Clin Pediatr (Phila) 2006 May; 45(4): 361-3 (Read article online)

Hayes D

SUMMARY: Narcolepsy is a rare neurologic sleep disorder with morbidity associated with functional impairment and frequent delay in diagnosis. Symptoms typically manifest in adolescence or early adulthood, but diagnosis of narcolepsy has been reported in early childhood. Diagnosis rates are as low as 50% of the total population of patients with narcolepsy and are delayed as much as 10 years after disease onset due to inadequate patient-physician communication and/or misdiagnosis. I present the complexity of diagnosing narcolepsy in early childhood in a patient with cataplexy that started soon after independent ambulation at age 10 months. Clin Pediatr. 2006;45:361-363.

J Pediatr Endocrinol Metab 2006 Apr; 19 Suppl 1: 423-9 (Read article online)

Müller HL, Müller-Stöver S, Gebhardt U, Kolb R, Sörensen N, Handwerker G

Prognosis in childhood craniopharyngioma survivors hinges upon late effects such as pituitary deficiency and obesity. Observations indicate that reduced physical activity and increased daytime sleepiness might be risk factors for obesity. We analyzed the degree of daytime sleepiness in 115 childhood craniopharyngioma patients (47% obese) using the Epworth Sleepiness Scale (ESS). Thirty-five (30%) displayed increased daytime sleepiness (ESS score > 10) of whom 14 were obese (26% of obese cohort). Polysomnography (PSG) and Multiple Sleep Latency Tests (MSLT) were conducted with 10 obese patients presenting increased daytime sleepiness, with only two craniopharyngioma patients revealing a sleep related breathing disorder. Four patients had repeated episodes of SOREM (sleep onset rapid eye movement), the classic PSG criterion for narcolepsy. Three patients displayed hypersomnia. All but one patient qualified as acutely obese. We speculate that secondary narcolepsy is an exacerbating condition of childhood craniopharyngioma obesity, supported by recent reports on orexin and narcolepsy which suggest hypothalamic failure in idiopathic narcolepsy.

Aviat Space Environ Med 2006 May; 77(5): 515-25 (Read article online)

Batéjat D, Coste O, Van Beers P, Lagarde D, Piérard C, Beaumont M

INTRODUCTION: Continuous military operations may disrupt sleep-wakefulness cycles, resulting in impaired performance and fatigue. We assessed the treatment efficacy of a hypnotic-psychostimulant combination to maintain sleep quality, performance, and alertness during a 42-h simulated military operation. METHODS: A 6-h prophylactic sleep period with zolpidem (ZOL) followed by a 18-h continuous work period with administration at midway of 300 mg of slow release caffeine (CAF) or 200 mg of modafinil (MOD) was performed by eight healthy male subjects. Performance level was assessed with a reaction time test, a memory search test, a dual task, an attention test, and a computerized Stroop test. Cortical activation level was evaluated by the Critical Flicker Frequency test. Subjective sleepiness was evaluated using a visual analog scale and questionnaires. Effects of drugs on prophylactic and recovery sleep were also quantified from EEG recordings. RESULTS: CAF and MOD maintained performance and alertness throughout the 18-h work period. As shown by EEG recordings, ZOL improved prophylactic sleep without any deleterious effect on performance immediately after waking. As a result of its positive effects on prophylactic sleep, a lower pressure for slow wave sleep during recovery sleep was observed; nevertheless, zolpidem did not enhance the effects of either psychostimulant on performance. DISCUSSION: MOD and CAF may be of value in promoting performance and wakefulness during shiftwork or military operations while zolpidem improves prophylactic sleep quality without any deleterious effect after waking. We concluded that a zolpidem/ caffeine or modafinil combination could be useful in a context of environmental conditions not conducive to sleep.

Chronobiol Int 2006; 23(1): 63-70 (Read article online)

Selbach O, Haas HL

The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep- and wake-promoting neurons in the hypothalamus to form a bistable switch that controlls the timing of behavioral state transitions. Hypocretin neurons integrate circadian-photic and nutritional-metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.

