosage of 50 or 70 mg/day as tolerated) versus placebo in adults ages 18–55 years with binge-eating disorder. Lisdexamfetamine at both dosages was more effective than placebo in reducing the total number of binge days. The active-treatment groups showed a reduction in binge-eating days from an average of 5 days/week to 1 day/week (versus a reduction to about 2 days/week in the placebo group). Compared with subjects who received placebo, those who received active treatment experienced greater overall improvement, as measured by the CGI–I score (McElroy et al. 2016).
Several preliminary studies suggested that lisdexamfetamine might be useful as an adjunctive treatment for major depressive disorder. Trivedi et al. (2013) found that 20–50 mg of lisdexamfetamine added to escitalopram for 6 weeks was superior to placebo in treating residual symptoms of depression. However, two subsequent Phase III randomized controlled trials failed to demonstrate a significant benefit for lisdexamfetamine over placebo in the adjunctive treatment of major depressive disorder. Still, there is some evidence that lisdexamfetamine may be more effective than placebo in treating executive function deficits in patients with major depressive disorder (Madhoo et al. 2014) and that it may have a role in the treatment of bipolar depression (McElroy et al. 2015b).
Although methylphenidate has two chiral centers, only one contributes to its clinical effect. The D- and L-threo enantiomers are in a racemic mixture, although a single-isomer form of methylphenidate, dexmethylphenidate [(R,R)-(+)], is currently being marketed under the brand name Focalin. There are some differences in the pharmacological parameters of the two isomers, as described in the following subsection.
Methylphenidate is almost totally absorbed on oral administration (as is the single isomer dexmethylphenidate), although it is absorbed at a faster rate in the presence of food (Chan et al. 1983). Methylphenidate has low protein binding (15%) and is fairly short acting; the effects last approximately 4 hours, with a half-life of 3 hours. The primary means of clearance is through the urine, in which 90% is excreted.
Although it is both a norepinephrine and a dopamine reuptake inhibitor, methylphenidate appears to exert its effects primarily through its action on dopamine neurobiology. It blocks the dopamine transporter (DAT) and increases extracellular dopamine. The amount of extracellular dopamine increase varies greatly among individuals depending on the extent of both DAT blockade and baseline dopamine release.
The common side effects of methylphenidate are similar to those of amphetamine and include nervousness, insomnia, and anorexia, as well as dose-related systemic effects such as increased heart rate and blood pressure. Overdose may lead to seizures, dysrhythmias, or hyperthermia (Klein-Schwartz 2002). At therapeutic dosages, discontinuation symptoms tend to be slight, but with chronic abuse, symptoms similar to those in amphetamine withdrawal, including lethargy, depression, and paranoia, can occur (Klein-Schwartz 2002).
Although theoretically a substrate of CYP2D6, methylphenidate was found not to have any significant metabolism in humans via this enzyme (DeVane et al. 2000). The prescribing information (Novartis 2007) does cite methylphenidate’s potential ability to inhibit the metabolism of warfarin, some antiepileptic agents, and tricyclic antidepressants (TCAs), and therefore caution should be observed. However, a review found that methylphenidate is relatively safe and has minimal drug–drug interactions, with the exception of concomitant MAOI use (Markowitz and Patrick 2001).
Modafinil is the first U.S. Food and Drug Administration (FDA)–designated “wakefulness-promoting agent”; it is approved by the FDA for the treatment of excessive sleepiness associated with narcolepsy, sleep apnea, and residual sleepiness after standard treatment for shift-work sleep disorder (Cephalon Inc. 2008). As described below, modafinil does little to prevent or alter sleep when one is trying to do so; however, it appears to permit more stable wakefulness (i.e., reduced sleep propensity) when one is attempting to stay awake in the presence of elevated sleep pressure.
Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) exists in racemic form. Both stereoisomers appear to have the same activity in animals.
Modafinil, the primary metabolite of adrafinil, lacks many of the side effects found in adrafinil, such as increased liver enzymes, anxiety, and stomach pain. Modafinil is rapidly absorbed but slowly cleared. It has fairly high protein binding (60%) and a Vd of 0.8 L/kg. Its half-life is 11–14 hours.
The metabolism of modafinil is complex. In contrast to excretion of amphetamines, less than 10% of modafinil is excreted unchanged.
Metabolism is primarily via CYP3A4/5. It has been reported that modafinil also has in vitro capacity to induce CYP3A4 (Robertson et al. 2000), especially gastrointestinal 3A4. A clinically significant reduction of triazolam has been reported (Robertson et al. 2002).
