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The Journal of Clinical Psychiatry Mar 2011Bipolar II disorder is a common, recurrent, and disabling psychiatric illness, and yet little is known about how best to treat it. The pressing clinical need for... (Review)
Review
OBJECTIVE
Bipolar II disorder is a common, recurrent, and disabling psychiatric illness, and yet little is known about how best to treat it. The pressing clinical need for evidence-based approaches to the treatment of bipolar II disorder, coupled with recent publication of pertinent studies, calls for an updated review of this literature. This review focuses on a critical examination of the evidence supporting the efficacy of treatments for acute depressive episodes in bipolar II disorder.
DATA SOURCES
A MEDLINE (via Ovid) search of journals, covering the period from January 1950 to January 2009, was performed to identify relevant studies. Keywords used were bipolar II disorder, bipolar disorder, bipolar depression, and pharmacotherapy. Studies were further limited to those that were in adult samples, published in peer-reviewed journals, and written in English.
STUDY SELECTION
We examined all randomized trials evaluating the use of pharmacotherapy in the treatment of acute bipolar II depression. Studies with mixed samples of bipolar I and II or bipolar II and unipolar depression were examined as well. Twenty-one randomized trials were identified and reviewed.
DATA EXTRACTION
Therapeutic agents were rated according to the quality of evidence supporting their efficacy as treatments for bipolar II depression.
DATA SYNTHESIS
Ninety percent of relevant trials were published after 2005. Quetiapine was judged as having compelling evidence supporting its efficacy. Lithium, antidepressants, and pramipexole were judged as having preliminary support for efficacy. Lamotrigine was considered to have mixed support.
CONCLUSIONS
Although progress has been made, further research on bipolar II depression is warranted.
Topics: Acute Disease; Antidepressive Agents; Antimanic Agents; Benzhydryl Compounds; Benzothiazoles; Bipolar Disorder; Dibenzothiazepines; Humans; Lamotrigine; Lithium Compounds; Modafinil; Pramipexole; Quetiapine Fumarate; Triazines
PubMed: 20816033
DOI: 10.4088/JCP.09r05192gre -
Journal of Psychiatric Research Jan 2015We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of modafinil or armodafinil (ar/mod) augmentation in schizophrenia. We searched... (Meta-Analysis)
Meta-Analysis Review
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of modafinil or armodafinil (ar/mod) augmentation in schizophrenia. We searched PubMed, clinical trial registries, reference lists, and other sources for parallel group, placebo-controlled RCTs. Our primary outcome variable was the effect of ar/mod on negative symptom outcomes. Eight RCTs (pooled N = 372; median duration, 8 weeks) met our selection criteria. Ar/mod (200 mg/day) significantly attenuated negative symptom ratings (6 RCTs; N = 322; standardized mean difference [SMD], -0.26; 95% CI, -0.48 to -0.04). This finding remained similar in all but one sensitivity analysis - when the only RCT in acutely ill patients was excluded, the outcome was no longer statistically significant (SMD, -0.17; 95% CI, -0.51 to 0.06). The absolute advantage for ar/mod was small: just 0.27 points on the PANSS-N (6 RCTs). Ar/mod attenuated total psychopathology ratings (7 RCTs; N = 342; SMD, -0.23; 95% CI, -0.45 to -0.02) but did not influence positive symptom ratings (5 RCTs; N = 302; mean difference, -0.58; 95% CI, -1.71 to 0.55). Although data were limited, cognition, fatigue, daytime drowsiness, adverse events, and drop out rates did not differ significantly between ar/mod and placebo groups. Fixed and random effects models yielded similar results. There was no heterogeneity in all but one analysis. Publication bias could not be tested. We conclude that ar/mod (200 mg/day) is safe and well tolerated in the short-term treatment of schizophrenia. Ar/mod reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia.
Topics: Adult; Antipsychotic Agents; Benzhydryl Compounds; Cognition; Fatigue; Female; Humans; Male; Middle Aged; Modafinil; Randomized Controlled Trials as Topic; Schizophrenia; Sleep Stages; Wakefulness-Promoting Agents
PubMed: 25306261
DOI: 10.1016/j.jpsychires.2014.09.013 -
Drug and Alcohol Dependence Feb 2015Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like... (Review)
Review
BACKGROUND
Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies.
METHODS
This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal-chemical perspective.