Curr Med Res Opin 2006 Apr; 22(4): 761-74 (Read article online)

Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T

OBJECTIVE: This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy. RESEARCH DESIGN AND METHODS: This was a multicenter double-blind study with 196 patients (aged 18-65 years) randomized to receive armodafinil 150 mg (n = 65), armodafinil 250 mg (n = 67), or placebo (n = 64) once daily for 12 weeks. MAIN OUTCOME MEASURES: Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20-min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory). RESULTS: Armodafinil significantly increased MWT mean sleep latency (at 0900-1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9 min in the 150-mg, 250-mg, and combined groups, respectively, compared with a decrease of 1.9 min for placebo (p < 0.01 for all three comparisons). Mean late-day MWT latency (1500-1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8 min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGIC rating from baseline to final visit in the armodafinil 150-mg, 250-mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness. CONCLUSIONS: Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.

Top Stroke Rehabil 2005; 12(4): 28-36 (Read article online)

Zorowitz RD, Smout RJ, Gassaway JA, Horn SD

Motor recovery after a stroke depends upon many upon different modalities. Intensive therapy using compensatory and facilitatory techniques is the primary method to improve movement and function in affected extremities. However, medications used to modulate neurotransmitters may be useful in augmenting therapy approaches. The Post-Stroke Rehabilitation Outcomes Project (PSROP) database was used to describe the frequency of prescribing neurostimulant medications; the types of neurostimulant medications used; and how the use of neurostimulant medications affected rehabilitation length of stay, motor recovery, cognitive recovery, and discharge destination. Of the 1,161 patients in the PSROP database, 929 (80.0%) patients did not receive any treatment with methylphenidate, modafinil, levodopa, amantadine, or bromocriptine. Patients who received neurostimulant medications did not have any more significant changes in length of stay, motor recovery, cognitive recovery, or discharge destination than patients who did not receive neurostimulant medications. Much research needs to be completed before clinicians know precisely whether and how rehabilitation therapies and medications interact to assist in functional recovery.

Nature 2006 May 10; (Read article online)

Lu J, Sherman D, Devor M, Saper CB

Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip-flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (gamma-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip-flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions-for example, in narcolepsy.

Neuro Endocrinol Lett 2006 Apr 29; 27(1-2): (Read article online)

Sonka K, Kemlink D, Pretl M

BACKGROUND: Narcolepsy with cataplexy is a debilitating sleep disease of which some symptoms can be treated with antidepressants. The antidepressant escitalopram is considered the most specific serotonin reuptake inhibitor. PATIENTS AND METHODS: Ten patients (5 men and 5 women, age range 18-77 years) suffering from narcolepsy with cataplexy occurring at least weekly were treated with escitalopram 5 or 10 mg a day for 28-98 days. These patients were barred from taking any drugs influencing cataplexy and also had no other diseases affecting sleep or vigilance. RESULTS: The mean number of cataplexies per week in 8 compliant patients declined significantly from 6.7 (+/-SD=7.2) to 0.3 (+/-0.6), P=0.02 (Sign test). Cataplexy completely disappeared in 6 patients. Subjective daytime sleepiness, power of concentration, quality of night sleep and mood remained unchanged. During the treatment, two patients had ejaculation disturbances. Two patients withdrew from the therapy (one because of ejaculation disturbance, the other for unknown reason). CONCLUSION: Escitalopram proved to have anticataplectic effects in this small-scale open-label study.

J Clin Psychiatry 2006 Apr; 67(4): 554-66 (Read article online)

Ballon JS, Feifel D

BACKGROUND: Modafinil is a novel wake-promoting agent that has U.S. Food and Drug Administration approval for narcolepsy and shift work sleep disorder and as adjunctive treatment of obstructive sleep apnea/hypopnea syndrome. Modafinil has a novel mechanism and is theorized to work in a localized manner, utilizing hypocretin, histamine, epinephrine, gamma-aminobutyric acid, and glutamate. It is a well-tolerated medication with low propensity for abuse and is frequently used for off-label indications. The objective of this study was to systematically review the available evidence supporting the clinical use of modafinil. DATA SOURCES: The search term modafinil OR Provigil was searched on PubMed. Selected articles were mined for further potential sources of data. Abstracts from major scientific conferences were reviewed. Lastly, the manufacturer of modafinil in the United States was asked to provide all publications, abstracts, and unpublished data regarding studies of modafinil. DATA SYNTHESIS: There have been 33 double-blind, placebo-controlled trials of modafinil. Additionally, numerous smaller studies have been performed, and case reports of modafinil's use abound in the literature. CONCLUSIONS: Modafinil is a promising drug with a large potential for many uses in psychiatry and general medicine. Treating daytime sleepiness is complex, and determining the precise nature of the sleep disorder is vital. Modafinil may be an effective agent in many sleep conditions. To date, the strongest evidence among off-label uses exists for the use of modafinil in attention-deficit disorder, postanesthetic sedation, and cocaine dependence and withdrawal and as an adjunct to antidepressants for depression.

