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.

Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management.

Excessive daytime sleepiness (EDS) affects approximately half of patients with obstructive sleep apnea (OSA) and can persist in some despite normalization of breathing, oxygenation, and sleep quality with primary OSA therapy, such as continuous positive airway pressure (CPAP). EDS is often overlooked and under discussed in the primary care setting and in the follow-up of CPAP-treated patients due to difficult assessment of such a multi-dimensional symptom. This review aims to provide suggestions for procedures that can be implemented into routine clinical practice to identify, evaluate, and manage EDS in patients treated for OSA, including how to appropriately use various self-report and objective assessments along the clinical pathway and options for pharmacotherapy. In addition, examples of when it is appropriate to refer a patient to a sleep specialist for evaluation are discussed.

Wake-Promoting and EEG Spectral Effects of Modafinil After Acute or Chronic Administration in the R6/2 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.

Solriamfetol for Excessive Sleepiness in Narcolepsy and Obstructive Sleep Apnea.

OBJECTIVE: The purpose of this article is to review the available clinical trial data that led to the Food and Drug Administration (FDA) approval of solriamfetol as well as its role in clinical practice. DATA SOURCES: A MEDLINE/PubMed search was conducted (January 2000 to February 2020) using the keyword solriamfetol to discover appropriate clinical trials. STUDY SELECTION AND DATA EXTRACTION: Articles were included that were published in the English language and related to the FDA approval of solriamfetol or provided novel information regarding this drug entity. DATA SYNTHESIS: The findings of the review show that solriamfetol may be a safe and effective option for the treatment of excessive sleepiness (ES) related to narcolepsy and obstructive sleep apnea (OSA). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Solriamfetol is distinguished from other stimulants in that it has lower binding affinity to dopamine and norepinephrine transporters and does not have the monoamine-releasing effects of amphetamines at usual therapeutic doses. Because of solriamfetol's unique mechanism of action, there may be a reduction in abuse potential compared with the other currently FDA-approved options. CONCLUSIONS: In clinical trials, solriamfetol has shown dose-dependent improvement in wakefulness over placebo and adds another option for clinicians when treating ES in narcolepsy and OSA.

Sleep and neurochemical modulation by cannabidiolic acid methyl ester in rats.

Cannabidiolic acid methyl ester (HU-580) is a more stable compound than cannabidiolic acid (CBDA) which has been shown to be effective in reducing nausea, anxiety, depression behaviors in animal models. Here we extend the investigation of this compound to determine its effect on the sleep-wake cycle in male Wistar rats. HU-580 dose-dependently (0.1, 1.0 or 100 µg/Kg, i.p.) prolonged wakefulness (W) and decreased slow wave sleep (SWS) duration whereas rapid eye movement sleep (REMS) showed no statistical change. In addition, the brain microdialysis probes either placed at nucleus accumbens (NAc) or into the basal forebrain in freely moving animals were used to evaluate the effects of HU-580 treatment on neurotransmitters related to the sleep-wake cycle modulation. HU-580 enhanced extracellular levels of dopamine, serotonin collected from NAc while adenosine and acetylcholine were increased in basal forebrain. In summary, HU-580 seems to possess wake-promoting pharmacological properties and enhances the levels of wake-related neurochemicals. This is the first report of effects of HU-580 on sleep modulation expanding the very limited existent data on the neurobiological effects of HU-580 on rats.

Returning to work after fatigue treatment and counseling in HIV/AIDS.

BACKGROUND: Employment rates for people with HIV/AIDS are low, compared to the general population. One widespread barrier is fatigue, accompanied by daytime sleepiness and a lack of stamina. Previous pharmacological studies have demonstrated improvement of fatigue-related symptoms without affecting work-related goal attainmentOBJECTIVE:In this pilot study, we sought to determine whether a pharmacologic-behavioral two-phase combined approach could facilitate returning to work. METHODS: HIV+ participants with fatigue were treated with armodafinil. If energy improved, 8 sessions of biweekly manualized Behavioral Activation (BA) counseling were added to medication maintenance. Outcome was assessed on a 3-point scale along with clinician and self-ratings. RESULTS: Of the 46 participants enrolled in BA, 15 (33%) did not complete all 8 sessions: 6 got jobs so they no longer needed counseling; 4 did not like BA, and 5 dropped out for reasons such as moving away or substance use relapse. Of the 46, 29 (63%) attained their vocational goal and showed significant changes on self-report scales. CONCLUSIONS: Our integrated treatment including armodafinil plus BA counseling significantly increased the success of achieving work-related goals. The two-phase medication plus counseling program was well-tolerated by participants and the manualized BA counseling was readily applied by counselors without advanced mental health training, making the method potentially feasible in community settings.