RESULTS
Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of Drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters.
CONCLUSIONS
Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse.
Topics: Animals; Benzhydryl Compounds; Benztropine; Central Nervous System Stimulants; Cocaine; Dopamine Plasma Membrane Transport Proteins; Drug Delivery Systems; Humans; Ligands; Modafinil; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 25548026
DOI: 10.1016/j.drugalcdep.2014.12.005 -
Neuropsychopharmacology : Official... Jan 2018We previously reported that acute and selective activation of GABA-releasing parafacial zone (PZ) neurons in behaving mice produces slow-wave-sleep (SWS), even in the...
We previously reported that acute and selective activation of GABA-releasing parafacial zone (PZ) neurons in behaving mice produces slow-wave-sleep (SWS), even in the absence of sleep deficit, suggesting that these neurons may represent, at least in part, a key cellular substrate underlying sleep drive. It remains, however, to be determined if PZ neurons actively maintain, as oppose to simply gate, SWS. To begin to experimentally address this knowledge gap, we asked whether activation of PZ neurons could attenuate or block the wake-promoting effects of two widely used wake-promoting psychostimulants, armodafinil or caffeine. We found that activation of PZ neurons completely blocked the behavioral and electrocortical wake-promoting action of armodafinil. In some contrast, activation of PZ neurons inhibited the behavioral, but not electrocortical, arousal response to caffeine. These results suggest that: (1) PZ neurons actively maintain, as oppose to simply gate, SWS and cortical slow-wave-activity; (2) armodafinil cannot exert its wake-promoting effects when PZ neurons are activated, intimating a possible shared circuit/molecular basis for mechanism of action; (3) caffeine can continue to exert potent cortical desynchronizing, but not behavioral, effects when PZ neurons are activated, inferring a shared and divergent circuit/molecular basis for mechanism of action; and 4) PZ neurons represent a key cell population for SWS induction and maintenance.
Topics: Animals; Behavior, Animal; Benzhydryl Compounds; Caffeine; Central Nervous System Stimulants; Electrocorticography; Electromyography; GABAergic Neurons; Male; Medulla Oblongata; Mice; Modafinil; Sleep Stages
PubMed: 28722021
DOI: 10.1038/npp.2017.152 -
Journal of Cancer Survivorship :... Jun 2017Cancer-related insomnia is associated with diminished quality of life (QOL), suggesting that improvement in insomnia may improve QOL in cancer survivors. Cognitive... (Randomized Controlled Trial)
Randomized 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.
Topics: Adult; Aged; Benzhydryl Compounds; Cognitive Behavioral Therapy; Female; Humans; Male; Middle Aged; Modafinil; Neoplasms; Quality of Life; Sleep Initiation and Maintenance Disorders; Survivors; Treatment Outcome; Wakefulness-Promoting Agents
PubMed: 28105576
DOI: 10.1007/s11764-017-0597-0 -
Dementia and Geriatric Cognitive... 2017Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB.
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.
Topics: Aged; Benzhydryl Compounds; Disorders of Excessive Somnolence; Drug Monitoring; Female; Humans; Lewy Body Disease; Male; Modafinil; Neurologic Examination; Outpatients; Pilot Projects; Polysomnography; Quality of Life; Treatment Outcome; Wakefulness; Wakefulness-Promoting Agents
PubMed: 28448998
DOI: 10.1159/000471507 -
Sleep Medicine Dec 2023Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and...
STUDY OBJECTIVES
Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil.
METHODS
Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to "bridge" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients' diaries.
RESULTS
41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly.
CONCLUSION
Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil.
CLINICAL TRIAL REGISTRATION NUMBER
Clinical Trials.gov Identifier NCT05321355.
Topics: Humans; Modafinil; Quality of Life; Narcolepsy; Piperidines; Disorders of Excessive Somnolence; Benzhydryl Compounds
PubMed: 37839272
DOI: 10.1016/j.sleep.2023.10.005 -
The Cochrane Database of Systematic... Jan 2023Fatigue is the most commonly reported symptom in people with advanced cancer. Cancer-related fatigue (CRF) is pervasive and debilitating, and can greatly impact quality... (Review)
Review
BACKGROUND
Fatigue is the most commonly reported symptom in people with advanced cancer. Cancer-related fatigue (CRF) is pervasive and debilitating, and can greatly impact quality of life (QoL). CRF has a highly variable clinical presentation, likely due to a complex interaction of multiple factors. Corticosteroids are commonly used to improve CRF, but the benefits are unclear and there are significant adverse effects associated with long-term use. With the increasing survival of people with metastatic cancer, the long-term effects of medications are becoming increasingly relevant. Since the impact of CRF can be immensely debilitating and can negatively affect QoL, its treatment warrants further review.
