Armodafinil as a Potential Pharmacological Treatment for Attention Deficit Hyperactivity Disorder in Adults: A Review.

INTRODUCTION: Armodafinil is a psychostimulant that promotes alertness, and it has been shown to improve attention, memory, and fatigue in healthy adults and adults with neurodevelopmental conditions that share symptoms with Attention Deficit Hyperactivity Disorder (ADHD). It is generally well tolerated and safe, and most of the adverse events reported are considered not serious. However, the available evidence on the efficacy of armodafinil for the treatment of ADHD in adults is scarce. OBJECTIVE: The present review aims to perform a systematized search of the available evidence on the possible therapeutic benefit of armodafinil treatment in adult patients with ADHD. METHODS: A literature review using PubMed was conducted to compile and summarize the available clinical and scientific evidence on the possible use of armodafinil as a pharmacological treatment in adult patients with ADHD. RESULTS: From the 86 articles reviewed, the available evidence showed that both acute and chronic treatment with armodafinil can improve wakefulness, memory, impulse control, and executive functions in adults with sleep disorders and other conditions. In addition, evidence of improvement in cognitive functions and mood alterations in other neuropsychiatric conditions was shown. CONCLUSION: Armodafinil could be useful for the treatment of ADHD in adults, according to the review of the literature from both pre-clinical and clinical studies.

Headache improves with armodafinil.

This case report recounts the details of a patient diagnosed with narcolepsy and cataplexy whose headaches improved once treatment with armodafinil began. The clinical significance of this report lies in the fact that armodafinil is known to cause headaches, at least initially. But perhaps through a reduced need for caffeine and/or a regulation of sleep/wake, armodafinil may reduce headache frequency and severity. CITATION: Barone DA. Headache improves with armodafinil. J Clin Sleep Med. 2024;20(3):469-470.

COMPARATIVE ANALYSIS OF EFFECTIVENESS OF OBESITY TREATMENT IN PRIMARY CARE USING PATIENT-ORIENTED APPROACH WITH MOTIVATIONAL COUNSELING FOR LIFESTYLE CORRECTION AND ITS COMBINATION WITH ARMODAFINIL THERAPY IN PATIENTS WITH CONCOMITANT SHIFT WORK SLEEP DISORDER.

OBJECTIVE: Aim: Conduct a comparative analysis of effectiveness of obesity treatment in primary care using patient-oriented approach with motivational counseling for lifestyle correction and its combination with armodafinil therapy in patients with concomitant shift work sleep disorder. PATIENTS AND METHODS: Materials and Methods: 75 patients with obesity were studied, 38 patients had shift work disorder. Patients were divided into 2 groups: I (37 patients with obesity treated with motivational counseling) and II (38 patients with obesity and shift work disorder treated additionally with armodafinil 150 mg daily). The examination was at baseline, after 1st, 3th and 6th months. Statistical analysis was provided. RESULTS: Results: After 1 month of treatment, there were improvement of eating behavior, level of anxiety and depression, prognosis of diabetes development. At 3rd month, more pronounced changes were observed in 2nd group: 10% body weight loss, changes in eating behavior, sleep quality, anxiety level (p<0.05). After 6 months, examined indicators in both groups normalized, but dynamics in 2nd group was more significant; armodafinil-treated group had significantly better results in body weight loss, BMI, WC, HC, ConI, AVI, BPs, HOMA index, serotonin, leptin, levels of anxiety and depression, eating behavior, daytime dysfunction, level of sleepiness, quality of life and risk of developing diabetes. CONCLUSION: Conclusions: The use of armofafinil in addition to patientoriented motivational counseling in lifestyle correction ("5 As" and "5R") in patients with obesity connected with shift work disorder and excessive daytime sleepiness allows to reduce body weight by more than 16,52%, in contrast to isolated use of the same technique of motivational counseling in obese patients without sleep disorder (only 5,51%).

Infant Exposure to Armodafinil Through Human Milk Following Maternal Use of Modafinil.