A double blind randomized placebo controlled pilot study of single-dose preoperative modafinil for functional recovery after general anesthesia in patients with obstructive sleep apnea.

BACKGROUND: We theorized that modafinil, an atypical psychomotor stimulant, utilized to improve daytime somnolence in patients with obstructive sleep apnea, would improve functional recovery after general anesthesia by improving time to extubation, post-anesthesia care unit (PACU) length of stay and subjective recovery after general anesthesia. METHODS: A double blind, randomized, placebo-controlled pilot study was performed. 102 patients with the diagnosis of obstructive sleep apnea (OSA) were randomized to receive either 200 mg of modafinil or placebo before general anesthesia. The trial was terminated for futility. The primary outcome was PACU length of stay between groups. Secondary functional metrics of improved post-anesthesia recovery were compared between groups. RESULTS: No difference between groups was found on the primary outcome of PACU length of stay (PACULOS). Emergence from general anesthesia was not significantly different when assessed by the time period between termination of volatile anesthetic and extubation. Similarly, no difference between groups was found in intraoperative bispectral index (BIS) values, postoperative pain scores or narcotic consumption (morphine equivalent units). In the post-anesthesia care unit, respiratory rate was increased and mean arterial pressure was lower in the modafinil group. CONCLUSIONS: Our results suggest that the use of single-dose preoperative modafinil may not improve functional recovery after general anesthesia in patients with the diagnosis of OSA. Further research is needed before use of atypical psychomotor stimulants in this surgical population.

Modafinil and the risk of cardiovascular events: Findings from three US claims databases.

PURPOSE: This study examined the potential risk of cardiovascular (CV) events associated with modafinil and the consistency of the risk estimates across databases. METHODS: A retrospective, inception cohort design of patients who initiated treatment with modafinil between 2006 and 2008 was used in three US health care claims databases. Modafinil users were matched with nonusers. Patients were further divided into two cohorts of obstructive sleep apnea (OSA) and non-OSA (NOSA) cohorts. Endpoints of interest, including myocardial infarction (MI), stroke, CV hospitalizations, and all-cause death, were assessed using incidence rates and Cox proportional hazard ratios (HRs), adjusted for potential confounding factors. RESULTS: The cohorts included a total of 175 524 patients in MarketScan CM; 77 266-in IMS LifeLink; and 8174-in MarketScan Medicaid. No increased risk for MI in the OSA and NOSA cohorts was observed across all three databases. The risks of CV hospitalization in the OSA and NOSA cohorts were not different between the modafinil users and nonusers, except for IMS LifeLink database where the HR was lower than one in the modafinil users compared with the nonusers (HR, 0.69; 95% confidence interval [CI], 0.54 to 0.87). For OSA patients with prior stroke, an adjusted HR of 1.96 (95% CI, 1.02 to 3.76) was observed for stroke among modafinil users compared with nonusers. Among the NOSA, the HRs for all-cause death in the OSA were inconsistent across databases. CONCLUSIONS: Except for few CV outcomes, applying one common protocol generated consistent risk estimates of CV events following modafinil use across cohorts and databases.

Systemic Injections of Cannabidiol Enhance Acetylcholine Levels from Basal Forebrain in Rats.

Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion. Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh). Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD. Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.

Cortico-Amygdala-Striatal Activation by Modafinil/Flecainide Combination.