OBJECTIVES
To determine the benefits and harms of corticosteroids compared with placebo or an active comparator in adults with advanced cancer and CRF.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL, Science Citation Index (ISI Web of Science), LILACS, and two clinical trial registries from inception to 18 July 2022. SELECTION CRITERIA: We included randomised controlled trials in adults aged ≥18 years. We included participants with advanced cancer who were suffering from CRF. We included trials that randomised participants to corticosteroids at any dose, by any route, administered for the relief of CRF; compared to placebo or an active comparator, including supportive care or non-pharmacological treatments.
DATA COLLECTION AND ANALYSIS
Three review authors independently assessed titles identified by the search strategy; two review authors assessed risk of bias; and two extracted data. We extracted the primary outcome of participant-reported fatigue relief using validated scales and secondary outcomes of adverse events, serious adverse events and QoL. We calculated the risk ratio with 95% confidence intervals (CIs) between groups for dichotomous outcomes. We measured arithmetic mean and standard deviation, and reported the mean difference (MD) with 95% CI between groups for continuous outcomes. We used standardised mean difference (SMD) with 95% CIs when an outcome was measured with different instruments measuring the same construct. We used a random-effects model to meta-analyse the outcome data. We rated the certainty of the evidence using GRADE and created two summary of findings tables. MAIN RESULTS: We included four studies with 297 enroled participants; data were available for only 239 participants. Three studies compared corticosteroid (equivalent ≤ 8 mg dexamethasone) to placebo. One study compared corticosteroid (dexamethasone 4 mg) to an active comparator (modafinil 100 mg). There were insufficient data to evaluate subgroups, such as dose and duration of treatment. One study had a high risk of performance and detection bias due to lack of blinding, and one study had a high risk of attrition bias. Otherwise, we assessed risks of bias as low or unclear. Comparison 1: corticosteroids compared with placebo Participant-reported fatigue relief The was no clear difference between corticosteroids and placebo (SMD -0.46, 95% CI -1.07 to 0.14; 3 RCTs, 165 participants, very low-certainty evidence) for relief of fatigue at one week of the intervention. We downgraded the certainty of the evidence three times for study limitations due to unclear risk of bias, imprecision, and inconsistency. Adverse events There was no clear difference in the occurrence of adverse events between groups, but the evidence is very uncertain (3 RCTs, 165 participants; very low-certainty evidence). Serious adverse events There was no clear difference in the occurrence of serious adverse events between groups, but the evidence is very uncertain (2 RCTs, 118 participants; very low-certainty evidence). Quality of lIfe One study reported QoL at one week using the Edmonton Symptom Assessment System (ESAS) well-being, and found no clear difference in QoL between groups (MD -0.58, 95% CI -1.93 to 0.77). Another study measured QoL using the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs (QoL-ACD), and found no clear difference between groups. There was no clear difference between groups for either study, but the evidence is very uncertain (2 RCTs, 118 participants; very low-certainty evidence). Comparison 2: corticosteroids compared with active comparator (modafinil) Participant-reported fatigue relief There was improvement in fatigue from baseline to two weeks in both groups (modafinil MD 10.15, 95% CI 7.43 to 12.87; dexamethasone MD 9.21, 95% CI 6.73 to 11.69), however no clear difference between the two groups (MD -0.94, 95% CI -4.49 to 2.61; 1 RCT, 73 participants, very low-certainty evidence). We downgraded the certainty of the evidence three times for very serious study limitations and imprecision. Adverse events There was no clear difference in the occurrence of adverse events between groups, but the evidence is very uncertain (1 RCT, 73 participants; very low-certainty evidence). Serious adverse events There were no serious adverse events reported in either group (1 RCT, 73 participants; very low-certainty evidence). Quality of lIfe One study measured QoL at two weeks, using the ESAS-well-being. There was marked improvement in QoL from baseline in both groups (modafinil MD -2.43, 95% CI -2.88 to -1.98; dexamethasone MD -2.16, 95% CI -2.68 to -1.64), however no clear difference between the two groups (MD 0.27, 95% CI -0.39 to 0.93; 1 RCT, 73 participants, very low-certainty evidence).
