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Advances in Pharmacology (San Diego,... 2024Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has...
Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an "atypical" CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders.
Topics: Humans; Modafinil; Central Nervous System Stimulants; Benzhydryl Compounds; Dopamine; Substance-Related Disorders
PubMed: 38467484
DOI: 10.1016/bs.apha.2023.10.006 -
Cureus Feb 2024This study aimed to evaluate the trends in the sociodemographic, clinical, and prescription characteristics of patients with psychotic illnesses seen in the outpatient...
A Naturalistic, Non-interventional Investigation of the Clinical and Sociodemographic Characteristics and Prescription Patterns in Patients With Psychotic Disorders at a Tertiary Care Facility in South Asia.
OBJECTIVES
This study aimed to evaluate the trends in the sociodemographic, clinical, and prescription characteristics of patients with psychotic illnesses seen in the outpatient psychiatry department of a tertiary care facility.
METHODS
Between March 2021 and April 2022, a cross-sectional, prospective, observational, naturalistic, non-interventional study was conducted. A total of two hundred prescriptions were analyzed. To assess the rationality of prescriptions, World Health Organization (WHO) indicators were also computed.
RESULTS
With a range of 18 to 75 years, the cohort's mean age was 40.26 years, and its average disease duration was 10.75 years. Sixty-seven patients (68.5%) were diagnosed with schizophrenia. Of the 200 prescriptions that were analyzed, 13 antipsychotic prescriptions were written 343 times. Olanzapine was prescribed as an antipsychotic the most frequently (132, 66%), followed by clozapine (75, 37.5%). Haloperidol (41, 20.5%), trifluoperazine (3, 1.5%), loxapine (1, 0.5%), and flupenthixol depot (1, 0.5%) were the most commonly prescribed typical antipsychotics. 91% (181/200) of patients received prescriptions for other drugs in addition to antipsychotics. Trihexyphenidyl (45%), escitalopram (30%), clonazepam (26.5%), sodium valproate (10%), propranolol (10.5%), and modafinil (9.5%) were the most frequently prescribed concurrent medicines. Forty-eight percent (95/200) of prescriptions demonstrated polypharmacy. Among patients, the frequency of antipsychotic prescriptions was 1 in 44% (88/200), 2 in 36.50% (73/200), 3 in 17% (34/200), 4 in 0.5% (1/200), and 5 again in 0.5% (1/200). Conclusions: On average, the cohort of the current study was young. The commonest diagnosis was mainly schizophrenia. Atypical antipsychotics accounted for the majority of antipsychotic prescriptions in the current study. In this study, a high prevalence of polypharmacy was noted.
PubMed: 38445139
DOI: 10.7759/cureus.53541 -
The European Journal of Neuroscience May 2024Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual...
Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.
Topics: Animals; Nucleus Accumbens; Receptors, sigma; Male; Dopamine Plasma Membrane Transport Proteins; Dopamine; Cocaine; Rats, Sprague-Dawley; Rats; Dopamine Uptake Inhibitors; Piperidines; Benzhydryl Compounds; Microdialysis; Modafinil
PubMed: 38444104
DOI: 10.1111/ejn.16293 -
JMIR Research Protocols Mar 2024Cerebral palsy (CP) is a prevalent nonprogressive disorder that leads to impaired movement (ie, spasticity), posture, and balance, which affects functions such as...
BACKGROUND
Cerebral palsy (CP) is a prevalent nonprogressive disorder that leads to impaired movement (ie, spasticity), posture, and balance, which affects functions such as walking and upper extremity tasks. Current medical treatments show efficacy in improving motor performance but have considerable side effects. Emerging off-label use of central nervous system (CNS) medications for improving motor performance has shown promising results in children with CP and other populations.
OBJECTIVE
The aim of this study is to describe a protocol for a pilot randomized controlled trial (RCT) to examine the safety, tolerability, and efficacy of methylphenidate (MPH) and modafinil on spasticity and motor performance in children with CP.
METHODS
This will be a protocol study for a pilot, triple-masked, placebo-controlled RCT (a class I trial following the American Academy of Neurology criteria) with blinded patients, outcome assessors, and intervention delivery team. Eligible children should be diagnosed with CP levels I or II based on the Gross Motor Function Classification System and be aged between 7 and 12 years. Thirty-six children with CP will be randomized into 3 groups to receive (1) MPH (2.5 mg of MPH + 100 mg placebo), (2) modafinil (100 mg modafinil + 2.5 mg placebo), or (3) a placebo (2.5 mg placebo + 100 mg placebo), in addition to physical therapy for 12 weeks. Primary outcomes include the Gross Motor Function Measure-66 and the Modified Ashworth Scale. Secondary outcomes include the Timed Up and Go test, 5 Time Sit to Stand test, Modified Clinical Test for Sensory Interaction of Balance, and 10-Meter Walk Test.
