Curr Psychiatry Rep (2014) 16:524 DOI 10.1007/s11920-014-0524-2

SLEEP DISORDERS (P GEHRMAN, SECTION EDITOR)

Wake-Promoting Pharmacotherapy for Psychiatric Disorders Bernardo Dell’Osso & Cristina Dobrea & Laura Cremaschi & Chiara Arici & A. Carlo Altamura

# Springer Science+Business Media New York 2014

Abstract Medications promoting wakefulness are currently used in psychopharmacology in different contexts and with different objectives. In particular, they may be used for the treatment of syndromes that primarily show significant impairment in alertness/wakefulness (e.g., excessive sleepiness and other sleep disorders) as well as for the symptomatic treatment of different neuropsychiatric disorders that, in turn, are not exclusively characterized by sleep-wake disturbances (like mood disorders, for instance). In addition, several psychotropic compounds, including some antipsychotics, mood stabilizers, antidepressants, and anxiolytics have wellestablished sedating side effects that may go beyond the therapeutic target and require the symptomatic use of wakepromoting agents. Even though such a clinical scenario reflects millions of individuals affected (alterations of wakefulness have a prevalence rate of 20–43 % in the general population), relatively few pharmacotherapies are available, mainly including compounds with psychostimulating effects, such as methylphenidate, modafinil, and armodafinil and some amphetaminic agents. In light of their side effects and potential for abuse, such compounds have received FDA approval only for a limited number of psychiatric disorders. Nonetheless, their clinical application has recently become more widespread, including attention deficit hyperactivity This article is part of the Topical Collection on Sleep Disorders B. Dell’Osso (*) : C. Dobrea : L. Cremaschi : C. Arici : A. C. Altamura Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Dipartimento di Salute Mentale, Fondazione IRCCS Ca' Granda, Università degli Studi di Milano, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy e-mail: [email protected] B. Dell’Osso : C. Dobrea : L. Cremaschi : C. Arici : A. C. Altamura Department of Psychiatry, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy

disorder, narcolepsy, treatment-resistant depression, bipolar disorder, shift work sleep disorder, schizophrenia, and addictions. Wake-promoting agents have different mechanisms of action, peculiar clinical strengths and specific limitations, with novel drugs in the field under extensive investigation. The present review is aimed to provide an updated overview of the aforementioned compounds as well as investigational drugs in the field, in terms of mechanism of action, indications and use in clinical practice. Keywords Wake-promoting agents . Stimulants . Neuropsychiatric disorders

Introduction Impaired alertness/wakefulness may be characteristic of disorders that primarily manifest such symptoms (e.g., excessive sleepiness and other sleep disorders) or of neuropsychiatric disorders that, on the other hand, are not primarily characterized by such disturbances (e.g., mood disorders). Moreover, altered alertness/wakefulness can potentially occur as a side effect of concomitant pharmacological therapy. In fact, several psychotropic medications, such as antipsychotics [1], mood stabilizers, antidepressants, and anxiolytics, have wellestablished sedating side effects that may require the symptomatic use of wake-promoting agents. Among the most frequently reported symptoms by psychiatric patients, alterations of circadian rhythms, manifesting as sleep modifications such as excessive daytime sleepiness (EDS) and fatigue, represent a substantial source of burden. Given its relevant prevalence rate (20–43 %) [2], sleepiness significantly affects several routine skills (e.g., driving, working and socializing), particularly in advanced societies requiring more challenging levels of productivity and work efficiency [3]. Along with a detrimental effect on everyday

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functioning and, overall, on quality of life [4], dysregulation of the wake system may also contribute to the onset of specific mental disorders and medical diseases, in particular metabolic ones [5•]. In this perspective, in the last decades, the use of psychostimulants, exerting wake-promoting effects, has become widespread in clinical psychiatric practice, in order to improve primary and secondary alterations in wakefulness and to complement the action of other concomitant medications, such as antidepressants [6•]. The specific interactions between neuromodulators underlying sleep homeostasis remains only partially understood and it is currently believed that the sleep-wake cycle is regulated by changes in cortical excitability, related to the concerted activity of monoamines and neuromodulators [7]. In particular, monoaminergic neurons promote wakefulness by directly exerting excitatory effects on the cerebral cortex and by inhibiting the sleep-promoting neurons of the hypothalamic ventrolateral preoptic nucleus (VLPO). During sleep, VLPO neurons inhibit monoamine-mediated arousal regions [8]. In fact, serotonin released by the dorsal raphe nucleus and dopamine produced by the ventral tegmental area (VTA) and the substantia nigra pars compacta promote waking and inhibit sleep, both slow-wave sleep and rapid-eye-movement sleep (REM) [9]. Wake-promoting agents represent a heterogeneous class of compounds with psychotropic effects whose mechanism of action at the level of the aforementioned neural circuits is not fully understood and needs to be further elucidated. They include different molecules such as methylphenidate, modafinil and armodafinil and some amphetaminic agents, with specific mechanisms of action, peculiar clinical strengths, and characteristic limitations. Nevertheless, wakepromoting agents exhibit similar activity-sustaining effects, including increased alertness, strength and endurance [3]. Therefore, apart from certain sleep disorders, some of these compounds have received indication for the treatment of specific psychiatric disorders, whereas their off-label use is likely more widespread and different novel drugs with wakepromoting effects are under extensive investigation. The main purpose of the present article was to review the role of such compounds in psychiatric disorders, due to their capacity to enhance arousal and provide relief in residual symptoms/side effects of concomitant pharmacological therapy. For each wake-promoting agent, a brief description of the mechanism of action, indications, and use in clinical practice is provided. Finally, an overview of the new drugs under development in the field is proposed.

Methods A systematic and comprehensive literature review, based on PubMed database, was conducted in order to identify

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published studies on the use of wake-promoting agents in psychiatric disorders, matching the following keywords: “wake-promoting agent,” “wake promoters,” “stimulants,” “stimulant-like agents,” “methylphenidate,” “modafinil,” “armodafinil,” “amphetamines,” and “psychiatric disorders.” The search was limited to articles written in English and published in peer-reviewed journals up to August 2014. Identified papers were filtered for relevance based on the content of their abstracts. Additional literature was searched from the reference list of retrieved studies.