The precise mechanism by which modafinil exerts its wakefulness-promoting effect in patients with excessive sleepiness due to narcolepsy is not yet known. Modafinil, given its efficacy in narcolepsy, is not surprisingly observed to increase c-fos activity of hypocretin cells, as well as in the tuberomammillary nucleus (which is primarily histaminergic), striatum, and cingulate cortex at higher dosages (Scammell et al. 2000). Additionally, in rats, an increase in histamine release in the anterior hypothalamus is seen (Ishizuka et al. 2003). However, modafinil’s wakefulness-promoting effects were not decreased in histamine knockout mice (Bonaventure et al. 2007).
What may be an important aspect of the pharmacology of modafinil is its lack of effect on the neuroendocrine system. A comparison of healthy volunteers who were sleep deprived for 36 hours with those who received modafinil during sleep deprivation found no difference in cortisol, melatonin, or growth hormone levels (Brun et al. 1998).
Modafinil appears to be well tolerated, with the most frequent side effects being headache and nausea. Side effects have been found to increase with dosages from 100 to 600 mg/day, and very high dosages (800 mg/day) have been found to be associated with higher rates of tachycardia and hypertension (Wong et al. 1999). Overall, only 5% of the patients in Phase III trials discontinued modafinil because of side effects (Cephalon Inc. 2008).
Modafinil appears to be fairly safe at high dosages. Reports indicate that 32 patients have safely taken 1,000 mg/day for more than 50 days; one individual safely took 1,200 mg/day for 21 consecutive days. Two patients took 4,000 mg and 4,500 mg, respectively, in a single dose and experienced only transient (<24 hours) agitation and insomnia with mild elevations in heart rate and blood pressure (Cephalon Inc. 2008). There have been no reports of seizures with modafinil.
During the attempts to obtain FDA approval of modafinil for the treatment of ADHD, concerns arose over the possibility that modafinil may carry a risk of Stevens-Johnson syndrome. Three cases of drug-induced rash were reported during clinical trials (U.S. Food and Drug Administration 2007).
The package insert notes a risk of “serious rash, including Stevens-Johnson syndrome,” in adults and children and cautions that modafinil is not indicated for children. The insert cites a rash incidence of 0.8% in pediatric patients, with one case of possible Stevens-Johnson syndrome and one case of multiorgan hypersensitivity reported, and concludes with the statement that although there are no known predictive factors, benign rashes do occur, and modafinil should be discontinued if rash develops.
As described earlier in this section, modafinil induces CYP3A4/5 and thus conceivably could lower the plasma concentrations of medications with substantial 3A4/5 metabolism. However, it is not clear if this induction is substantial only on the gastrointestinal cytochrome and is thus relevant only for other drugs undergoing significant first-pass metabolism.
Modafinil inhibits CYP2C19 in vitro (Robertson et al. 2000). It is prudent to assume that the effect of modafinil on the cytochrome system is not well characterized and to be vigilant for these potential drug–drug interactions.
Armodafinil, properly l-(R)-modafinil (or [−]-[R]-modafinil), is the longer-acting isomer of racemic modafinil. In 2007, it received FDA approval for the same indications as modafinil—specifically, excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS) as an adjunct to standard treatment, and shift-work sleep disorder (SWSD).
Armodafinil and racemic modafinil produce comparable peak plasma concentrations, although the peak for armodafinil occurs later than that for modafinil and is maintained for 6–14 hours postdose (Dinges et al. 2006).
Published data on armodafinil are still limited. Two 12-week double-blind studies using armodafinil 150 mg as an adjunct to continuous positive airway pressure (CPAP), both in patients who were otherwise stable except for some residual sleepiness (Hirshkowitz et al. 2007) and in patients who were still symptomatic (Roth et al. 2006), found improvements in wakefulness measures. Armodafinil also significantly improved the quality of episodic secondary memory (i.e., the ability to recall unrehearsed information). Whether this effect was due directly to the medication, to improved wakefulness, or to decreased hypoxia (as a function of being more awake) is unclear. However, armodafinil did not adversely affect the CPAP or any other physiological parameters.
A 12-week double-blind study of armodafinil in narcolepsy found improvements similar to those seen with modafinil. These included improved wakefulness (as measured by the Maintenance of Wakefulness Test), improved Clinical Global Impression of Change (CGI-C) scores, and improvement in memory and attention. Armodafinil 150 mg/day and 250 mg/day were similarly effective (Harsh et al. 2006).
