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Psychopharmacology Feb 2021At all times humans have made attempts to improve their cognitive abilities by different means, among others, with the use of stimulants. Widely available stimulants... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONAL
At all times humans have made attempts to improve their cognitive abilities by different means, among others, with the use of stimulants. Widely available stimulants such as caffeine, but also prescription substances such as methylphenidate and modafinil, are being used by healthy individuals to enhance cognitive performance.
OBJECTIVES
There is a lack of knowledge on the effects of prescription stimulants when taken by healthy individuals (as compared with patients) and especially on the effects of different substances across different cognitive domains.
METHODS
We conducted a pilot study with three arms in which male participants received placebo and one of three stimulants (caffeine, methylphenidate, modafinil) and assessed cognitive performance with a test battery that captures various cognitive domains.
RESULTS
Our study showed some moderate effects of the three stimulants tested. Methylphenidate had positive effects on self-reported fatigue as well as on declarative memory 24 hours after learning; caffeine had a positive effect on sustained attention; there was no significant effect of modafinil in any of the instruments of our test battery. All stimulants were well tolerated, and no trade-off negative effects on other cognitive domains were found.
CONCLUSIONS
The few observed significant positive effects of the tested stimulants were domain-specific and of rather low magnitude. The results can inform the use of stimulants for cognitive enhancement purposes as well as direct further research to investigate the effects of stimulants on specific cognitive domains that seem most promising, possibly by using tasks that are more demanding.
Topics: Adult; Attention; Caffeine; Central Nervous System Stimulants; Cognition; Double-Blind Method; Fatigue; Humans; Male; Methylphenidate; Modafinil; Nootropic Agents; Pilot Projects; Treatment Outcome; Young Adult
PubMed: 33201262
DOI: 10.1007/s00213-020-05691-w -
The Lancet. Neurology Jan 2021Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their...
BACKGROUND
Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.
METHODS
In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.
FINDINGS
Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).
INTERPRETATION
Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.
FUNDING
Patient-Centered Outcomes Research Institute.
Topics: Adult; Amantadine; Central Nervous System Stimulants; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Fatigue; Female; Humans; Male; Methylphenidate; Middle Aged; Modafinil; Multiple Sclerosis; Outcome Assessment, Health Care; Severity of Illness Index
PubMed: 33242419
DOI: 10.1016/S1474-4422(20)30354-9 -
European Journal of Neurology Sep 2021Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based...
BACKGROUND AND AIM
Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.
METHODS
The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.
RESULTS
A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.
CONCLUSION
The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.
Topics: Adult; Cataplexy; Child; Humans; Modafinil; Narcolepsy; Sleep; Sodium Oxybate
PubMed: 34173695
DOI: 10.1111/ene.14888 -
Journal of Clinical Sleep Medicine :... Sep 2021This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children.
INTRODUCTION
This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children.
METHODS
The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations.
RECOMMENDATIONS
The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment.
1
We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG).
2
We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG).
3
We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG).
4
We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG).
5
We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL).
6
We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL).
7
We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL).
8
We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG).
9
We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL).
10
We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL).
11
We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL).
12
We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL).
13
We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL).
14
We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL).
15
We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL).
16
We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL).
17
We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL).
18
We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL).
19
We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL).
20
We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL).
21
We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL).
22
We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL).
CITATION
Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. . 2021;17(9):1881-1893.
Topics: Adult; Child; Disorders of Excessive Somnolence; Humans; Idiopathic Hypersomnia; Modafinil; Narcolepsy; Sleep; United States
PubMed: 34743789
DOI: 10.5664/jcsm.9328 -
Human Brain Mapping Oct 2022Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional... (Randomized Controlled Trial)
Randomized Controlled Trial
Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.
Topics: Adult; Brain; Brain Mapping; Caffeine; Central Nervous System Stimulants; Cognition; Double-Blind Method; Humans; Magnetic Resonance Imaging; Male; Methylphenidate; Modafinil; Neural Pathways
PubMed: 35670369
DOI: 10.1002/hbm.25949 -
Revue Neurologique Oct 2023Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS) are rare disorders of central hypersomnolence of unknown cause, affecting young people. However, increased... (Review)
Review
Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS) are rare disorders of central hypersomnolence of unknown cause, affecting young people. However, increased sleep time and excessive daytime sleepiness (EDS) occur daily for years in IH, whereas they occur as relapsing/remitting episodes associated with cognitive and behavioural disturbances in KLS. Idiopathic hypersomnia is characterized by EDS, prolonged, unrefreshing sleep at night and during naps, and frequent morning sleep inertia, but rare sleep attacks, no cataplexy and sleep onset in REM periods as in narcolepsy. The diagnosis requires: (i) ruling out common causes of hypersomnolence, including mostly sleep apnea, insufficient sleep syndrome, psychiatric hypersomnia and narcolepsy; and (ii) obtaining objective EDS measures (mean latency at the multiple sleep latency test≤8min) or increased sleep time (sleep time>11h during a 18-24h bed rest). Treatment is similar to narcolepsy (except for preventive naps), including adapted work schedules, and off label use (after agreement from reference/competence centres) of modafinil, sodium oxybate, pitolisant, methylphenidate and solriamfetol. The diagnosis of KLS requires: (i) a reliable history of distinct episodes of one to several weeks; (ii) episodes contain severe hypersomnia (sleep>15h/d) associated with cognitive impairment (mental confusion and slowness, amnesia), derealisation, major apathy or disinhibited behaviour (hypersexuality, megaphagia, rudeness); and (iii) return to baseline sleep, cognition, behaviour and mood after episodes. EEG may contain slow rhythms during episodes, and rules out epilepsy. Functional brain imaging indicates hypoactivity of posterior associative cortex and hippocampus during symptomatic and asymptomatic periods. KLS attenuates with time when starting during teenage, including less frequent and less severe episodes. Adequate sleep habits, avoidance of alcohol and infections, as well as lithium and sometimes valproate (off label, after agreement from reference centres) help reducing the frequency and severity of episodes, and IV methylprednisolone helps reducing long (>30d) episode duration.