INTRODUCTION: Narcolepsy, a condition adversely affecting psychological, social, and cognitive function, is more prevalent in females of childbearing age than the general population. Modafinil and armodafinil are central nervous system stimulants approved for treatment of narcolepsy. Infant exposure to these agents through human milk has not been investigated. Poor quality medication safety information during lactation is associated with early cessation of breastfeeding and suboptimal healthcare for the breastfeeding family. MAIN ISSUE: In this case study, we measured the concentration of armodafinil (the most active form of modafinil) in human milk and infant plasma to quantify infant exposure. MANAGEMENT: The participant was a 30-year-old primipara with narcolepsy, taking modafinil (300 mg morning, 100 mg noon) while breastfeeding her 6-week-old infant despite the paucity of safety information. Armodafinil concentrations were measured in eight serial human milk samples collected over a 26-hr period and in single maternal and infant plasma samples using ultra performance liquid chromatography - tandem mass spectrometry. The average concentration of armodafinil in human milk was 1.96 mg/L; the relative infant dose was 4.85%; the theoretical infant dose was 0.294 mg/kg/day. Maternal and infant plasma concentrations of armodafinil were 12.02 mg/L and 0.19 mg/L, respectively. The participant continued to exclusively breastfeed the infant, who had normal growth and development. CONCLUSION: Based on these findings, relatively small amounts of armodafinil pass into human milk, with consequent limited infant exposure. Consideration can be given to the use of modafinil or armodafinil during breastfeeding, provided the infant is monitored. Further studies are needed to confirm these findings.

Preparation of Deuterium-Labeled Armodafinil by Hydrogen-Deuterium Exchange and Its Application in Quantitative Analysis by LC-MS.

Armodafinil, the R enantiomer of modafinil, was approved in 2007 by the US Food and Drug Administration as a wake-promoting agent for excessive sleepiness treatment. Due to its abuse by students and athletes, there is a need of its quantification. Quantitative analysis by liquid chromatography-mass spectrometry, however, though very common and sensitive, frequently cannot be performed without isotopically labeled standards which usually have to be specially synthesized. Here we reported our investigation on the preparation of deuterated standard of armodafinil based on the simple and inexpensive hydrogen-deuterium exchange reaction at the carbon centers. The obtained results clearly indicate the possibility of introduction of three deuterons into the armodafinil molecule. The introduced deuterons do not undergo back exchange under neutral and acidic conditions. Moreover, the deuterated and non-deuterated armodafinil isotopologues revealed co-elution during the chromatographic analysis. The ability to control the degree of deuteration using different reaction conditions was determined. The proposed method of deuterated armodafinil standard preparation is rapid, cost-efficient and may be successfully used in its quantitative analysis by LC-MS.

Intranasal hydrogel of armodafinil hydroxypropyl-ß-cyclodextrin inclusion complex for the treatment of post-traumatic stress disorder.

Armodafinil inclusion complex (AIC) hydrogel was prepared and evaluated for its therapeutic effect on Post-traumatic Stress Disorder (PTSD). After computer simulation and physicochemical property investigation, the AIC was formed by lyophilization of armodafinil with ethanol as solvent and hydroxypropyl-beta-cyclodextrin (HP-ß-CD) aqueous solution, in which the molar ratio of armodafinil and HP-ß-CD was 1-1. The AIC encapsulation efficiency (EE) was (90.98 ± 3.72)% and loading efficiency (LE) was (13.95 ± 0.47)% and it increased the solubility of armodafinil in aqueous solution to 21 times. AIC hydrogel was prepared by adding AIC to methylcellulose (MC) hydrogels (3.33% w/v), and its higher drug release amount and slower release rate were testified by the in-vitro release assay and the rheological test. The mucosa irritation of AIC hydrogel was also evaluated. Healthy group, Model group, Sertraline group with 30 mg/kg sertraline gavage, AIC Hydrogel group with 20 mg/kg AIC hydrogel intranasal administration and AIC Aqueous Solution group with 20 mg/kg AIC aqueous solution gavage were set up for the treatment of mice with PTSD generated from foot shock method. Based on freezing response test in fear-conditioning box and open field test, compared with other groups, PTSD mice in AIC Hydrogel group showed significant improvement in behavioral parameters after 11 days of continuous drug administration and 5 days of drug withdrawal. After sacrifice, the plasma CORT level of PTSD mice in AIC Hydrogel group was elevated compared to Model group. Besides, the western blot (WB) of hippocampal brain-derived neurotrophic factor (BDNF) and amygdala dopamine transporter (DAT) immunohistochemistry sections indicated that AIC hydrogel had a protective effect on the brain tissue of PTSD mice. The brain targeting of intranasal administration was evaluated by fluorescence imaging characteristics of Cy7 hydrogel in the nasal route of drug administration, pharmacokinetics and in-vivo distribution of armodafinil. In short, AIC hydrogel is a promising formulation for the treatment of PTSD based on its high brain delivery and anti-PTSD effect.