In SWSD, armodafinil 150 mg/day was tested against placebo in a 12-week study, showing significant prolongation of time to sleep onset and an improvement in overall clinical condition by CGI-C. Armodafinil had no effect on daytime sleep polysomnography (Roth et al. 2005).
Although stimulants have been used for many years in a number of clinical scenarios, double-blind, randomized controlled trials examining their safety, efficacy, and effectiveness in neurobehavioral disorders other than ADHD are relatively rare. Most of the support for their use comes from open-label studies and case series. Randomized trials of modafinil for neurobehavioral disorders with symptoms of sleepiness and fatigue are beginning to be published.
Multiple double-blind, placebo-controlled studies have shown the efficacy of stimulants for ADHD, and their use is well investigated in both adults and children (Greenhill et al. 2002; Wilens et al. 2002). Some studies are aimed at showing the superiority of one preparation relative to another, although this approach is not always fruitful; for example, one study comparing various single-dose amphetamine preparations with one another and with placebo over 8 weeks found that they were all superior to placebo. However, immediate-release amphetamines had a faster onset but shorter duration of action; spansules, although much slower to take effect than the others, lasted several hours longer (James et al. 2001).
With respect to individual stimulants, all appear to be equally efficacious in the treatment of ADHD, but they have been reported to have different time courses. In a double-blind, double-control (placebo and methylphenidate) study, the mixed amphetamine salts of Adderall were found to exert their effects rapidly but to dissipate quickly over the course of the day, although Adderall lasted longer than methylphenidate (Swanson et al. 1998). Interestingly, higher doses of Adderall lasted longer than lower doses, indicating a dose-dependent effect in duration of action not found with methylphenidate. Thus, although stimulants may appear to be of equal efficacy overall, there is considerable variability in individual response to each stimulant.
The decision to choose amphetamines or methylphenidate for the treatment of ADHD is often based on the clinician’s preference and degree of experience with the medication. At least one important blinded crossover study found that in performance tasks, both drugs were generally equally efficacious (Efron et al. 1997).
Modafinil is not FDA approved for the treatment of ADHD. A 4-week double-blind study with an 8-week open-label extension found modafinil to be efficacious across all ADHD rating subscales for the duration of the open-label extension (Boellner et al. 2006). Interestingly, 10% of the 220 children studied lost an average of 3 kg, while 4% gained the same amount. Another such double-blind study found significant efficacy with dosages of 300 mg/day, although heavier children (≥30 kg) required 400 mg/day (Biederman et al. 2006). A pooled analysis of three trials (638 patients) found that modafinil produced similar and impressive improvements in ADHD rating scales between stimulant-naive and prior-stimulant subgroups relative to placebo (Wigal et al. 2006). As in other studies, insomnia and headache were the most common, but infrequent, side effects. A 9-week trial (Biederman et al. 2005) found that almost half of patients (mean age 10 years, mean dosage 368 mg/day) were much or very much improved, and efficacy was seen in both inattentive and hyperactive subgroups and both school and home ratings. Some small but controlled trials (Rugino and Samsock 2003; Turner et al. 2004) found efficacy with modafinil, and in one study (Taylor and Russo 2000), equivalence to dextroamphetamine was shown. Modafinil is currently indicated only for the treatment of excessive sleepiness associated with narcolepsy, OSAHS, and SWSD.
The results from studies on the effects of stimulants in patients who had strokes or traumatic brain injury are mixed. Although small early studies showed some superiority of amphetamine to placebo in improving motor function poststroke (Crisostomo et al. 1988; Walker-Batson et al. 1995), a double-blind study found that 10 mg/day of amphetamine combined with physiotherapy in geriatric stroke patients was not superior to placebo plus physiotherapy in improving activities of daily living or motor function 5 weeks later (Sonde et al. 2001). Neither was amphetamine found to be superior to placebo in improving somatosensory training outcomes (Knecht et al. 2001). Modafinil also has not been consistently effective in the treatment of fatigue associated with traumatic brain injury (Jha et al. 2008). In contrast, relative to placebo, dextroamphetamine 10 mg/day significantly improved language recovery in poststroke aphasic patients when immediately coupled with a session of speech therapy; this effect was seen as quickly as within 1 week (Walker-Batson et al. 2001). A review lamented the lack of good data in brain-injured patients but did note that available data suggest that the bulk of stimulant efficacy may lie with its improvements in mood and cognitive processing (Whyte et al. 2002).