Results Wake-promoting agents used in clinical psychiatry are mainly represented by stimulants and stimulant-like agents (e.g., methylphenidate, modafinil/armodafinil, and some amphetaminic compounds). Their use appears mostly related to the augmentative treatment of unipolar and bipolar depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, schizophrenia, cocaine addiction, obsessive compulsive disorders (OCD) and eating disorders [6•]. These compounds typically increase arousal, vigilance and attention because of their sympathomimetic action [10]. Some agents, moreover, when administered at high doses and/or through parenteral route, may also induce euphoria, enhanced energy and confidence, thus leading to a significant risk of addiction [3]. On the other hand, their cautious use at proper doses may produce several beneficial effects in specific psychiatric disorders with poor response to standard pharmacological treatment [11]. Herein, main wake-promoting agents and their applications in psychiatric practice are briefly reviewed and their clinical approved and off-label uses are synthesized in Table 1.

Methylphenidate Methylphenidate hydrochloride [12] is a mild stimulant and administered 2–3 times daily (average dosage of 20–30 mg), preferably before meals. It is readily absorbed, with a peak plasma concentration after 1–2 h and it is primarily metabolized via de-esterification to ritalinic acid, its main urinary metabolite, which has no significant pharmacologic activity. The mean terminal half-life of methylphenidate, following administration of 20 mg, is about 2.8 h in healthy adult volunteers [13]. Methylphenidate is also available as sustained-release tablets of 20 mg for oral administration [14]. Several new longacting formulations have been synthesized, different from the first-generation compound. As they include various proportions of immediate- and extended-release components, these formulations provide a rapid onset of action and a longer effect throughout the course of the day [15–22].

Curr Psychiatry Rep (2014) 16:524 Table 1 Primary indications and off-label uses of main wakepromoting agents for psychiatric disorders

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Wake-promoting agents

Primary indications

Off-label uses

Methylphenidate

ADHD

Modafinil

Narcolepsy

MDD in augmentation BD in augmentation Eating disorders (three case reports) ADHD Affective disorders (MDD + BD)

SWSD Armodafinil

Dextroamphetamine ADHD attention deficit hyperactivity disorder, SWSD shift work sleep disorder, MDD major depressive disorder, BD bipolar disorder

Lisdexamfetamine

Orexine-agonists

There is considerable evidence suggesting that methylphenidate increases norepinephrine and dopamine actions, in particular, by blocking their reuptake [23]. Such effect on the dorsolateral prefrontal cortex level is supposed to improve attention, concentration, executive functions and wakefulness [24]. In addition, enhancement of dopamine action in the basal ganglia may improve hyperactivity, whereas increase in dopamine and norepinephrine levels at the medial prefrontal cortex and hypothalamus may improve depressive symptoms, fatigue and sleepiness [25]. Methylphenidate has received indication for the treatment of uncomplicated ADHD, according to the most recent guidelines update [26]. It has also shown effectiveness for ADHD patients with coexistent subsyndromal depressive (SSD) symptoms, although adolescents with ADHD and high scores at depression rating scales appear to be less responsive to methylphenidate and are potentially better candidates for selective serotonin reuptake inhibitor (SSRI) treatment as a supplement [27]. Beyond the aforementioned contexts, the clinical application of methylphenidate has been extended to other affective disorders: first reports documented a significant improvement of depressive symptoms, particularly when used in add-on to SSRI treatment, thus achieving a more rapid and sustainable remission [28]. More recently, a large, multicentre controlled trial with 145 major depressive patients, who had failed between one and three previous antidepressant therapies, reported a significant attenuation of apathy and fatigue after the administration of augmentative methylphenidate, though no significant improvement was documented in primary outcome scales [29]. Furthermore, available evidence in bipolar depressed patients seems to support a cautious use of augmentative methylphenidate to mood stabilizers, as it may likely

Narcolepsy SWSD ADHD Narcolepsy ADHD

Schizophrenia (controversial) Cocaine addiction Cocaine and methamphetamine addiction ADHD Affective disorders (MDD + BD) Depression Affective disorders (MDD + BD) Schizophrenia (for negative symptoms in augmentation) Narcolepsy

provide clinical relief in target symptoms as well as a consistent improvement of overall bipolar illness in specific subgroups of patients [30]. Nevertheless, particular attention should be paid to patients with bipolar disorder (BD) due to the possible induction of switches and overall mood destabilization. In addition, treatment-emergent psychotic or manic symptoms in children and adolescents without a prior history of psychotic illness or mania, likely related to the use of stimulants at normal doses, have been reported [31]. In addition, the use of methylphenidate should be particularly monitored in emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because they may increase dosage on their own initiative as well as in patients with a past or family history of psychotic episodes [32]. Methylphenidate-induced psychosis, in fact, has been repeatedly reported [33]. Evidence supporting methylphenidate use in narcolepsy is sparse and not updated, though it may reasonably increase wakefulness in this group of patients [6•]. Literature on methylphenidate use in eating disorders is limited and outdated. A previous case report in a patient with bulimia nervosa treated with methylphenidate (5 mg per os and then transdermal) showed clinical improvement, which persisted after 18 months of follow-up [34]. A subsequent study on two subjects with bulimia nervosa and Axis II cluster B traits, who had not responded to psychotherapy and SSRI, reported beneficial effects after the administration of methylphenidate (the first patient up to 20 mg/day with substantial clinical benefits after 10 months of follow-up, while the second one 15 mg/day with benefits persisting after 4 months [35]). Among side effects of methylphenidate, anorexia, nausea and insomnia are the most commonly reported, but they are

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usually well controlled by taking the drug with meals and before 6 p.m. [36]. Other reactions include dermatological hypersensitivity, dizziness, headache, dyskinesia, drowsiness, abdominal pain, and weight loss during prolonged therapy. Reported cardiological effects comprehend palpitations, blood pressure and pulse changes, tachycardia, angina, and arrhythmias [12]. Contraindications include the presence of significant anxiety, tension, and agitation, since the drug may aggravate these symptoms. Its use in patients with tic disorder or family history of Tourette syndrome is still controversial [37]. Food and Drug Administration (FDA), in fact, contraindicates the use of methylphenidate in case of comorbidity with such disorders; however, a recent meta-analysis showed that the compound does not seem to worsen tic manifestations [38•]. As it may inhibit the metabolism of warfarin, methylphenidate may increase its levels. Association with anticonvulsants (which seem to reduce methylphenidate efficacy) appears to be safe, but caution is recommended [39]. Tricyclic antidepressant levels were increased in vitro when these compounds were combined with methylphenidate [32]. Even though in vivo studies did not confirm such data, caution is needed. Concomitant treatment with monoamine oxidase inhibitors (MAOI) should be avoided as well, as hypertensive crises and serotonergic syndrome may result [39]. Although FDA gave methylphenidate a pregnancy category of C, recent literature reported that the compound may increase the rates of fetal loss [40].