Background: Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional communication as administration of a low dose of flecainide, an astroglial connexin inhibitor, enhanced the wake-promoting and procognitive activity of modafinil in rodents and healthy volunteers. The aim of this study is to investigate changes in glucose cerebral metabolism in rodents, induced by the combination of modafinil+flecainide low dose (called THN102). Methods: The impact of THN102 on brain glucose metabolism was noninvasively investigated using 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography imaging in Sprague-Dawley male rats. Animals were injected with vehicle, flecainide, modafinil, or THN102 and further injected with 18F-2-fluoro-2-deoxy-D-glucose followed by 60-minute Positron Emission Tomography acquisition. 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography images were coregistered to a rat brain template and normalized from the total brain Positron Emission Tomography signal. Voxel-to-voxel analysis was performed using SPM8 software. Comparison of brain glucose metabolism between groups was then performed. Results: THN102 significantly increased regional brain glucose metabolism as it resulted in large clusters of 18F-2-fluoro-2-deoxy-D-glucose uptake localized in the cortex, striatum, and amygdala compared with control or drugs administered alone. These regions, highly involved in the regulation of sleep-wake cycle, emotions, and cognitive functions were hence quantitatively modulated by THN102. Conclusion: Data presented here provide the first evidence of a regional brain activation induced by THN102, currently being tested in a phase II clinical trial in narcoleptic patients.

Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A.

Intranasal drug delivery is a noninvasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, nonhuman primates, and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective antinarcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH3-Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and nonhuman primate. Through positron emission tomography (PET) imaging of [11C]CH3-Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [125I]Orexin A indicated intranasal administration of Orexin A affords similar brain uptake when compared to intravenous administration across most brain regions, with possible increased brain uptake localized to the olfactory bulbs.

Modafinil in schizophrenia: is the risk worth taking?

Schizophrenia is a severe mental disorder characterised by positive and negative symptoms. Negative symptoms are difficult to treat and there is no specific treatment. In small trials, modafinil has been studied in association with antipsychotic treatment. We present three cases of its use; two have developed positive symptoms and one developed renal impairment. Further studies are needed to assess its usefulness in schizophrenia and safety in this group of patients.

Pharmacological management of narcolepsy with and without cataplexy.

INTRODUCTION: Narcolepsy is an orphan neurological disease and presents with sleep-wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life. Areas covered: This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies. First- and second-line options are discussed as well as combination therapies. In addition, treatment options for frequent coexisting co-morbidities and different phenotypes of narcolepsy are presented. Finally, this review considers potential future management strategies. Non-pharmacological approaches are important in the management of narcolepsy but will not be covered in this review. Expert opinion: Concise evaluation of symptoms and type of narcolepsy, coexisting co-morbidities and patients´ distinct needs is mandatory in order to identify a suitable, individual pharmacological treatment. First-line options include Modafinil/Armodafinil (for excessive daytime sleepiness, EDS), Sodium Oxybate (for EDS and/with cataplexy), Pitolisant (for EDS and cataplexy) and Venlafaxine (for cataplexy (off-label) and co-morbid depression). New symptomatic and causal treatment most probably will be completed by hypocretin-replacement and immune-modifying strategies.

Efficacy, Safety, and Tolerability of Armodafinil Therapy for Hypersomnia Associated with Dementia with Lewy Bodies: A Pilot Study.

BACKGROUND/AIMS: Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB. METHODS: We performed a 12-week pilot trial of armodafinil therapy (125-250 mg orally daily) in DLB outpatients with hypersomnia. The patients underwent neurologic examinations, a neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method. RESULTS: Of 20 participants, 17 completed the protocol. The median age was 72 years, most of the participants were men (80%), and most had spouses as caregivers. The Epworth Sleepiness Scale (p < 0.001), Maintenance of Wakefulness Test (p = 0.003), and Clinical Global Impression of Change (p < 0.001) scores improved at week 12. The Neuropsychiatric Inventory total score (p = 0.003), visual hallucinations (p = 0.003), and agitation (p = 0.02) improved at week 4. Caregiver overall quality of life improved at week 12 (p = 0.004). No adverse events occurred. CONCLUSION: These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies for managing hypersomnolence in these patients.

MIDAS (Modafinil in Debilitating Fatigue After Stroke): A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial.