Topics: Adolescent; Humans; Kleine-Levin Syndrome; Idiopathic Hypersomnia; Disorders of Excessive Somnolence; Sleep; Narcolepsy
PubMed: 37684104
DOI: 10.1016/j.neurol.2023.08.010 -
Brain and Nerve = Shinkei Kenkyu No... May 2023Treatment of narcolepsy is based on the need to regulate life rhythms. Psychostimulants such as modafinil, methylphenidate-immediate release, and pemoline are used to...
Treatment of narcolepsy is based on the need to regulate life rhythms. Psychostimulants such as modafinil, methylphenidate-immediate release, and pemoline are used to treat hypersomnia. A psychosocial approach is considered the mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD), and medication is used to treat moderate or severe ADHD symptoms. Two of the four drugs approved in Japan for ADHD therapy (osmotic-release oral system methylphenidate and lisdexamfetamine dimesylate) are psychostimulants, which are administered via the ADHD proper distribution management system.
Topics: Humans; Central Nervous System Stimulants; Lisdexamfetamine Dimesylate; Attention Deficit Disorder with Hyperactivity; Methylphenidate; Modafinil
PubMed: 37194538
DOI: 10.11477/mf.1416202385 -
Current Neurology and Neuroscience... Mar 2023This paper reviews how sleep is impacted in patients with Prader-Willi syndrome (PWS), focusing on sleep-related breathing disturbances and excessive daytime sleepiness... (Review)
Review
PURPOSE OF REVIEW
This paper reviews how sleep is impacted in patients with Prader-Willi syndrome (PWS), focusing on sleep-related breathing disturbances and excessive daytime sleepiness (EDS).
RECENT FINDINGS
Hypothalamic dysfunction may underlie several aspects of the PWS phenotype. Central sleep apnea (CSA) can persist beyond infancy. Nocturnal hypoventilation is common and may occur without central or obstructive sleep apnea (OSA). Adenotonsillectomy, a mainstay of OSA treatment, may cause velopharyngeal insufficiency. Growth hormone (GH) is considered safe, but close surveillance for OSA remains important. Cardiac autonomic dysfunction occurs during slow wave sleep and may increase the risk of cardiovascular events. EDS and narcolepsy are also common. Modafinil and pitolisant are treatment options currently being studied. Sleep disorders are prevalent in individuals with PWS. Sleep-related breathing disorders present as CSA in infancy and later in life as OSA and hypoventilation. GH therapy has improved the clinical outcomes of patients with PWS, but close surveillance and treatment for OSA is recommended. EDS can persist even after sleep-related breathing disorders are treated, and some individuals may even develop narcolepsy. Early recognition and treatment of sleep-related disorders may prevent morbidity and result in improved survival of patients with PWS.
Topics: Humans; Prader-Willi Syndrome; Hypoventilation; Polysomnography; Sleep; Sleep Apnea, Obstructive; Disorders of Excessive Somnolence; Narcolepsy
PubMed: 36790642
DOI: 10.1007/s11910-023-01254-6 -
Annals of Internal Medicine May 2023Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. (Meta-Analysis)
Meta-Analysis
Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea : A Systematic Review and Network Meta-analysis.
BACKGROUND
Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown.
PURPOSE
To compare the effectiveness of drugs for EDS in OSA using network meta-analysis.
DATA SOURCES
MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022.
STUDY SELECTION
Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention.
DATA EXTRACTION
Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.
DATA SYNTHESIS
Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events.
LIMITATIONS
There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies.
CONCLUSION
Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol.
PRIMARY FUNDING SOURCE
None.
Topics: Humans; Autoreceptors; Disorders of Excessive Somnolence; Modafinil; Network Meta-Analysis; Sleep Apnea, Obstructive; Wakefulness-Promoting Agents
PubMed: 37155992
DOI: 10.7326/M22-3473 -
Molecular Psychiatry Apr 2023Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has...
Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.
Topics: Adult; Child, Preschool; Female; Humans; Infant; Pregnancy; Amphetamines; Attention Deficit Disorder with Hyperactivity; Clonidine; Cohort Studies; Denmark; Gestational Age; Methylphenidate; Modafinil; Mothers; Neurodevelopmental Disorders; Prenatal Exposure Delayed Effects; Registries
PubMed: 36759544
DOI: 10.1038/s41380-023-01992-6