Modafinil Modafinil is a racemic compound with a half-life, after multiple doses, of about 15 h [41]. It is rapidly absorbed and reaches peak plasma concentration after 2–4 h (recommended dose of 200 mg/day). The major route of elimination is hepatic metabolism (through hydrolytic deamination, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation), with subsequent renal elimination [24]. The mechanism of action of the compound is not fully understood. The pharmacological profile of modafinil, in fact, is distinct from other sympathomimetic amines: it is supposed to bind competitively to the cell membrane dopamine transporter (DAT) and its wake-promoting effect seems to depend on catecholaminergic (dopaminergic and adrenergic) signaling [42]. The molecule seems, moreover, to activate tuberomammillary nucleus neurons releasing histamine in hypothalamic wakefulness center and other hypothalamic neurons releasing orexin/hypocretin [24]. Modafinil has the potential of interacting with drugs from several classes, by inducing/inhibiting different cytochrome P450 isoenzymes (CYP3A4, CYP2B6, CYP1A2, CYP2C19, CYP2C9) [43]. Chronic treatment does not seem to exert any

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significant effect on the pharmacokinetics of warfarin, when compared to placebo; nonetheless, more frequent monitoring of prothrombin times/INR is advisable [44]. The compound shows no interaction in vitro with CYP2D6; however, in case of CYP2D6 deficit, the levels of CYP2D6 substrates, such as tricyclic antidepressants and SSRIs, which are eliminated through CYP2C19, may be increased by adjunctive modafinil [41]. Caution should be observed when the compound is concomitantly administered with inhibitors of monoamine oxidase (MAOI) [45]. With respect to clinical indications, modafinil was found to improve excessive sleepiness and illness severity in narcolepsy, shift work sleep disorder (SWSD) and obstructive sleep apnea (OSA) with residual symptoms, despite optimal use of continuous positive airway pressure. In spite of having specific FDA indication only for the abovementioned disorders, its off-label application in psychiatric field has been extended to ADHD, affective disorders, schizophrenia, and cocaine addiction [46•]. In relation to narcolepsy, two multicenter, 9-week, placebocontrolled, double-blind studies documented the efficacy of modafinil in improving patients’ global functioning, at 200 and 400 mg/day, with no particular effect on night-time sleep [47, 48]. Such results were confirmed by a subsequent study, showing a relevant decrease in fatigue in patients who had been treated with modafinil for 6 weeks [49]. With respect to SWSD, modafinil and armodafinil are the only two compounds with an FDA approval [50]. They have also been recommended by the American Academy for Sleep Medicine (AASM) and the British Association of Psychopharmacology guidelines for increasing alertness during night time [51]. In subjects with SWSD, modafinil was found to significantly prolong the time to sleep onset compared to placebo, improving global functioning as well [52]. Moreover, the compound reduced performance impairments, particularly in relation to psychomotor speed, visual attention, and reaction time; it also reduced inadvertent sleep during waking hours [53]. In ADHD patients, the efficacy of modafinil (clinical dosage 200 mg/day) was found to be similar to that observed with other stimulants [54], with a positive influence on cognitive functioning [55]. In spite of its efficacy in children and adolescents, the compound has not been approved by the FDA due to the risk of serious dermatological toxicity (StevensJohnson syndrome), whereas serious skin rashes in adult were reported to be very unfrequent (five reports in 673,000 subjects from 1999 to 2006) [56]. Multiorgan hypersensitivity reactions, a potential fatal adverse event, have been documented in a limited number of reports in children, but the risk of its occurrence is hard to predict [6•]. Adjunctive use of modafinil to antidepressant therapy, at doses ranging from 100 to 290 mg/day, in bipolar depression was found to yield appreciable benefits, with a significant

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improvement in outcome, especially in relation to residual fatigue, tiredness and sleepiness [31]. According to the Canadian Network for Mood and Anxiety Treatments (CANMAT) and American Psychiatric Association (APA) Guidelines, modafinil was included among third line augmentative interventions for patients with major depressive disorder (MDD) and partial response to antidepressants [57•, 58•]. Moreover, in a recent meta-analysis, based on six randomized controlled trials and a total of 910 patients with MDD or bipolar depression, modafinil was found to be a valid augmentative option in patients with residual symptoms (e.g., low mood and neurovegetative symptoms such as fatigue) [46•]. Current data on schizophrenic patients are controversial, with some reports suggesting benefits on cognitive performance and a low risk of psychotic exacerbations [59], while other studies provide inconsistent evidence of efficacy on reducing clinical symptoms, relapses and sedation related to antipsychotic treatment [60]. No particular beneficial effect of modafinil was found for the treatment of cocaine addiction in a previous study [45], even though, more recently, a double-blind, placebocontrolled trial showed a likely craving reduction and an increased number of consecutive non-use days for cocaine for patients with cocaine dependence on modafinil compared to placebo [61]. In relation to safety and tolerability profile, modafinil appears to be well tolerated. The compound may have cardiological effects (e.g., angina, palpitations, dyspnea), with no significant influence on blood pressure, although its monitoring is recommended during treatment. Adjustment dose is advised in elderly patients and in those with hepatic disease/ severe renal insufficiency [45]. Modafinil received a pregnancy category of C and, even though its excretion in human milk has not been established, caution is recommended in nursing women. Recent data from a decennial study reported that pregnant women treated with modafinil had an increased risk of induced abortion and miscarriage [62].