BACKGROUND AND PURPOSE: This study aimed to assess the efficacy of modafinil, a wakefulness-promoting agent in alleviating post-stroke fatigue ≥3 months after stroke. We hypothesized that 200 mg of modafinil daily for 6 weeks would result in reduced symptoms of fatigue compared with placebo. METHODS: This single-center phase 2 trial used a randomized, double-blind, placebo-controlled, crossover design. The key inclusion criterion was a multidimensional fatigue inventory score of ≥60. Patients were randomized to either modafinil or placebo for 6 weeks of therapy, then after a 1 week washout period swapped treatment arms for a second 6 weeks of therapy. The primary outcome was the multidimensional fatigue inventory; secondary outcomes included the Montreal cognitive assessment, the Depression, Anxiety, and Stress Scale (DASS), and the Stroke-Specific Quality of Life (SSQoL) scale. The multidimensional fatigue inventory is a self-administered questionnaire with a range of 0 to 100. Treatment efficacy was assessed using linear regression by estimating within-person, baseline-adjusted differences in mean outcomes after therapy. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000350527). RESULTS: A total of 232 stroke survivors were screened and 36 were randomized. Participants receiving modafinil reported a significant decrease in fatigue (multidimensional fatigue inventory, -7.38; 95% CI, -21.76 to -2.99; P<0.001) and improved quality of life (SSQoL, 11.81; 95% CI, 2.31 to 21.31; P=0.0148) compared with placebo. Montreal cognitive assessment and DASS were not significantly improved with modafinil therapy during the study period (P>0.05). CONCLUSIONS: Stroke survivors with nonresolving fatigue reported reduced fatigue and improved quality of life after taking 200 mg daily treatment with modafinil. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368268. Unique identifier: ACTRN12615000350527.

Effects of cognitive behavioral therapy for insomnia and armodafinil on quality of life in cancer survivors: a randomized placebo-controlled trial.

PURPOSE: Cancer-related insomnia is associated with diminished quality of life (QOL), suggesting that improvement in insomnia may improve QOL in cancer survivors. Cognitive behavioral therapy for insomnia (CBT-I) has been shown to improve insomnia, but less is known regarding its effect on QOL and whether improvement in insomnia corresponds to improved QOL. The present analysis examines the effects of CBT-I, with and without armodafinil, on QOL both directly and indirectly through improvements of insomnia. METHODS: This is an analysis of 95 cancer survivors for a specified secondary aim of a four-arm randomized controlled trial assessing the combined and individual effects of CBT-I and armodafinil to improve insomnia. QOL and insomnia severity were assessed before, during the intervention, at post-intervention, and 3 months later by Functional Assessment of Cancer Therapy-General and Insomnia Severity Index, respectively. RESULTS: Mean change in QOL from pre- to post-intervention for CBT-I + placebo, CBT-I + armodafinil, armodafinil, and placebo was 9.6 (SE = 1.8; p < 0.0001), 11.6 (SE = 1.8; p < 0.0001), -0.2 (SE = 3.2; p = 0.964), and 3.3 (SE = 2.0; p = 0.124), respectively. ANCOVA controlling for pre-intervention scores showed that participants receiving CBT-I had significantly improved QOL at post-intervention compared to those not receiving CBT-I (p < 0.0001, effect size = 0.57), with benefits being maintained at the 3-month follow-up. Path analysis revealed that this improvement in QOL was due to improvement in insomnia severity (p = 0.002), and Pearson correlations showed that changes in QOL from pre- to post-intervention were significantly associated with concurrent changes in insomnia severity (r = -0.56; p < 0.0001). Armodafinil had no effect on QOL for those who did or did not receive it (p = 0.976; effect size = -0.004). CONCLUSION: In cancer survivors with insomnia, CBT-I resulted in clinically significant improvement in QOL via improvement in insomnia. This improvement in QOL remained stable even 3 months after completing CBT-I. IMPLICATIONS FOR CANCER SURVIVORS: Considering the high prevalence of insomnia and its detrimental impact on QOL in cancer survivors and the effectiveness of CBT-I in alleviating insomnia, it is important that evidence-based non-pharmacological sleep interventions such as CBT-I be provided as an integral part of cancer care.

Oral modafinil facilitates intracranial self-stimulation in rats: comparison with methylphenidate.