Bioorg Med Chem Lett 2006 Apr 16; (Read article online)

Musachio JL, Hong J, Ichise M, Seneca N, Brown AK, Liow JS, Halldin C, Innis RB, Pike VW, He R, Zhou J, Kozikowski AP

(11)C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([(11)C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([(11)C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [(11)C]5 and [(11)C]6 display high affinity for the NET in vitro (K(i)=0.94 and 0.68nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.

Swiss Med Wkly 2006 Mar 4; 136(9-10): 149-54 (Read article online)

Schwegler K, Klaghofer R, Nirkko AC, Mathis J, Hersberger KE, Bloch KE

BACKGROUND AND OBJECTIVE: Sleep disturbances are prevalent but often overlooked or underestimated. We suspected that sleep disorders might be particularly common among pharmacy customers, and that they could benefit from counselling. Therefore, we described the prevalence and severity of symptoms associated with sleep and wakefulness disorders among Swiss pharmacy customers, and estimated the need for counselling and treatment. METHODS: In 804 Swiss pharmacies (49% of all community pharmacies) clients were invited to complete the Stanford Sleep Disorders Questionnaire (SDQ), and the Epworth Sleepiness Scale (EPW). The SDQ was designed to classify symptoms of sleep and wakefulness into the four most prevalent disorders: sleep apnoea syndrome (SAS), insomnia in psychiatric disorders (PSY), periodic leg movement disorders/restless legs (RLS) and narcolepsy (NAR). Data were entered into an internet-linked database for analysis by an expert system as a basis for immediate counselling by the pharmacist. RESULTS: Of 4901 participants, 3238 (66.1%) were female, and 1663 (33.9%) were male. The mean age (SD) of females and males was 52.4 (18.05), and 55.1 (17.10) years, respectively. The percentages of female and male individuals above cut-off of SDQ subscales were 11.4% and 19.8% for sleep apnoea, 40.9% and 38.7% for psychiatric sleep disorders, 59.3% and 46.8% for restless legs, and 10.4% and 9.4% for narcolepsy respectively. The prevalence of an Epworth Sleepiness Scale score >11 was 16.5% in females, and 23.9% in males. Reliability assessed by Cronbach's alpha was 0.65 to 0.78 for SDQ subscales, and for the Epworth score. CONCLUSIONS: Symptoms of sleep and wakefulness disorders among Swiss pharmacy customers were highly prevalent. The SDQ and the Epworth Sleepiness Scale score had a satisfactory reliability to be useful for identification of pharmacy customers who might benefit from information and counselling while visiting pharmacies. The internet-based system proved to be a helpful tool for the pharmacist when counselling his customers in terms of diagnostic classification and severity of symptoms associated with the sleeping and waking state.

Expert Rev Neurother 2006 Apr; 6(4): 455-68 (Read article online)

Turner D

Modafinil (Provigil) is a novel wakefulness-promoting agent that has been shown to have greater efficacy than placebo in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. In particular, three large, drug-company sponsored trials of a film-coated formulation of modafinil (modafinil-ADHD; Sparlon) in children and adolescents with ADHD demonstrated consistent improvements in ADHD symptoms compared with placebo. Mean reductions in symptom ratings (measured using the ADHD-Rating Scale-IV school version questionnaire) ranged from 15.0 to 19.7 (7.3 to 10.1 for placebo). The most common adverse events were insomnia, headache and decreased appetite. Modafinil was generally well tolerated with most side effects considered mild to moderate in severity. Modafinil may have advantages over current therapies for ADHD in that it can be administered once daily and has fewer reinforcing properties than traditional stimulants. Modafinil could potentially be a valuable new treatment option for patients with ADHD. However, rigorous comparative studies with current first-line treatments for ADHD and longer-term independent studies are necessary before modafinil's role in the treatment of ADHD can be fully established.