[Adrenal crisis associated with modafinil use]. / Crisis adrenal asociada al uso de modafinilo.

Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treatment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembolism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose replacement in subjects receiving metabolism-inducing drugs.

La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser desencadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Application of armodafinil-loaded microneedle patches against the negative influence induced by sleep deprivation.

Cognition maintenance is essential for healthy and safe life if sleep deprivation happens. Armodafinil is a wake-promoting agent against sleep deprivation related disorders. However, only the tablet formulation is available, which may limit its potential in some circumstances. Here, we report the synthesis of a new formulation of armodafinil, microneedle patches, which can be conveniently used by any individual and removed in time if not wanted. To produce the needles of higher mechanical strength and higher drug loading, polyvinylpyrrolidone (PVP) K90 was used to fabricate armodafinil-loaded microneedles by applying the mold casting method after dissolving in methanol and drying. The higher mechanical strength was validated by COMSOL Multiphysics® software stimulation and universal mechanical testing machines. The obtained armodafinil microneedles can withstand a force of 70 N and penetrate the skin to a depth of 230 µm, and quickly released the drug within 1.5 h in vitro. The pharmacokinetic analysis showed that microneedle administration can maintain a more lasting and stable blood concentration as compared to oral administration. After the treatment of sleep deprived mice with microneedles, the in vivo pharmacodynamics study clearly demonstrated that armodafinil microneedles could eliminate the effects of sleep deprivation and improve the cognitive functions of sleep-deprived mice. A self-administered, high drug-loaded microneedle patch were prepared successfully, which appeared to be highly promising in preserving cognition by transdermal administration.

Crisis adrenal asociada al uso de modafinilo / Adrenal crisis associated with modafinil use

Resumen La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser des encadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Abstract Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treat ment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembo lism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose re placement in subjects receiving metabolism-inducing drugs.

Drugs for patients with epilepsy and excessive daytime sleepiness.

Excessive daytime sleepiness (EDS) and attentional deficits are often observed in people with epilepsy. They may be the consequence of seizures and subclinical discharges as well as of comorbid conditions as obstructive sleep apnea/hypopnea syndrome (OSAS), attention deficit hyperactivity disorder (ADHD), or other less frequent disorders. Excessive daytime sleepiness may also be caused or worsened by antiseizure medications (ASMs). Several meta-analyses suggested that lamotrigine, lacosamide, and perhaps eslicarbazepine are less sedative than other traditional and new ASMs and, in patients prone to somnolence, might be preferred over ASMs with more sedative properties. In patients with severe EDS and/or ADHD, advantages and risks of a treatment with a psychostimulant need to be considered. Methylphenidate, modafinil, armodafinil, pitolisant, and solriamfetol are authorized for use in ADHD and EDS in patients with narcolepsy and some of them also in OSAS. These agents are off-label for the treatment of EDS associated with epilepsy. They do not have proconvulsant effects, although there are several possible risks for patients with epilepsy. The risks of cardiovascular events and psychiatric symptoms should be carefully evaluated as such disorders can coexist with epilepsy and be triggered by these agents. Finally, combination of psychostimulants with ASMs may be associated with several pharmacokinetic drug-drug interactions.

Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea.