RESULTS
The protocol has been accepted by Kuwait University (VDR/EC-225) and the Ministry of Health of Kuwait (2022/2157). The inclusion of participants will start in June 2024.
CONCLUSIONS
The combination of CNS stimulant medications and controlling for rehabilitation has not been studied yet. The findings of this study may determine if using CNS stimulant medications is beneficial for the reduction of spasticity and improvement of physical function in children with spastic CP.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05675098; https://clinicaltrials.gov/study/NCT05675098.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
PRR1-10.2196/53728.
PubMed: 38441919
DOI: 10.2196/53728 -
Bipolar Disorders May 2024Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder... (Review)
Review
Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.
BACKGROUND
Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD.
METHODS
We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials.
RESULTS
Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias.
CONCLUSIONS
Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Cognitive Dysfunction; Central Nervous System Stimulants; Off-Label Use; Methylphenidate
PubMed: 38433530
DOI: 10.1111/bdi.13414 -
Neuropsychopharmacology : Official... Mar 2024People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of...
People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.
PubMed: 38429498
DOI: 10.1038/s41386-024-01826-1 -
World Neurosurgery May 2024Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating...
BACKGROUND
Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating fatigue in stroke survivors, but data pertaining to its use in the acute setting are scarce. This study sought to assess the effects of modafinil use on mental status after aSAH.
METHODS
Modafinil timing and dosage, neurological examination, intubation status, and physical and occupational therapy participation were documented. Repeated-measures paired tests were used for a before-after analysis of modafinil recipients. Propensity score matching (1:1 nearest neighbor) for modafinil and no-modafinil cohorts was used to compare outcomes.
RESULTS
Modafinil (100-200 mg/day) was administered to 21% (88/422) of aSAH patients for a median (IQR) duration of 10.5 (4-16) days and initiated 14 (7-17) days after aSAH. Improvement in mentation (alertness, orientation, or Glasgow Coma Scale score) was documented in 87.5% (77/88) of modafinil recipients within 72 hours and 86.4% (76/88) at discharge. Of 37 intubated patients, 10 (27%) were extubated within 72 hours after modafinil initiation. Physical and occupational therapy teams noted increased alertness or participation in 47 of 56 modafinil patients (83.9%). After propensity score matching for baseline covariates, the modafinil cohort had a greater mean (SD) change in Glasgow Coma Scale score than the no-modafinil cohort at discharge (2.2 [4.0] vs. -0.2 [6.32], P = 0.003).
CONCLUSIONS
A temporal relationship with improvement in mental status was noted for most patients administered modafinil after aSAH. These findings, a favorable adverse-effect profile, and implications for goals-of-care decisions favor a low threshold for modafinil initiation in aSAH patients in the acute-care setting.
Topics: Humans; Modafinil; Male; Subarachnoid Hemorrhage; Female; Middle Aged; Wakefulness-Promoting Agents; Aged; Adult; Treatment Outcome; Benzhydryl Compounds; Glasgow Coma Scale; Stroke
PubMed: 38367859
DOI: 10.1016/j.wneu.2024.02.056 -
Journal of Pharmaceutical and... May 2024The goal of this research is the development of multiple monolithic fiber-solid phase microextraction (MMF-SPME) using a new integrated fiber for the determination of...
Application of novel metal organic framework-deep eutectic solvent/molecularly imprinted polymer multiple monolithic fiber for solid phase microextraction of amphetamines and modafinil in unauthorized medicinal supplements with GC-MS.
The goal of this research is the development of multiple monolithic fiber-solid phase microextraction (MMF-SPME) using a new integrated fiber for the determination of amphetamine derivatives and modafinil from unauthorized medicinal supplements. For this purpose, a monolithic fiber of metal organic framework MIL-Al (53)-deep eutectic solvent (DES)/molecularly imprinted polymers (MOF-DES/MIP) was synthesized. To find optimum microextraction conditions gas chromatography-mass spectrometer (GC-MS) was used and the influences of effective variables were investigated using one factor at a time method. After that, the significant variables were optimized using a Box-Behnken design (BBD) combined with a desirability function (DF). Under optimized conditions (desorption solvent=1500 µL of 1-octanol, pH=3.5, extraction time=35 min, [NaCl]=0% w/v and stirring rate=600 rpm), calibration graphs of analytes were linear in a concentration range of 0.1-400 μg L with correlation coefficients > 0.9966. Limits of detection and quantification were in the ranges of 0.023-0.033 μg L and 0.088-0.113 μg L, respectively. This procedure was successfully employed in determining target analytes in spiked and unspiked unauthorized medicinal supplement samples with recoveries ranging from 95.14 to 104.63%.