Armodafinil Armodafinil is the R-enantiomer of modafinil, which is long acting and metabolically more stable than the S-enantiomer [63]. It is metabolized by the liver and has a half-life of approximately 3–4 times longer than that of the S-isomer, thus providing longer-lasting wake-promoting effects than modafinil, when given once daily [64]. With regard to its mechanism of action, armodafinil binds in vitro to the DAT, thereby inhibiting dopamine reuptake [65]. Both the R- and S-enantiomers bind to a DAT site which significantly overlaps with the S1 binding site for dopamine

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and cocaine [66]. However, 10–15 higher doses of modafinil and armodafinil compared to cocaine are needed to reach the same dopamine levels, suggesting they have a low abuse potential. Since armodafinil is twice as potent as modafinil (therapeutic dosage 50–250 mg/day vs 200–600 mg/day), it is likely to have an improved side-effect profile [67]. The most frequent adverse events associated with armodafinil are headache, nausea, dizziness and insomnia [63]. Armodafinil moderately induces CYP3A4, interfering with steroidal contraceptives, midazolam, ciclosporin, and triazolam; it also moderately inhibits CYP2C19, interfering with diazepam and phenytoin. Even though there are no documented data of interaction with MAOI and warfarin, caution is recommended in any case [65]. As already mentioned, armodafinil has been studied for ADHD in children/adults, and it also seems a promising treatment for cocaine and methamphetamine addiction [67]. It has been approved by the FDA with the same indications of modafinil for EDS associated with narcolepsy, OSA and SWSD [68]. Of note, augmentative armodafinil has been given a level 2 of evidence in CANMAT Guidelines for bipolar I depressed patients [57]. In fact, when administered in augmentation to mood stabilizers in such patients (mean dose 150 mg/day), the compound was found to significantly improve depressive symptoms, according to primary outcome measures, with no increase in terms of incidence or severity of suicidality, depression or mania, nor any change in metabolic profile [69]. Armodafinil was also studied in 249 patients with OSA and comorbid mild depression. Beneficial effects were reported in terms of reduction of EDS and general clinical improvement, but no specific reduction of depressive symptoms was found [70].

Amphetamines Amphetamines are non-catecholamine, sympathomimetic amines with central nervous system (CNS) stimulant activity. First synthesized in 1887, they have been restricted to doctors’ prescription in the late ’50s because of the risk of abuse and major side effects (e.g., heart attacks and strokes) [71]. They differ from methylphenidate, as they promote wakefulness primarily by enhancing the amount of dopamine in the CNS, although their effect is ultimately related to the reuptake inhibition, the main mechanism of action of methylphenidate [72]. Peripheral actions include minor elevations of blood pressure and heart rate [73], as well as weak bronchodilator and respiratory stimulant action [74]. Currently, in the USA, amphetamines have found medical use as adjunctive treatment for short-term weight control, ADHD, narcolepsy and SWSD. They have also been used as off-label therapy with promising

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results in treatment-resistant unipolar and bipolar depressive patients for melancholic symptoms [75]. Lisdexamfetamine has been used in schizophrenic patients with ADHD, showing a significant reduction of negative symptoms without worsening positive ones [76]. As they seem to exacerbate, in a minority of patients, motor and phonic tics in patients with Tourette’s syndrome [77], a specific clinical evaluation in these patients and their families should precede the use of these medications. In 2010, the European Medicines Agency no longer contraindicated the use of stimulants in patients with tic disorders, but caution is recommended particularly for amphetamines, as high doses of dextroamphetamine may worsen tics and such a phenomenon may persist even after drug withdrawal in a high percentage of patients [38•, 78]. It is difficult to establish an association between chronic amphetamine administration and growth inhibition; however, a close monitoring of this parameter during treatment is recommended. Indeed, growth deficit seems to be dose dependent and reversible after the withdrawal of the medication [79]. Caution is needed when using amphetamines for their potential adverse cardiovascular effects [80] and risk of abuse [81]. With respect to other drugs interactions, amphetamines may enhance the activity of tricyclic and sympathomimetic agents, thus possibly increasing the overall risk of cardiovascular effects [82]. Even though, previously, MAOI and stimulants association has been related with cases of hypertensive crisis and malignant hyperpyrexia, sometimes with fatal results [83], more recently, experienced clinicians cautiously combined them for the treatment of resistant depression and for sedation secondary to MAOI. Such combination did not determine any serious adverse events, as previously documented. Moreover, the use of a novel drug combination between tranylcypromine and stimulants for depressive patients has been reported [84].

Dextroamphetamine Dextroamphetamine sulfate [85] is the dextrarotatory enantiomer of amphetamine, and it also represents the active metabolite of the prodrug lisdexamfetamine. Among amphetamines, dextroamphetamine sulfate is available in sustained-release (SR) capsules. After the administration of 15 mg SR, maximal plasma concentration is reached in approximately 8–10 h [86], with an average plasma half-life of approximately 12 h [87]. The compound has found application in some psychiatric disorders, such as narcolepsy, ADHD and depression. More in detail, it has received primarily indication in patients from 6 to 16 years (5–60 mg daily in 1–3 administrations), suffering from narcolepsy and ADHD, in association with

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psychological and socio-educational programs, as it may contribute to increase attention and decrease impulsiveness and hyperactivity [6•, 88]. Dextroamphetamine 20 mg/day treatment has been also included in the Maudsley Prescribing Guidelines as monotherapy in uncomplicated depression secondary to medical illness as well as in augmentation for severe depression [89]. As already mentioned for amphetamines, dextroamphetamine may enhance the activity of tricyclic and sympathomimetic agents; therefore, the association with desipramine or protriptyline and possibly other tricyclics may cause striking and sustained increases in the dextroamphetamine concentration [82]. Dextroamphetamine was given a pregnancy category of C, as there are no adequate and well-controlled studies in pregnant women. An increased risk of premature delivery and low birth weight has been related to amphetamine dependence, meanwhile dysphoria, agitation, anhedonia and social inhibition represent possible withdrawal signs [90]. As it is excreted in human milk, nursing should be avoided [85].