Although there is a dearth of placebo-controlled studies, there are some interesting reports in which stimulants were compared with antidepressants in patients with poststroke depression. One such study, comparing methylphenidate with TCAs, found similar and significant response to both drugs, although the stimulant worked faster (Lazarus et al. 1994).
Modafinil has been reported to have some therapeutic efficacy in some types of brain injury. Two double-blind studies by the same group (Saletu et al. 1990, 1993) found modafinil effective in improving cognition and accelerating improvement in patients with alcoholic brain syndrome. In addition, there is some evidence that modafinil may help with cognition in patients with traumatic brain injury (Dougall et al. 2015; Maksimowski and Tampi 2016).
It may not be surprising that a double-blind study showed sustained-release dextroamphetamine to be superior to placebo in reducing cocaine use (Grabowski et al. 2001). However, similarly designed studies by the same authors did not find this effect with methylphenidate (Grabowski et al. 1997) or with risperidone (Grabowski et al. 2000). A double-blind, placebo-controlled study found that modafinil did not increase the euphoria or craving for cocaine; it may, in fact, have blunted the euphoria (Dackis et al. 2003). A double-blind, placebo-controlled study of 62 patients found that modafinil-treated patients had a longer duration of cocaine abstinence (>3 weeks), with no dropouts due to adverse events (Dackis et al. 2005). Likewise, a 48-day double-blind trial found that under controlled laboratory conditions, modafinil significantly attenuated self-administration and effects of cocaine (Hart et al. 2008). However, a large randomized controlled study of modafinil in the treatment of 210 subjects with DSM-IV-TR (American Psychiatric Association 2000)–defined cocaine dependence did not find modafinil generally efficacious in improving abstinence from cocaine use (Dackis et al. 2012), although there was a trend for male patients receiving a modafinil dosage of 400 mg/day to be less likely to use cocaine. More study is needed to determine which, if any, patients with cocaine dependence might benefit from modafinil treatment.
Basic research suggests that amphetamine appears to have an unexpected effect in alcohol use disorder. In rats, amphetamines reduced alcohol consumption during choice trials; this reduction was specific to alcohol intake, because amphetamine administration had no effect on rodents’ intake of water (Yu et al. 1997). This effect of amphetamine on alcohol consumption may involve the neurobiology of reward systems. Much more research is needed to identify the mechanisms by which stimulants affect alcohol intake.
Stimulants have traditionally been used for the treatment of excessive sleepiness associated with narcolepsy. Narcolepsy is characterized by excessive sleepiness that is typically associated with cataplexy and other REM sleep phenomena such as sleep paralysis and hypnagogic hallucinations. Modafinil’s approval for treatment of excessive sleepiness in narcolepsy was based on substantial evidence from large multicenter clinical trials (Broughton et al. 1997; U.S. Modafinil in Narcolepsy Multicenter Study Group 1998, 2000). Modafinil is less disruptive of sleep than amphetamines and is rated as having a lower abuse potential (Shelton et al. 1995) (see Table 44–1). One study found that taking an extra dose (200 mg) at midday improved wakefulness in patients with narcolepsy without causing insomnia at night (Schwartz et al. 2004). Importantly, cataplexy—the sudden occurrence of muscle weakness in association with experiencing laughter, anger, or surprise—is responsive to amphetamines but not to modafinil (Shelton et al. 1995).
The use of stimulants for the treatment of fatigue syndromes may seem intuitive, but evidence from large-scale controlled clinical trials to warrant this use is scant. In one of the only double-blind, placebo-controlled studies, men with HIV, depression, and fatigue had significantly less fatigue with dextroamphetamine (73% response) (Wagner and Rabkin 2000). Tolerance, dependence, and abuse were not observed, even across a 6-month open phase. A double-blind study of methylphenidate and pemoline in a similar group of 144 patients with HIV who had severe fatigue found both stimulants effective in improving fatigue and quality of life (Breitbart et al. 2001). Rabkin et al. (2011) found that a significant majority of HIV patients—including those with comorbid hepatitis C—reported an improvement in fatigue with armodafinil. Likewise, in a Phase III trial of modafinil treatment in 631 patients with cancer-related fatigue, Jean-Pierre et al. (2010) found that modafinil was more effective than placebo in helping patients with severe fatigue. However, modafinil did not separate from placebo in cancer patients with mild or moderate fatigue at baseline. Similarly, in a Phase III study of armodafinil 150 mg/day for 8 weeks in the treatment of cancer-related fatigue in multiple myeloma patients, armodafinil failed to separate from placebo (Berenson et al. 2015). In addition, no advantage was found for armodafinil in a controlled study of the treatment of brain radiation–related fatigue (Page et al. 2015).