Modafinil is a low-potency inhibitor of dopamine transporters (DAT) approved clinically to promote wakefulness. In most procedures used for abuse-liability assessment, modafinil produces effects similar to those of abused DAT inhibitors such as cocaine and methylphenidate, although modafinil often shows lower effectiveness. However, modafinil has failed to maintain drug self-administration or produce conditioned place preferences in rats. The low potency and poor solubility of modafinil complicate its delivery by parenteral routes of administration commonly used in rats, and this may contribute toward negative results. This study evaluated the effects of orally administered modafinil in rats using an assay of intracranial self-stimulation (ICSS) that has been used to examine the effects of other DAT inhibitors. Adult male Sprague-Dawley rats equipped with electrodes in the medial forebrain bundle responded for pulses of brain stimulation that varied across a range of frequencies (158-56 Hz) during daily behavioral sessions. Modafinil (20-600 mg/kg, orally) and methylphenidate (1.0-10 mg/kg, intraperitoneally; 3.2-32 mg/kg, orally) produced dose-dependent and time-dependent facilitation of ICSS, an effect produced by abused DAT inhibitors and other classes of abused drugs. These results are in agreement with other evidence for stimulant-like abuse liability of modafinil and show the sensitivity of ICSS to orally administered drug.

Modafinil alters decision making based on feedback history - a randomized placebo-controlled double blind study in humans.

Modafinil is becoming increasingly popular as a cognitive enhancer. Research on the effects of modafinil on cognitive function have yielded mixed results, with negative findings for simple memory and attention tasks and enhancing effects for more complex tasks. In the present study we examined whether modafinil, due to its known effect on the dopamine level in the striatum, alters feedback-related choice behaviour. We applied a task that separately tests the choice of previously rewarded behaviours (approach) and avoidance of previously punished behaviours. 18 participants received a single dose of 200 mg modafinil. Their performance was compared to a group of 22 participants who received placebo in a double-blind design. Modafinil but not placebo induced a significant bias towards approach behaviour as compared to the frequency of avoidance behaviour. General attention, overall feedback-based acquisition of choice behaviour and reaction times in high vs low conflict choices were not significantly affected by modafinil. This finding suggests that modafinil has a specific effect on dopamine-mediated choice behaviour based on the history of feedback, while a contribution of noradrenaline is also conceivable. The described change in decision making cannot be considered as cognitive enhancement, but might rather have detrimental effects on decisions in everyday life.

Long-term safety and efficacy of armodafinil in bipolar depression: A 6-month open-label extension study.

BACKGROUND: Safe/well-tolerated treatments for bipolar I depression remain limited. We assessed safety/tolerability of adjunctive open-label armodafinil, a wakefulness-promoting agent evaluated in 3 acute, controlled efficacy studies with variable efficacy results. METHODS: Completers of three 8-week, double-blind, placebo-controlled adjunctive armodafinil studies (150-200 mg/day added to ongoing stable maintenance doses of 1 or 2 protocol-defined mood stabilizers) in bipolar I depression could enter this 6-month, open-label extension study. Objectives included evaluation of safety/tolerability (primary) and efficacy (secondary). RESULTS: 867 patients enrolled; 863 received ≥1 dose of armodafinil and 506 (58%) completed the 6-month study. Headache, insomnia, and anxiety were the most common adverse events (AEs) reported, whereas akathisia, nausea, sedation/somnolence, and weight increase were uncommon. Mean measures assessing emergence of mania, anxiety, insomnia, or suicidality showed no worsening. Discontinuations due to AEs occurred in 57 (7%) patients. Serious AEs occurred in 27 (3%) patients and were considered treatment-related in 8 (1%) patients. Depressive symptoms improved over the 6 months, as did patient functioning. LIMITATIONS: Lack of placebo control. CONCLUSIONS: Adjunctive armodafinil was generally safe and well tolerated over 6 months of open-label treatment at 150-200 mg/day when taken with protocol-defined mood stabilizers for bipolar I depression. This 6-month open-label study suggested that armodafinil augmentation of bipolar maintenance therapies may have a favorable risk profile and may improve depressive symptoms in some patients with bipolar I depression.