Lisdexamfetamine Lisdexamfetamine, the dextroamphetamine prodrug, is the first long-acting prodrug stimulant, with a duration of action up to 14 h in adults [91]. After absorption, it is metabolized by red blood cells by rate-limited, enzymatic hydrolysis and converted to dextroamphetamine and L-lysine [92]. The release and absorption are slower with lisdexamfetamine compared to dextroamphetamine, thereby limiting its administration-related euphoria and, hence, the abuse potential [93]. The compound has been approved by the FDA for the management of ADHD in children (2007) and adults (2008) [94]. It is also approved for ADHD in children and adults in Canada, Australia, Brazil and many European countries [6•]. Augmentative lisdexamfetamine has moreover shown beneficial effects on depressive symptoms, as augmentation therapy in major depressive patients with residual symptoms after treatment with escitalopram, compared to augmentative placebo [95]. In a recent study, the compound was administered in augmentation in ADHD patients with comorbid BD, showing a favorable tolerability as well as a reduction of depressive symptoms, metabolic parameters and body weight [96]. In addition, a recent multicenter, randomized, placebocontrolled withdrawal study, investigating its augmentative use to atypical antipsychotics in clinically stable schizophrenic patients with predominant negative symptoms, showed a significant improvement in negative symptomatology, without exacerbating positive symptoms, whereas its discontinuation did not result in symptom worsening [76].

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Other wake-promoting agents In the last decade, significant advances have been made in understanding the role of hypocretin/orexin system as a master regulator of the sleep-wake cycle [97]. Orexins, two neuropeptides released by the perifornical area, dorsomedial and lateral hypothalamus [98], are likely involved in sleep regulation, arousal, behavioral/neuroendocrine responses to stress and reward-seeking behavior [5]. In relation to sleep modulation, orexins are supposed to affect wake-active areas consisting of histaminergic, monoaminergic and cholinergic neurons through orexin-1 and -2 receptors [99]. More in detail, orexin-2 receptors seem to play an important role in sustaining wakefulness and regulating the transition to non-REM sleep, whereas both receptors can modulate REM sleep suppression [100]. The loss of this regular orexin function was found to be associated with the etiology of narcolepsy [97]. In this regard, low or undetectable levels of orexins were found in the cerebrospinal fluid of approximately 90 % of patients with narcolepsy and cataplexy [101]. Moreover, a selective loss of orexins, dynorphin and neuronal activity-regulated pentraxin, all generated by orexin neurons, has been documented in narcolepsy [102]. Therefore, orexin receptor agonists may be a promising valuable option for the treatment of narcolepsy and, in general, in other cases of excessive sleepiness [103]. Nevertheless, to date, such hypothesis has been supported only by significant preclinical evidence [104] and no novel orexin agonist has been tested in clinical practice yet [103].

Discussion Beyond the application of wake-promoting agents as first-line treatment for specific sleep disorders (e.g., narcolepsy, SWSD), their off-label use was found to provide some benefits in other conditions in the psychiatric field. Furthermore, the management of sleep-wake cycle disorders and daytime sleepiness remains a significant challenge for psychiatrists and general practitioners. Firstly, a careful diagnostic assessment is required to take into consideration all potential causes. On one hand, such symptomatology may be secondary to specific psychiatric illnesses (e.g., affective disorders, particularly with melancholic features). One the other hand, it may represent a frequent consequence of concomitant neuropsychopharmacological treatment, including antipsychotics (e.g., olanzapine, quetiapine and asenapine), mood stabilizers (e.g., carbamazepine, gabapentin and sodium valproate), antidepressants (e.g., some tricylics and SSRIs), and hypno-sedative medications (e.g., benzodiazepines), thus influencing patients’ adherence to prescribed therapy. In the second case, the dose adjustment and the eventual shift or augmentation to another drug of either

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the different or similar molecular class, with less sedative properties, should be considered at first [24]. Eventually, daytime sleepiness could be a sign of untreated sleep disorders, such as sleep apnea. Moreover, an accurate assessment of the risk-benefit ratio of the eventual addition of a wake-promoting agent is advisable before including it in the concomitant treatment, in light of the specific medical and psychiatric patient’s history. Such agents may be useful in enhancing patient compliance, given their potential of reducing residual symptoms and sleepiness/ sedation due to pharmacological treatment. However, few studies specifically investigated the effect of such compounds on treatment-induced sedation. Modafinil seemed to have the potential of improving wakefulness and reducing fatigue associated with SSRIs [105] and antipsychotics [1, 60, 106, 107]. Adjunctive methylphenidate and amphetamines showed a beneficial effect on clozapine-induced sedation in a small group of patients [108], whereas dextroamphetamine appeared to significantly reverse the sedative and memoryimpairing effects of triazolam in healthy adult volunteers [109]. In contrast, stimulant co-treatment in youth, administered with an atypical antipsychotic for clinically relevant aggression or oppositionality, was not significantly useful in improving side effects, including sedation and body weight [110]. However, although international treatment guidelines support the effective use of stimulant compounds for the abovementioned purposes, such medications should be preferably prescribed for a limited period of time and their administration should be particularly cautious for several reasons. They should be avoided in schizophrenic patients with positive symptoms [32] and strictly monitored in bipolar subjects, particularly those with a past history of psychosis, as they may increase the probability of psychotic exacerbations and mania switching [31]. Attention must be paid for their potential of abuse. In fact, in spite of being stimulants widely available, their larger medical use has progressively raised specific concerns, mainly due to the higher risk of abuse and misuse [111]. This aspect has to be taken into account in case of both acute and chronic misuse, the latter being responsible for several medical problems (cardiological, pulmonary, neurological and dermatological problems) [112]. The risk of these adverse events may be enhanced by the concomitant consumption of other neuropharmacological treatment. Vulnerability towards abuse is directly proportional to the rapidity of drug onset [113]: a faster onset leads to a worse symptomatology and a greater positive reinforcement [114]. In this perspective, modified-release formulations vs immediate-release ones, currently available for methylphenidate, may represent a safer option in terms of abuse potential [115•]. Among wakepromoting agents, modafinil and particularly armodafinil seem to be characterized by a relatively low abuse potential [42].

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In conclusion, the present review found that the use of wake-stimulating compounds has been extended beyond specific sleep disorders to other psychiatric conditions, characterized by residual symptoms and poor response to standard treatments. Such conditions mainly include affective disorders, which have shown some degree of benefit, when treated with stimulant/wake-promoting agents, mainly as augmentation strategy. The main unmet need in the field is represented by the limited controlled evidence documenting their efficacy, with a subsequently wide off-label use in clinical practice with potential risks of poor efficacy and abuse in specific contexts. Further studies are therefore needed to better define causal mechanisms of wake alterations and related pharmacological approach, including larger and longer-term RCTs of stimulant compounds, particularly in disorders whose overall therapy already includes their wide off-label application [116].