Peptides 2006 Apr 18; (Read article online)

Fujiki N, Yoshida Y, Zhang S, Sakurai T, Yanagisawa M, Nishino S

Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.

Curr Opin Psychiatry 2005 May; 18(3): 265-70 (Read article online)

Vocci FJ, Elkashef A

PURPOSE OF REVIEW: This review examines progress being made in the treatment of cocaine abuse and dependence, with a particular focus on pharmacotherapies. Medications with apparently very different mechanisms of action have been reported to reduce cocaine use in controlled clinical trials in outpatient settings. This review will summarize the latest findings in this area. RECENT FINDINGS: Of all the medications tested to date, disulfiram has demonstrated the most consistent effect to reduce cocaine use. Several medications have been reported to reduce cocaine use in double-blind, placebo-controlled clinical trials, namely baclofen, modafinil, tiagabine, and topiramate. All pharmacotherapy trials in cocaine-dependent patients include a behavioral therapy that is common to all participants. Consequently, these pharmacotherapy trials can be considered to evaluate whether the medication is adding to the effect of the behavioral therapy. SUMMARY: Confirmatory clinical studies are necessary to replicate the initial efficacy findings for baclofen, modafinil, tiagabine, and topiramate. More research is needed in both cocaine and cocaine-alcohol dependent populations. Once confirmatory studies have been carried out, testing of rational medication combinations with different behavioral therapies is an obvious next step to increase the ability to manage cocaine dependence.

Brain 2006 Apr 5; (Read article online)

Mignot E, Lin L, Finn L, Lopes C, Pluff K, Sundstrom ML, Young T

The diagnosis of narcolepsy without documented cataplexy is based on the observation of two or more sleep-onset REM periods (SOREMPs) during the Multiple Sleep Latency Test (MSLT). We report on the prevalence and correlates of SOREMPs in the community-based Wisconsin Sleep Cohort Study. MSLTs were conducted following nocturnal polysomnography (NPSG) and daily sleep diaries in 289 males and 267 females (age 35-70, 97% Caucasians). Multiple SOREMPs were observed in 13.1% of males and 5.6% of females. An MSLT mean sleep latency /=2 SOREMPs (diagnostic of narcolepsy) was observed in 5.9% (males) and 1.1% (females), all without cataplexy. Because of significant sex interactions, analyses were stratified by sex. Increased prevalence of HLA-DQB1*0602, a marker of narcolepsy, was observed in males but not in females with >/=2 SOREMPs. Males with multiple SOREMPs compared with those with no SOREMPs had shorter rapid eye movement (REM) latency during NPSG, were sleepier on the MSLT and reported increased sleepiness, hypnagogic hallucinations and cataplexy-like symptoms, suggesting a narcolepsy-like phenotype. In males only, the occurrence of SOREMPs increased with shift work and some indirect markers of sleep restriction, such as shorter sleep a day before NPSG. SOREMPs were unrelated to age, body mass index, depression (Zung Scale), anxiety (State-Trait Anxiety Scale) and the number of apnea and hypopnea events per hour of sleep (AHI), but were associated with decreased mean lowest oxygen saturation in males. Finally, we found that both males and females with SOREMPs reported taking more antidepressants, but those were of the types known not to suppress REM sleep. These results suggest a high prevalence of narcolepsy without cataplexy, as defined by the International Classification of Sleep Disorders, and/or a large number of false-positives for the MSLT.

Rev Neurol Dis 2005; 2(4): 203-10 (Read article online)

Culebras A

Summary of presentations given at the Teaching Course at the 19th Annual Meeting of the Associated Professional Sleep Societies, June 18-23, 2005, Denver, CO. Medical professionals gathered in Denver, CO, in June 2005 to explore the current knowledge base of idiopathic narcolepsy and the symptomatic narcolepsies. Dr. Culebras summarizes notable presentations concerning clinical features, role of hypocretin, sleep laboratory assessments, updates of the conditions, and pharmacologic management, ending with future treatment options.