STUDY OBJECTIVES: Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment comparison meta-analysis was performed to compare efficacy and safety of medications (solriamfetol, modafinil, and armodafinil) approved to treat excessive daytime sleepiness associated with obstructive sleep apnea. METHODS: Efficacy and safety measures assessed in this indirect treatment comparison included Epworth Sleepiness Scale (ESS), 20-minute Maintenance of Wakefulness Test (MWT20), Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), and incidence of treatment-emergent adverse events (any, serious, or leading to discontinuation). RESULTS: A systematic literature review identified 6 parallel-arm, placebo-controlled randomized controlled trials that randomized 1,714 total participants to placebo, solriamfetol, modafinil, or armodafinil. In this indirect treatment comparison, all comparators were associated with greater improvements than placebo on the ESS, MWT20, and CGI-C after 4, 8, and 12 weeks of treatment. Relative to comparators and placebo at 12 weeks, solriamfetol at 150 mg or 300 mg had the highest probabilities of improvement in the ESS, MWT20, and CGI-C. Modafinil (200 or 400 mg) and solriamfetol (150 or 300 mg) were associated with greater improvement on the FOSQ than placebo at 12 weeks. Less than 2% of patients using placebo or comparators experienced serious or discontinuation-related treatment-emergent adverse events. CONCLUSIONS: The results of this indirect treatment comparison show 12 weeks of treatment with solriamfetol, modafinil, and armodafinil resulted in varying levels of improvement on the ESS, MWT20, and CGI-C and similar safety risks in participants with excessive daytime sleepiness associated with obstructive sleep apnea. CITATION: Ronnebaum S, Bron M, Patel D, et al. Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea. J Clin Sleep Med. 2021;17(12):2543-2555.

Effects of armodafinil nanocrystal nasal hydrogel on recovery of cognitive function in sleep-deprived rats.

Armodafinil is typically used in clinical practice to maintain cognition and wakefulness in patients suffering from sleep deprivation. However, its poor water solubility and large dosage limit its effective application. Herein, we formulated armodafinil in a nanocrystal hydrogel (NCsG) with appropriate fluidity and viscosity, capable of rapidly dissolving after staying in the nasal cavity for > 4 h and then penetrating the mucosa as quickly as possible in vitro. We found that armodafinil NCsG was biologically safe, as it had no visible ciliary toxicity, as well as extremely stable due to the existence of intermolecular hydrogen-bonding forces. Nasal administration of armodafinil NCsG proved to be more efficient and targeted than oral administration due to its preferential absorption in plasma and more-concentrated distribution in the brain. In addition, compared with the model group, sleep-deprived rats treated with NCsG undergoing Morris water maze (MWM) behavioral experiments had shorter escape latency and much more shuttle times across the platform. Meanwhile, in the open-field test (OFT), these same rats had longer periods of movement in the center, longer time spent upright, and lower anxiety, which clearly demonstrated improved cognitive awareness and wakefulness after intranasal administration. Moreover, we speculated that armodafinil NCsG had a protective effect on hippocampal neurons in Cortical Area 1 (CA1), which is closely related to cognitive function, by upregulating brain-derived neurotrophic factor (BDNF) protein expression. Consequently, the intranasal administration of armodafinil NCsG could serve as a promising integrated-control measure for sleep deprivation.

A scoping review of the evidence for the impact of pharmacological and non-pharmacological interventions on shift work related sleep disturbance in an occupational setting.

Background: Shift work is essential in society but can be detrimental to health and quality of life and is associated with decreased productivity and increased risk of accidents. Interventions to reduce these consequences are needed, but the extent and range of trial evidence for interventions for those most affected by their shift-work schedules is unclear. We therefore carried out a scoping review to assess the availability of evidence to inform the development and evaluation of future interventions. Methods: We aimed to identify clinical trials of any intervention for shift work-related sleep disturbance that included a comparator group, where the intervention was delivered in an occupational setting. We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, EMBASE, Medline and Science Citation Index from inception to 30 th March 2020 for relevant citations. Citations were screened by two independent reviewers, a third reviewer resolved disagreements. Data were extracted by two independent reviewers. Results: From 1250 unique citations, 14 studies met inclusion criteria for comparative trials of treatment in an occupational setting. There were five trials of hypnotics, five trials of stimulants, and four trials of non-pharmacological therapies (cognitive behavioural therapy, light therapy, aromatherapy and herbal medicine). Outcomes included sleep parameters, day-time sleepiness, and quality of life. There were no consistently reported outcomes across trials. Conclusions: Interventions fell into three distinct groups investigated in distinct time periods without progression from efficacy trials to wider-scale interventions. The lack of consistent patient-reported outcome measures limits synthesising findings. Some trials focussed on optimising sleep, others on reducing wake-time sleepiness. Adequately powered trials of existing interventions are needed, with the development and testing of novel combination treatments in patients with well-defined shift work sleep disorder. A core set of clinically relevant outcomes will develop and standardise the evidence-base for shift work sleep disorder.