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11. Compliance With Ethics Guidelines 12. Conflict of Interest Cristina Dobrea, Laura Cremaschi and Chiara Arici declare that they have no conflict of interest. Bernardo Dell’Osso has been part of the Speaker Bureau of Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag, Eli Lilly, Pfizer, Glaxo Smith Kline, Lundbeck, Cyberonics and Italfarmaco. A. Carlo Altamura is a consultant for Roche, Merck, Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag, Lundbeck, Sanofi, Eli Lilly and Pfizer. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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References

19. 20.

Papers of particular interest, published recently, have been highlighted as: • Of importance 1.

2.

3.

4.

5.•

Saraf G, Viswanath B, Narayanaswamy JC, Holla B, Math SB. Modafinil for the treatment of antipsychotic-induced excessive daytime sedation: does it exacerbate tics? J Neuropsychiatry Clin Neurosci. 2013;25:E35–6. Hasler G, Buysse DJ, Gamma A, Ajdacic V, Eich D, Rössler W, et al. Excessive daytime sleepiness in young adults: a 20-year prospective community study. J Clin Psychiatry. 2005;66:521–9. Boutrel B, Koob GF. What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications. Sleep. 2004;27(6):1181–94. Sheng P, Hou L, Wang X, Wang X, Huang C, Yu M, et al. Efficacy of modafinil on fatigue and excessive daytime sleepiness associated with neurological disorders: a systematic review and metaanalysis. PLoS One. 2013;8(12):e81802. Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV. Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Front Neurosci. 2014;8:36. This review illustrates possible future targets for the treatment of excessive

21. 22.

23.

24.

25.

26.

sleepiness in psychiatric disorder, using molecules acting on orexin system. Sinita E, Coghill D. The use of stimulants medication for non-core aspects of ADHD and in other disorders. Neuropsychopharmacology. 2014; in press. The present article reviews the major applications of stimulant agents in psychiatric disorders and other medical conditions. Steriade M. Presynaptic dendrites of thalamic local-circuit neurons and sculpting inhibition during activated states. J Physiol. 2003;546(Pt 1):1. Hiyoshi H, Terao A, Okamatsu-Ogura Y, Kimura K. Characteristics of sleep and wakefulness in wild-derived inbred mice. Exp Anim. 2014;63(2):205–13. Monti JM, Jantos H. The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. Prog Brain Res. 2008;172:625–46. Westfall TC, Westfall DP. In: Brunton LL, Lazo JS, Parker KL, editors. Adrenergic agonsists and antagonists, in Goodman & Gilman s The Pharmacological Basis of Therapeutics. 11th ed. New York: The McGraw-Hill Companies; 2006. Wood S, Sage JR, Shuman T, Anagnostaras SG. Psychostimulants and cognition: a continuum of behavioral and cognitive activation. Pharmacol Rev. 2013;66(1):193–221. Ritalin®. Summary of product characteristics. Available at http:// www.medicines.org.uk/emc/medicine/1316/SPC/ritalin/. Kimko HC1, Cross JT, Abernethy DR. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet. 1999;37(6):457–70. Ritalin SR ® prescribing information. http://www.pharma.us. novartis.com/product/pi/pdf/ritalin_ritalin-sr.pdf. Biphentin® product monograph. http://www.purdue.ca/files/ Biphentin%Capsules%20PM%20EN.pdf. Daytrana ® prescribing information. http://www.daytrana.com/ documents/daytrana-prescribing-information.pdf. Concerta XL® summary of product characteristics. http://www. medicines.org.uk/EMC/medicine/8382/SPC/Concerta+XL+18+ mg+−+36+mg+prolonged+release+tablets/. Equasym XL® summary of product characteristics. http://www. medicines.org.uk/emc/medicine/15804/SPC/Equasym+XL+10+ mg,+20+mg+or+30+mg+Capsules. Focalin XR ® prescribing information. http://www.pharma.us. novartis.com/product/pi/pdf/focalinXR.pdf. Medikinet XL® 5 Mg summary of product characteristics. http:// www.medicines.org.uk/emc/medicine/24854/. Ritalin LA® prescribing information. http://www.pharma.us. novartis.com/product/pi/pdf/ritalin_la.pdf. Coghill D, Banaschewski T, Zuddas A, Pelaz A, Gagliano A, Doepfner M. Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies. BMC Psychiatry. 2013;13:237. Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ. Mechanism of action of methylphenidate: insights from PET imaging studies. J Atten Disord. 2002;6 Suppl 1:S31–43. Stahl SM. The prescriber’s guide. Stahl’s essential psychopharmacology. 3rd Edition. Cambridge University Press. 2009. pp 77–81. Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, et al. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry. 2006;60(10):1111–20. Bolea-Alamanac B, Nutt DJ, Adamou M, Asherson P, Bazire S, Coghill D, et al. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28:179–203.

Curr Psychiatry Rep (2014) 16:524 27.

28.

29.

30. 31.

32.

33.

34.

35.

36.

37. 38.•

39.

40. 41. 42. 43. 44.

45. 46.•

Golubchik P, Kodesh A, Weizman A. Attention-deficit/hyperactivity disorder and comorbid subsyndromal depression: what is the impact of methylphenidate on mood? Clin Neuropharmacol. 2013;36(5):141–5. Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO. Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry. 1996;57:72–76. Ravindran AV, Kennedy SH, O'Donovan MC, Fallu A, Camacho F, Binder CE. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebocontrolled trial. J Clinical Psychiatry. 2008;69:87–94. El-Mallakh RS. An open study of methylphenidate in bipolar depression. Bipolar Disord. 2000;1:56–9. Dell′Osso B, Ketter TA, Cremaschi L, Spagnolin G, Altamura AC. Assessing the roles of stimulants/stimulant-like drugs and dopamine-agonists in the treatment of bipolar depression. Curr Psychiatry Rep. 2013;15(8):378. Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents and adults. J Am Acad Child Adolesc Psychiatry. 2002;41(2 Suppl):26S–49S. Hesapcioglu ST, Gokerb Z, Bilginerc C, Kandilc S. Methylphenidate induced psychotic symptoms: two cases report. Journal of Medical Cases. 2013;4(2):106–8. Schweickert LA, Strober M, Moskowitz A. Efficacy of methylphenidate in bulimia nervosa comorbid with attention-deficit hyperactivity disorder: a case report. Int J Eat Disord. 1997;21(3): 299–301. Sokol MS, Gray NS, Goldstein A, Kaye WH. Methylphenidate treatment for bulimia nervosa associated with a cluster B personality disorder. Int J Eat Disord. 1999;25(2):233–7. Di Jeffrey E, Kelsey CB, Nemeroff D. Principles of psychopharmacology for mental health professionals. New Jersey: Wiley; 2006. Kurlan R. Tourette’s syndrome: are stimulants safe? Curr Neurol Neurosci Rep. 2003;3(4):285–8. Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF. Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry. 2009;48:884–93. This meta-analysis focuses on the debate on the use of psychostimulants in ADHD patients with comorbid tics. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7(1):34–59. Besag FM. ADHD treatment and pregnancy. Drug Saf. 2014;37(6):397–408. Provigil A. ® (Modafinil) Tablets [C-IV] [Package Insert]. Frazer, PA: Cephalon, Inc; 2010. Wisor J. Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol. 2013;4:139. Robertson Jr P, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123–37. Robertson Jr P, Hellriegel ET, Arora S, Nelson M. Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers. J Clin Pharmacol. 2002;42(2):205–14. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803–39. Goss AJ, Kaser M, Costafreda SG, Sahakian BJ, Fu CH. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2013;74(11):1101–7. This article reviews the effectiveness of augmentative Modafinil in reducing overall depressive scores, especially fatigue.