Topics: Metal-Organic Frameworks; Molecularly Imprinted Polymers; Polymers; Modafinil; Solid Phase Microextraction; Deep Eutectic Solvents; Gas Chromatography-Mass Spectrometry; Chromatography, Gas; Amphetamines
PubMed: 38364343
DOI: 10.1016/j.jpba.2024.116005 -
Medicine Feb 2024Although patients with central disorders of hypersomnolence (CDH) exhibit characteristic symptoms of hypersomnia frequently, it takes 5 to 15 years from the onset for...
RATIONALE
Although patients with central disorders of hypersomnolence (CDH) exhibit characteristic symptoms of hypersomnia frequently, it takes 5 to 15 years from the onset for its diagnosis due to the lack of symptom recognition. Here, we present a case of idiopathic hypersomnia (IH), a CDH, wherein early diagnosis was aided by a video footage of a spontaneous sleep attack.
PATIENT CONCERNS
A 21-year-old man lost consciousness while driving and experienced an accident. He had complained of excessive daytime sleepiness (EDS) over half a year. During his hospitalization for close monitoring of the loss of consciousness, an in-room surveillance camera captured a 14-minutes long spontaneous sleep attack, during which he experienced general muscle weakness and loss of consciousness without warnings or convulsions leading to a fall from the bed. There were no abnormalities in vital signs.
DIAGNOSES
There was no significant cataplexy and less than 2 sleep-onset rapid eye movements (SOREM) in 2 sleep latency tests, with a mean sleep latency of 2.1 and 4.6 minutes. Other sleep deprivation syndromes were excluded from differential diagnosis and finally, a diagnosis of IH was confirmed according to the criteria of the Third Edition of the International Classification of Sleep Disorders. During the course of the disease, attention-deficit/hyperactive disorder (ADHD) and a gaming disorder also diagnosed.
INTERVENTIONS
Pharmacological treatment with modafinil was administered for IH and methylphenidate for ADHD. Cognitive behavioral therapy was performed for the gaming disorder.
OUTCOMES
The EDS improved, and sleep attacks were no longer observed. The disruption of daily life caused by the gaming disorder was also reduced.
LESSONS
Video recordings of sleep attacks are beneficial for identifying the cause of loss of consciousness. Home video recordings may be helpful in the early diagnosis of IH.
Topics: Humans; Male; Young Adult; Disorders of Excessive Somnolence; Idiopathic Hypersomnia; Modafinil; Sleep; Unconsciousness
PubMed: 38363934
DOI: 10.1097/MD.0000000000036782 -
Expert Review of Neurotherapeutics Apr 2024Gambling disorder (GD) is a mental health condition characterized by persistent and problematic betting behavior. GD generates distress and impairment, and treatment... (Review)
Review
INTRODUCTION
Gambling disorder (GD) is a mental health condition characterized by persistent and problematic betting behavior. GD generates distress and impairment, and treatment options include psychological and pharmacological interventions.
AREAS COVERED
This narrative review explores existing pharmacological treatments for GD. The following classes of medications were considered: opioid-receptor antagonists (e.g. naltrexone and nalmefene), serotonin reuptake inhibitors (e.g. fluvoxamine, paroxetine, sertraline, escitalopram, and citalopram), glutamatergic agents (e.g. N-acetylcysteine (NAC), acamprosate, and memantine), mood stabilizers (e.g. topiramate, carbamazepine, lithium), and other medications (e.g. modafinil, nefazodone, olanzapine, haloperidol, tolcapone, and bupropion).
EXPERT OPINION
Due to the limitations of the studies reviewed, solid conclusions regarding the optimal choice of pharmacotherapy for individuals with GD are challenging to draw at this time. Despite some medications, such as naltrexone and nalmefene, showing promising results, efficacy has varied across studies. The review highlights current gaps/limitations, including small sample sizes, limited diversity in participant demographics, the need for exploring different gambling subtypes and treatment responses, high placebo response rates, lack of longer-term longitudinal information, limited investigation of neurobiological correlates and co-occurring disorders, and the importance of implementation research. Further research is needed to address these gaps and explore additional medications, as well as interventions like neuromodulation.
Topics: Humans; Gambling; Naltrexone; Behavior, Addictive; Narcotic Antagonists; Selective Serotonin Reuptake Inhibitors
PubMed: 38357896
DOI: 10.1080/14737175.2024.2316833