AUTHORS' CONCLUSIONS
There is insufficient evidence to support or refute the use of systemic corticosteroids in adults with cancer and CRF. We included four small studies that provided very low-certainty of evidence for the efficacy of corticosteroids in the management of CRF. Further high-quality randomised controlled trials with larger sample sizes are required to determine the effectiveness of corticosteroids in this setting.
Topics: Humans; Adult; Adolescent; Quality of Life; Modafinil; Adrenal Cortex Hormones; Neoplasms; Dexamethasone; Fatigue
PubMed: 36688471
DOI: 10.1002/14651858.CD013782.pub2 -
Psychopharmacology Aug 2022Modafinil has been proposed as a potentially effective clinical treatment for neuropsychiatric disorders characterized by cognitive control deficits. However, the...
RATIONALE
Modafinil has been proposed as a potentially effective clinical treatment for neuropsychiatric disorders characterized by cognitive control deficits. However, the precise effects of modafinil, particularly on brain network functions, are not completely understood.
OBJECTIVES
To address this gap, we examined the effects of modafinil on resting-state brain activity in 30 healthy adults using microstate analysis. Electroencephalographic (EEG) microstates are discrete voltage topographies generated from resting-state network activity.
METHODS
Using a placebo-controlled, within-subjects design, we examined changes to microstate parameters following placebo (0 mg), low (100 mg), and high (200 mg) modafinil doses. We also examined the functional significance of these microstates via associations between microstate parameters and event-related potential indexes of conflict monitoring and automatic error processing (N2 and error-related negativity) and behavioral responses (accuracy and RT) from a subsequent flanker interference task.
RESULTS
Five microstates emerged following each treatment condition, including four canonical microstates (A-D). Modafinil increased microstate C proportion and occurrence regardless of dose, relative to placebo. Modafinil also decreased microstate A proportion and microstate B proportion and occurrence relative to placebo. These modafinil-related changes in microstate parameters were not associated with similar changes in flanker ERPs or behavior. Finally, modafinil made transitions between microstates A and B less likely and transitions from A and B to C more likely.
CONCLUSIONS
Previous fMRI work has correlated microstates A and B with auditory and visual networks and microstate C with a salience network. Thus, our results suggest modafinil may deactivate large-scale sensory networks in favor of a higher order functional network during resting-state in healthy adults.
Topics: Adult; Brain; Cognition Disorders; Cognitive Dysfunction; Electroencephalography; Humans; Modafinil
PubMed: 35471613
DOI: 10.1007/s00213-022-06149-x -
Tijdschrift Voor Psychiatrie 2010For more than two decades psychiatrists have known about and have promoted modafinil, a very promising stimulant that boosts wakefulness in cases of narcolepsy and also... (Review)
Review
BACKGROUND
For more than two decades psychiatrists have known about and have promoted modafinil, a very promising stimulant that boosts wakefulness in cases of narcolepsy and also enhances cognitive functions. At present, however, we must conclude that modafinil is hardly ever used to treat illness other than narcolepsy.
AIM
To review current attitudes and practice with regard to the use and efficacy of modafinil in the treatment of psychiatric disorders.
METHOD
Relevant placebo-controlled studies were retrieved via PubMed (Medline) and Web of Science.
RESULTS
Modafinil is used experimentally to treat ADHD, mood disorders, schizophrenia and substance-dependence. Compared to placebo, modafinil achieves positive but mainly variable results on different clinical and cognitive measures. It achieves results very rapidly, within a week, but over a period of time the results stabilise.
CONCLUSION
Modafinil is particularly successful in the treatment of ADHD, depression and cocaine-dependency on measures of attention and hyperactivity, fatigue and cocaine-use respectively. There is a need for further placebo-controlled trials with longer follow-up periods and larger sample size in order to ensure the safety of the product and to refine its area of efficacy.
Topics: Attention Deficit Disorder with Hyperactivity; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine-Related Disorders; Humans; Mental Disorders; Modafinil; Narcolepsy; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; Wakefulness
PubMed: 21064019
DOI: No ID Found