Two controlled trials (Adler et al. 2003; Högl et al. 2002) found modafinil effective in reducing excessive sleepiness in Parkinson’s disease. Findings from open-label studies of modafinil for fatigue in multiple sclerosis (Rammohan et al. 2002) and myotonic dystrophy (Damian et al. 2001) suggest modafinil’s utility in management of fatigue. A small double-blind crossover study of modafinil in myotonic dystrophy found a reduction in fatigue but no improvement on activity measures (Wintzen et al. 2007). This result would be consistent with modafinil’s rather selective effect on wakefulness and minimal impact on motor or autonomic parameters. In the same vein, studies of modafinil in patients with fibromyalgia (Schwartz et al. 2007) and of armodafinil in patients with sarcoidosis (Lower et al. 2013) did find that the medications were useful in treating the fatigue associated with these disorders.
There are two placebo-controlled studies of modafinil in the treatment of residual sleepiness in patients with DSM-IV-TR–defined obstructive sleep apnea (Kingshott et al. 2001; Pack et al. 2001). The studies show modafinil’s efficacy in treating the residual daytime sleepiness experienced by some OSAHS patients who were compliant in their use of CPAP treatment.
Importantly, modafinil’s use was studied in—and should be limited to—the treatment of OSAHS only after CPAP has been instituted and optimized. OSAHS carries significant cardiovascular risks if the airway collapse during sleep is not treated appropriately with CPAP and related therapies. It is conceivable that lessened daytime sleepiness from use of modafinil might fool the patient into thinking that CPAP is unnecessary, thus posing a risk via the untreated underlying OSAHS.
That amphetamines are anorectic is well known; however, the extent of the effect may be overstated. Bray and Greenway (1999) summarized the studies of obesity treatments, wherein they cited a large review of more than 200 short-term (3-month) double-blind studies of various noradrenergic agents, including amphetamine and amphetamine derivatives. Patients taking stimulants were twice as likely as those taking placebo to lose 1 lb/week; however, the percentage of patients who lost 3 lb/week was quite small (10%). A small study found that high doses of amphetamine (30 mg) decreased overall caloric intake but did so primarily through a decrease in fat consumption; carbohydrate consumption actually increased (Foltin et al. 1995). This mild effect on appetite is important when considering the use of stimulants in elderly patients who lack both energy and motivation and have poor appetite.
As described earlier in this chapter, the only large-scale randomized controlled trials of a stimulant in the treatment of depression have involved lisdexamfetamine. Whereas early controlled studies suggested a benefit from adjunctive lisdexamfetamine (Trivedi et al. 2013) in the treatment of depression, subsequent Phase III trials failed to demonstrate the efficacy of lisdexamfetamine in the treatment of residual depressive symptoms after selective serotonin reuptake inhibitor (SSRI) treatment.
Beyond the lisdexamfetamine data, the bulk of the evidence for the utility of stimulants in the treatment of depression derives from case series by Feighner et al. (1985) and Fawcett et al. (1991), which suggested the efficacy of stimulants combined with MAOIs and MAOI/TCA combinations as well as their safety in not causing hypertensive or hyperthermic crises, and case series by Stoll et al. (1996) and Metz and Shader (1991), in which a combination of stimulant and SSRI was used. Another case series argued for amphetamine’s ability to augment an antidepressant effect in patients with only partial response, although the effects were, not unexpectedly, primarily in improving fatigue and apathy (Masand et al. 1998).
In an open-label trial of depressed cancer patients, both amphetamine and methylphenidate were reported to improve depressive symptoms to the same extent, and effects were seen within 2 days. In this series, stimulants did not cause anorexia; in fact, they improved appetite in more than half of the patients studied (Olin and Masand 1996), suggesting that these agents are not contraindicated solely on the basis of concerns about anorexia.
In a review, Orr and Taylor (2007) noted the paucity of high-quality data and suggested a possible role for stimulants in depression, particularly as adjunctive agents, in specific patient subgroups.