Expert Opin Pharmacother 2006 May; 7(7): 837-48 (Read article online)

Krebs M, Leopold K, Hinzpeter A, Schaefer M

With the exception of dementia, the use of neuroprotective agents in psychiatric disorders is not yet well established. However, recent data from brain imaging studies and clinical trials support the view that neurodegenerative mechanisms may play a role in the pathophysiology of schizophrenia and affective disorders. Further evidence for the use of neuroprotective agents can be drawn from the findings that second-generation antipsychotics, mood stabilizers and antidepressants have been shown to have neuroprotective effects in vitro and in vivo. Neuroprotective agents as add-on therapies (e.g., modafinil, erythropoietin, glycine, D-serine, memantine and celecoxib) are currently being evaluated in schizophrenia and related disorders. This paper reviews the current options for neuroprotective treatment approaches focusing on schizophrenia and affective disorders.

J Am Acad Child Adolesc Psychiatry 2006 Mar 10; (Read article online)

Greenhill LL, Biederman J, Boellner SW, Rugino TA, Sangal RB, Earl CQ, Jiang JG, Swanson JM

OBJECTIVE:: To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). METHOD:: In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impression of Improvement (CGI-I) scale. RESULTS:: Two hundred patients were randomized. Modafinil produced significant reductions in ADHD-RS-IV total scores at school (n = 128; mean change +/- SD: -17.5 +/- 13.1 points) compared with placebo (n = 66; -9.7 +/- 10.3 points; p < .0001). Similarly, modafinil reduced ADHD-RS-IV total scores at home compared with placebo (-17.6 +/- 13.3 versus -7.5 +/- 11.8 points; p < .0001). Fifty-two percent of patients randomized to modafinil and 18% of those randomized to placebo met prestudy criteria for responder on the CGI-I (p < .0001). Randomization to modafinil was associated with significantly more insomnia, headache, decreased appetite, and weight loss than randomization to placebo, but discontinuation attributed to adverse events did not differ statistically between treatment groups (modafinil, 5%; placebo, 6%). CONCLUSION:: Modafinil was well tolerated and reduced ADHD symptoms at school and home compared with placebo.

J Child Neurol 2006 Feb; 21(2): 112-4 (Read article online)

Hurst D, Cedrone N

Two patients with spastic cerebral palsy recently treated with modafinil at the Walter Reed Army Medical Center child neurology clinic have stopped drooling. This occurred after starting modafinil for spasticity and without other changes in the patients' treatment programs. The decrease in drooling is to a remarkable degree. Both patients had a chronic problem with drooling. One patient has gone from wearing a bib or bandanna, which was constantly wet from drooling to being essentially dry. After starting modafinil, both patients stopped drooling. The parents initially observed decreased drooling at home. Clinic appointment examinations and evaluations at physical therapy confirmed these observations. Better coordination and speech have been noted in each patient. Modafinil improves drooling in at least some patients with spastic cerebral palsy. The decreased drooling is due to improvements noted in swallowing. (J Child Neurol 2006;21:112-114; DOI 10.2310/7010.2006.00038).

Psychopharmacology (Berl) 2006 May; 185(4): 433-40 (Read article online)

van Vliet SA, Jongsma MJ, Vanwersch RA, Olivier B, Philippens IH

RATIONALE: Modafinil is increasingly used in sleep disturbances in general and in neurodegenerative diseases and is recently being used in healthy people for attention control. However, the application of modafinil is possibly not only restricted to alertness enhancing effects. More insight in this compound may lead to new applications. Not all behavioral aspects have been studied sufficiently; therefore, more detailed investigations on modafinil's positive and aversive behavioral effects are addressed in this paper. OBJECTIVES: Determination of effects of modafinil in marmoset monkeys with observational methods and with behavioral tests measuring locomotor activity, hand-eye coordination, response to a threat situation and startle response. MATERIALS AND METHODS: Two hours after oral administration of modafinil in doses of 50, 100, 150, and 225 mg/kg, animals were observed and tested in the behavioral test systems. RESULTS: Locomotor activity was increased after 100 mg/kg modafinil in the Bungalow test and after 100, 150, and 225 mg/kg, as found in the movement parameters of the human threat test. Moreover, modafinil showed anxiolytic-like effects in the human threat test. No other side effects were observed, nor were the hand-eye coordination and startle response affected. CONCLUSIONS: Besides psychostimulation, modafinil has no aversive effects in the doses used in the domains measured. The potential anxiolytic-like effects of modafinil may create new possibilities for the therapeutic use of modafinil.