Page 9 of 11, 524 47.

48.

49.

50. 51. 52.

53.

54.

55.

56.

57.•

58.•

59.

60.

61.

62.

63. 64.

US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43(1):88–97. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Neurology. 2000;54(5):1166–75. Becker PM, Schwartz JR, Feldman NT, Hughes RJ. Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy. Psychopharmacology (Berl). 2004;171(2):133–9. Thorpy MJ. Managing the patient with shift-work disorder. J Fam Pract. 2010;59:S24–31. Roth T. Appropriate therapeutic selection for patients with shift work disorder. Sleep Med. 2012;13:335–41. Czeisler CA, Walsh JK, Roth T, Hughes RJ, Wright KP, Kingsbury L, et al. U.S. Modafinil in Shift Work Sleep Disorder Study Group. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353:476–86. Grady S, Aeschbach D, Wright Jr KP, Czeisler CA. Effect of modafinil on impairments in neurobehavioral performance and learning associated with extended wakefulness and circadian misalignment. Neuropsychopharmacology. 2010;35(9):1910–20. Taylor FB, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol. 2000;10:311– 20. Turner DC, Clark L, Dowson J, Robbins TW, Sahakian BJ. Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 2004;55: 1031–40. Rugino T. A review of modafinil film-coated tablets for attentiondeficit/hyperactivity disorder in children and adolescents. Neuropsychiatr Dis Treat. 2007;3(3):293–301. Ravindran AV, Lam RW, Filteau MJ, Lespérance F, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT).Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. V. Complementary and alternative medicine treatments. J Affect Disord. 2009;117 Suppl 1:S54–64. These guidelines represent an updated milestone for the treatment of Major Depressive and Anxiety Disorders in adults. American Psychiatric Association practice guideline for the treatment of patients with major depressive disorder, 3rd edition. 2010. Available at: http://psychiatryonline.org/content.aspx?bookid= 28§ionid=1667485. These guidelines provide an helpful tool in managing the treatment of Major Depressive Disorder. Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology. 2004;29:1363–73. Makela EH, Miller K, Cutlip 2nd WD. Three case reports of modafinil use in treating sedation induced by antipsychotic medications. J Clinical Psychiatry. 2003;64:485–86. Anderson AL, Reid MS, Li SH, Holmes T, Shemanski L, Slee A, et al. Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend. 2009;104(1–2):133–9. Haervig KB, Mortensen LH, Hansen AV, Strandberg-Larsen K. Use of ADHD medication during pregnancy from 1999 to 2010: a Danish register-based study. Pharmacoepidemiol Drug Saf. 2014;23(5):526–33. Nuvigil A. ® (Armodafinil) Tablets [C-IV] [Package Insert]. Frazer, PA: Cephalon, Inc; (2010). Wong YN, Simcoe D, Hartman LN, Laughton WB, King SP, McCormick GC, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and

524, Page 10 of 11

65. 66.

67.

68.

69.

70.

71. 72.

73.

74. 75.

76.

77.

78.

79.

80.

81.

82.

tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol. 1999;39:30–40. Garnock-Jones KP, Dhillon S, Scott LJ. Armodafinil. CNS drugs. 2009;23:793–803. Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, et al. The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci. 2008;11(7):780–9. Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, et al. R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry. 2012;72(5):405–13. De la Herrán-Arita AK, García-García F. Current and emerging options for the drug treatment of narcolepsy. Drugs. 2013;73(16): 1771–81. Calabrese JR, Frye MA, Yang R, Ketter TA; for the Armodafinil Treatment Trial Study Network. Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: a randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014 [Epub ahead of print]. Krystal AD, Harsh JR, Yang R, Rippon GA, Lankford DA. A double-blind, placebo-controlled study of armodafinil for excessive sleepiness in patients with treated obstructive sleep apnea and comorbid depression. J Clin Psychiatry. 2010;71(1):32–40. Karch SB, Drummer O. Karch’s pathology of drug abuse, fourth edition. 2008. CRC Press. Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present—a pharmacological and clinical perspective. J Psychopharmacol. 2013;27:479–96. Stiefel G, Besag FM. Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attentiondeficit hyperactivity disorder. Drug Saf. 2010;33(10):821–42. Rasmussen N. America’s first amphetamine epidemic 1929–1971. Am J Public Heatlh. 2008;98(6):974–85. Parker G, Brotchie H, McClure G, Fletcher K. Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: a medium-term evaluation of cost benefits. J Affect Disord. 2013;151(1):360–4. Lasser RA, Dirks B, Nasrallah H, Kirsch C, Gao J, Pucci ML, et al. Adjunctive lisdexamfetamine dimesylate therapy in adult outpatients with predominant negative symptoms of schizophrenia: open-label and randomized-withdrawal phases. Neuropsychopharmacology. 2013;38:2140–149. Castellanos FX, Giedd JN, Elia J, Marsh WL, Ritchie GF, Hamburger SD, et al. Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry. 1997;36(5):589–96. European Medicines Agency. (2010). Available from: http://www. ema.europa.eu/docs/en_GB/document_library/Other/2010/08/ WC500095687.pdf. Cortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, et al. on behalf of the European ADHD Guidelines Group Practitioner Review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry. 2013;54(3):227–46. Westover AN, Halm EA. Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review. BMC Cardiovasc Disord. 2012;12:41. Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry. 2012;21(9):477–92. Weiner CP, Buhimschi C. Drugs for pregnant and lactating women. 2009. Elsevier Health Sciences, 2nd edition.