Adjunctive treatment with psychostimulants and stimulant-like drugs for resistant bipolar depression: a systematic review and meta-analysis.

BACKGROUND: Depression is considered to be the most difficult to treat phase of bipolar disorder as patients experience residual symptoms causing long-term disability. This work aims to explore the role of add-on stimulant and stimulant-like medication in resistant bipolar depression patients. METHODS: Systematic review of add-on stimulants and stimulant-like drugs in resistant bipolar depression by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Analysis was performed using the random-effects models. Heterogeneity was evaluated with Cochran's Q and I2 statistics. RESULTS: Six randomized controlled trials of add-on modafinil, armodafinil, and lisdexamphetamine (LDX) (n = 813) vs placebo (n = 815) in the treatment of resistant bipolar depression were included. These drugs were more likely to induce remission from an episode of resistant bipolar depression (relative risk [RR] = 1.37; 95% confidence interval [CI]: 1.06-1.77; number needed to treat for an additional beneficial outcome = 16). Moreover, they did not induce more dropouts than placebo (RR = 1.04; 95% CI: 0.91-1.18), nor did they increase the risk of adverse effects (53/772 vs 41/771) at the end of treatment (RR = 1.30; 95% CI: 0.81-2.10; number needed to treat for an additional harmful outcome = 62). Suicidality and manic switch were not affected by active treatment. Heterogeneity was low (Cochran's Q: P > .05), but sometimes with a large CI. CONCLUSIONS: LDX, modafinil, and armodafinil seem to offer a reasonably well-tolerated and safe treatment in resistant bipolar depression. Treatment guidelines should, therefore, be revised to include these medications earlier in the therapeutic algorithm for resistant acute bipolar depression. Further research is, however, necessary for the elucidation of the clinical usefulness of these and other similar compounds.

Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects.

Modafinil is a nonamphetamine nootropic drug with an increasingly therapeutic interest due to its different sites of action and behavioral effects in comparison to cocaine or amphetamine. A review of modafinil (and of its prodrug adrafinil and its R-enantiomer armodafinil) chemical, pharmacokinetic, pharmacodynamic, toxicological, clinical and forensic aspects was performed, aiming to better understand possible health problems associated to its unconscious and unruled use. Modafinil is a racemate metabolized mainly in the liver into its inactive acid and sulfone metabolites, which undergo primarily renal excretion. Although not fully clarified, major effects seem to be associated to inhibition of dopamine reuptake and modulation of several other neurochemical pathways, namely noradrenergic, serotoninergic, orexinergic, histaminergic, glutamatergic and GABAergic. Due its wake-promoting effects, modafinil is used for the treatment of daily sleepiness associated to narcolepsy, obstructive sleep apnea and shift work sleep disorder. Its psychotropic and cognitive effects are also attractive in several other pathologies and conditions that affect sleep structure, induce fatigue and lethargy, and impair cognitive abilities. Additionally, in health subjects, including students, modafinil is being used off-label to overcome sleepiness, increase concentration and improve cognitive potential. The most common adverse effects associated to modafinil intake are headache, insomnia, anxiety, diarrhea, dry mouth and raise in blood pressure and heart rate. Infrequently, severe dermatologic effects in children, including maculopapular and morbilliform rash, erythema multiforme and Stevens-Johnson Syndrome have been reported. Intoxication and dependence associated to modafinil are uncommon. Further research on effects and health implications of modafinil and its analogs is steel needed to create evidence-based policies.

Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: A meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of the dopaminergic-enhancing agent modafinil/armodafinil (MoArm) as adjunctive treatment for bipolar depression. METHODS: A comprehensive search of major electronic databases was conducted to identify randomized controlled trials (RCTs) of adjunctive MoArm that included patients with bipolar I (BP-I) or bipolar II (BP-II) depression. Data for response/remission and all-cause discontinuation were analyzed. Effect size was summarized by relative risk (RR) using a random effect model. RESULTS: Of 58 studies, five RCTs (N = 795 drug, N = 792 placebo) met inclusion criteria. Four armodafinil studies included only BP-I patients and one modafinil study included both bipolar subtypes with limited heterogeneity (I2  = 34%, P = .19; I2  = 18%, P = .30). Compared to placebo, augmentation with MoArm was associated with significantly greater rates of treatment response (RR, 1.18; 95% CI, 1.01-1.37; P = .03) and remission (RR, 1.38; 95% CI, 1.10-1.73; P = .005). All-cause discontinuation was not different than placebo (RR, 1.08; 95% CI, 0.89-1.30; P = .45) with no evidence of increased risk of mood switch or suicide attempts with MoArm (RR, 0.99; 95% CI, 0.39-2.5; P = .98; RR, 1.02; 95% CI, 0.37-2.85; P = .97). CONCLUSION: This narrower scope meta-analysis of one drug for one disease suggests that adjunctive MoArm may represent a novel therapeutic intervention. Further studies delineating the subtypes of bipolar depression responsive to these novel dopaminergic-enhancing agents are encouraged.

Excessive sleepiness in shift work disorder: a narrative review of the last 5 years.

INTRODUCTION: Shift work sleep disorder (SWSD), also known as shift work disorder (SWD), is a circadian rhythm sleep disorder characterized by insomnia and/or excessive sleepiness, associated with a recurring work schedule that overlaps the usual time designated for sleeping. PURPOSE: This article aims to provide a narrative review of the pharmacological trials conducted on SWD in the last 5 years, to better address safety and health issues inherent to this disorder. METHODS: An electronic literature search was conducted using PubMed. All eligible randomized controlled trials (RCTs) and cross-over RCTs with employees undertaking shift work (including night shifts) were considered, yielding three articles. RESULTS: All three studies showed the efficacy of armodafinil in improving subjective and objective sleepiness, clinical conditions, and global functioning regardless of shift duration. Both performance and driving simulator performance tests administered during the night shift bore better results following armodafinil administration than after placebo. However, armodafinil only reduced subjective disability in individuals working more than 9 h; furthermore, even after armodafinil, alertness was reduced but not normalized. CONCLUSION: These studies underscore the importance of preventing and/or minimizing disturbances due to shift work. This may be achieved through various strategies, such as the employer's commitment to adopt ergonomic criteria in shift design and to implement work-environment interventions like controlled bright light. Health personnel is of pivotal importance to detect potential factors of intolerance to shift work or early symptoms of SWD. Additional and improved studies are needed to further evaluate the effectiveness and safety of both pharmacological and non-pharmacological interventions.

Preparation and characterization of armodafinil nanocrystals / 国际药学研究杂志

Objective: To prepare and characterize armodafinil nanocrystals, and investigate its release in vitro. Methods: Anti-solvent precipitation technology was used to prepare the armodafinil nanocrystals. The formulation and preparation process of the armodafinil nanosuspension were optimized by the orthogonal design experiment with the average particle diameter as the evaluation index. The suspension was prepared into nanocrystals by freeze-drying technology. The particle size and the polydispersity coefficient of the armodafinil nanocrystals were measured. The X-ray powder diffraction method was used to investigate the crystal form transition of the armodafinil. The dissolution behavior of the armodafinil nanocrystals and raw substances was investigated and compared with each other by the slurry method. Results: The prepared amodafinil nanocrystals had a quite uniformly distributed particle size around 100 nm. The nanocrystals appeared to be in irregular form. After amodafinil was made into nanocrystals, the solubility and dissolution were significantly improved. The crystal form of amodafinil significantly changed after nanocrystallization. Conclusion: The preparation of a small and uniformly distributed particle size of amodafinil nanocrystals could significantly improve the dissolution performance of amodafinil, which is beneficial to improving the bioavailability of insoluble drugs.