The utility of modafinil in depressive states is still not well characterized, the majority of evidence being either anecdotal or retrospective. More work is likely forthcoming, but there are two studies that bear some examination. The mood-altering properties of modafinil were studied in 32 normal volunteers in a double-blind crossover inpatient study (Taneja et al. 2007). Modafinil had positive results on general mood, especially on alertness and energy measures, but also had a negative effect on feeling calm (i.e., increased anxiety).
A double-blind, placebo-controlled trial (Dunlop et al. 2007) examining the effects of modafinil initiated at the outset of treatment with an SSRI in depressed patients with fatigue found no difference in the primary outcome measure of the Epworth Sleepiness Scale but found some improvement in the hypersomnia items of the 31-item Hamilton Rating Scale for Depression. Two other controlled trials (DeBattista et al. 2003; Fava et al. 2005) and two open-label trials (DeBattista et al. 2001; Menza et al. 2000) suggest that modafinil may have some utility as an augmentation agent to antidepressants in depressed patients with fatigue or excessive sleepiness.
Both modafinil and armodafinil have shown some preliminary benefit in the treatment of bipolar depression. Frye et al. (2007) found that the addition of modafinil at dosages of 100–200 mg/day for 6 weeks to a standard mood stabilizer was more effective than the addition of placebo in 85 patients with bipolar depression. In a larger randomized controlled multicenter study (Calabrese et al. 2010), 257 patients with bipolar depression on either lithium or valproate were randomly assigned to receive augmentation treatment with 150 mg/day armodafinil or placebo. Armodafinil appeared to help some—but not all—patients with bipolar depression, and the differences between groups did not reach statistical significance. Likewise, a study of 399 bipolar depressed patients randomly assigned to receive adjunctive armodafinil or placebo for 8 weeks failed to demonstrate armodafinil’s benefit on the primary outcome measure (mean change from baseline on the 30-Item Inventory of Depressive Symptomatology—Clinician-Rated [IDS-C30] total score) (Frye et al. 2015). However, armodafinil was efficacious on a number of secondary measures, including IDS-C30 remission and Global Assessment of Functioning.
Whereas positive symptoms of schizophrenia are often responsive to antipsychotics, negative symptoms and cognitive deficits are often not (Tandon 2011). Because the negative symptoms and cognitive impairments of schizophrenia are frequently more disabling than the positive symptoms, there has been interest in developing effective treatments for these symptoms and deficits. A number of studies have explored the efficacy of modafinil and armodafinil in the treatment of negative symptoms and cognitive deficits in schizophrenia, with mixed results. For example, whereas some studies have found that modafinil or armodafinil improves negative symptoms (Arbabi et al. 2012; Kane et al. 2010) and working memory (Scoriels et al. 2012) in some schizophrenic patients, other studies have found no benefit (Bobo et al. 2011; Pierre et al. 2007; Sevy et al. 2005). Despite these mixed results, modafinil has been well tolerated in most studies in schizophrenia. By contrast, stimulants such as dextroamphetamine may worsen positive symptoms of schizophrenia and have been less commonly studied in the treatment of negative symptoms and cognitive impairments. Further study is required to determine the role of stimulants and wakefulness-promoting agents in schizophrenia.
The safety and efficacy of stimulants for the treatment of ADHD have been established. Modafinil and armodafinil are also firmly established as efficacious wakefulness-promoting agents in narcolepsy, sleep apnea, and shift work sleep disorder. The utility of these drugs in other areas is being examined. Although there is intense interest in the potential use of stimulants and modafinil in other psychiatric and neurobehavioral conditions, controlled studies on their safety and efficacy are limited. It is unclear why stimulants have not been extensively investigated for clinical utility for indications other than the treatment of ADHD. The approval of armodafinil, as the newest of the wakefulness-promoting compounds, may perhaps spur further research. Well-designed large-scale controlled trials are needed to define and characterize the role of stimulants and modafinil in various psychiatric illnesses. It is hoped that this will be an area of continued interest and development, from the elucidation of the molecular mechanisms of stimulants and modafinil to the demonstration through controlled trials of their potential clinical safety and benefits.
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This chapter is an update and revision of Ballas CA, Evans DL, Dinges DF: “Psychostimulants and Wakefulness-Promoting Agents,” in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Schatzberg AF, Nemeroff CB. Washington, DC, American Psychiatric Publishing, 2009, pp. 843–860.