Curr Psychiatry Rep (2014) 16:524 83. 84.

85.

86.

87. 88.

89. 90.

91.

92.

93.

94.

95.

96.

97. 98.

99.

100.

101.

Lloyd JT, Walker DR. Death after combined dexamphetamine and phenelzine. Br Med J. 1965;2(5454):168–9. Feinberg SS. Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication. J Clin Psychiatry. 2004;65(11):1520–4. Dexedrine. Prescribing information. Available at: http://dailymed. nlm.nih.gov/dailymed/lookup.cfm?setid=a37b6ef9-78b4-4b188797ecb583502500. Galloway GP, Buscemi R, Coyle JR, Flower K, Siegrist JD, Fiske LA, et al. A randomized, placebo-controlled trial of sustainedrelease dextroamphetamine for treatment of methamphetamine addiction. Clin Pharmacol Ther. 2011;89(2):276–82. Green WH. Child and Adolescent Clinical Psychopharmacology. 2007. Ed Lippincott Williams and Wilkins, 4th edition. Fitzgerald KT, Bronstein AC. Adderall® (amphetaminedextroamphetamine) toxicity. Top Companion Anim Med. 2013;28(1):2–7. Taylor D, Paton C, Kapur S. Psychostimulants in depression. Maudsley Prescr. Guidel. Psychiatry. 2012. p. 239. Kitanaka J, Kitanaka N, Takemura M. Neurochemical consequences of dysphoric state during amphetamine withdrawal in animal models: a review. Neurochem Res. 2008;33(1):204–19. Boellner SW, Stark JG, Krishnan S, Zhang Y. Pharmacokinetics of lisdexamfetamine dimesylate and its active metabolite, d-amphetamine, with increasing oral doses of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: a singledose, randomized, open-label, crossover study. Clin Ther. 2010;32:252–64. Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010;6:317–27. Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother. 2014;48(2):209–25. Mattingly G. Lisdexamfetamine dimesylate: a prodrug stimulant for the treatment of ADHD in children and adults. CNS Spectr. 2010;15(5):315–25. Trivedi MH, Cutler AJ, Richards C, Lasser R, Geibel BB, Gao J, et al. A randomized controlled trial of the efficacy and safety of lisdexamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry. 2013;74(8):802–9. McIntyre RS, Alsuwaidan M, Soczynska JK, Szpindel I, Bilkey TS, Almagor D, et al. The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder. Hum Psychopharmacol. 2013;28(5):421–7. Hoyer D, Jacobson LH. Orexin in sleep, addiction and more: is the perfect insomnia drug at hand? Neuropeptides. 2013;47(6):477–88. De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A. 1998;95(1): 322–7. Dugovic C, Shelton JE, Yun S, Bonaventure P, Shireman BT, Lovenberg TW. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism. Front Neurosci. 2014;8:28. Mieda M, Hasegawa E, Kisanuki YY, Sinton CM, Yanagisawa M, Sakurai T. Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci. 2011;31(17): 6518–26. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553–62.

Curr Psychiatry Rep (2014) 16:524 102.

Crocker A, España RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, et al. Concomitant loss of dynorphin, NARP and orexin in narcolepsy. Neurology. 2005;65(8):1184–8. 103. Mieda M, Sakurai T. Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status CNS Drugs. 2013;27(2): 83–90. 104. Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci U S A. 2004;101(13):4649–54. 105. Schwartz TL, Azhar N, Cole K, Hopkins G, Nihalani N, Simionescu M, et al. An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy. J Clin Psychiatry. 2004;65(9):1223– 7. 106. Sudhakar TP, Prasada Rao G, Lakshmi Prasuna P, John Vijay Sagar K. Study of effects of modafinil add-on therapy on excessive day time drowsiness and weight gain in patients on atypical antipsychotics. Indian J Psychol Med. 2008;301:24– 31. 107. Saavedra-Velez C, Yusim A, Anbarasan D, Lindenmayer JP. Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J Clin Psychiatry. 2009;70(1):104–12. 108. Carlson PJ, Merlock MC, Suppes T. Adjunctive stimulant use in patients with bipolar disorder: treatment of residual depression and sedation. Bipolar Disord. 2004;6(5):416–20.

Page 11 of 11, 524 109.

110.

111.

112.

113.

114.

115.•

116.

Mintzer MZ, Griffiths RR. Triazolam-amphetamine interaction: dissociation of effects on memory versus arousal. J Psychopharmacol. 2003;17(1):17–29. Penzner JB, Dudas M, Saito E, Olshanskiy V, Parikh UH, Kapoor S, et al. Lack of effect of stimulant combination with secondgeneration antipsychotics on weight gain, metabolic changes, prolactin levels, and sedation in youth with clinically relevant aggression or oppositionality. J Child Adolesc Psychopharmacol. 2009;19(5):563–73. National Institute on Drug Abuse. 2011. Prescription drug abuse. Available at: http://www.drugabuse.gov/publications/researchreports/prescription-drugs. Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, et al. Toxicity of amphetamines: an update. Arch Toxicol. 2012;86(8):1167–231. Busto U, Sellers EM. Pharmacokinetics determinants of drug abuse and dependence. A conceptual perspective Clin Pharmacokinet. 1986;11(2):144–53. Abreu ME, Bigelow GE, Fleisher L, Walsh SL. Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans. Psychopharmacology (Berl). 2001;154(1):76–84. Romach MK, Schoedel KA, Sellers EM. Human abuse liability evaluation of CNS stimulant drugs. Neuropharmacology. 2014. [Epub ahead of print]. This article highlights the clinical and biological aspects of the assessment of stimulants’ abuse potential. Launois SH, Tamisier R, Lévy P, Pépin JL. On treatment but still sleepy: cause and management of residual sleepiness in obstructive sleep apnea. Curr Opin Pulm Med. 2013;19(6):601–8.