The Influence of Migraine on Driving: Current Understanding, Future Directions, and Potential Implications of Findings.

OBJECTIVE: To review the published findings relevant to migraine and driving performance, with an intent to encourage discussion on research which may broaden understanding in this area and help educate healthcare providers and their patients. BACKGROUND: Motor vehicle crashes result in more than 35,000 deaths and more than 2 million injuries annually in the United States. Migraine is one of the most prevalent diseases in the world, and many symptoms associated with migraine attacks have the potential to negatively influence driving ability. METHODS: We reviewed the published findings related to migraine and driving performance. Study findings relevant to symptoms of migraine and their potential effect on driving were also reviewed. This required a more expansive exploration of the literature beyond migraine, for example, review of the literature relating to the effect of pain, sleepiness, visual disturbances, or vertigo on driving. Finally, the potential effects of treatment for migraine on driving were reviewed. RESULTS: Literature on the effect of migraine on driving performance is sparse and, in general published studies on the topic have a number of limitations. Based on review of the literature pertaining to other disorders, it seems feasible that some symptoms occurring as part of the migraine attack could impact driving performance, although formal study in this area is lacking. Many of the approved treatments for migraine have the potential to impact driving, yet this has not been specifically studied, and the extent to which these risks are communicated to patients is not clear. CONCLUSION: The impact of migraine on driving performance has been largely neglected, with few studies specifically designed to address the topic, and relevant studies were generally small with limited control of confounders. This area requires more focus, given a potential for impact on road safety.

Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine.

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Effects of lasmiditan on simulated driving performance: Results of two randomized, blinded, crossover studies with placebo and active controls.

OBJECTIVE: To evaluate the impact of lasmiditan, an oral, centrally-penetrant, selective serotonin 1F (5-HT1F ) receptor agonist developed for the acute treatment of migraine, on simulated driving. METHODS: Healthy adult volunteers enrolled in two randomized, placebo and active comparator-controlled, crossover studies. Study 1 (N = 90) tested lasmiditan (50-, 100-, 200-mg), alprazolam (1-mg), and placebo at 1.5 hr post-dose. Study 2 (N = 68) tested lasmiditan (100-, 200-mg), diphenhydramine (50-mg, administered 2 hr pre-assessments), and placebo at 8, 12 and 24 hr post-dose. Driving performance was assessed using a validated driving simulator employing a 100 km driving scenario. Standard deviation of lateral position (SDLP), a measure of lane position control, was the primary endpoint. RESULTS: Assay sensitivity was confirmed by increased SDLP for active comparators at 1.5- and 8-hr time points. Lasmiditan doses showed significant driving impairment versus placebo at 1.5 hr post-dose. Lasmiditan doses were non-inferior to placebo at 8 hr. Driving impairment was concentration-dependent at 1.5 hr but not at 8 hr. Common adverse events were central nervous system-related and mild-to-moderate in severity. CONCLUSIONS: Lasmiditan was associated with impaired simulated driving performance at 1.5 hr post-dose, but showed no clinically meaningful impairment at 8 hr post-dose.

Lasmiditan for acute treatment of migraine in patients with cardiovascular risk factors: post-hoc analysis of pooled results from 2 randomized, double-blind, placebo-controlled, phase 3 trials.

BACKGROUND: In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs. METHODS: SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects. RESULTS: In this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations. CONCLUSIONS: When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.

The Prevalence and Diagnostic Validity of Short-Duration Hypomanic Episodes and Major Depressive Episodes.

Current diagnostic criteria for a hypomanic episode, as outlined in both the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV and DSM-5), require a minimum duration of four consecutive days of symptoms of mood elevation. The 4-day criterion for duration of hypomania has been challenged as arbitrary and lacking empirical support, with many arguing that shorter-duration hypomanic episodes are highly prevalent and that those experiencing these episodes are clinically more similar to patients with bipolar disorder than to those with unipolar major depressive disorder. We review the current evidence regarding the prevalence, diagnostic validity, and longitudinal illness correlates of shorter-duration hypomanic episodes and summarize the arguments for and against broadening the diagnostic criteria for hypomania to include shorter-duration variants. Accumulating findings suggest that patients with major depressive episodes and shorter-duration hypomanic episodes represent a complex clinical phenotype, perhaps best conceptualized as being on the continuum between those with unipolar depressive episodes alone and those with DSM-5-defined bipolar II disorder. Further investigation is warranted, ideally involving large prospective, controlled studies, to elucidate the diagnostic and treatment implications of depression with shorter-duration hypomanic episodes.

Ixekizumab Is Effective in Subjects With Moderate to Severe Plaque Psoriasis With Significant Nail Involvement: Results From UNCOVER 3.

BACKGROUND: Ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, has been established as safe and effective in 3 Phase 3 trials for the treatment of moderate to severe plaque psoriasis. The lifetime incidence of psoriatic nail disease is 80%-90% of patients, and approximately 50% of patients with psoriasis have nail involvement.
MATERIALS AND METHODS: The design of UNCOVER-3, a Phase 3, multicenter, double-blind, placebo- and active-controlled trial that evaluated the efficacy and safety of ixekizumab for moderate to severe psoriasis, has been published previously. Patients were randomized to receive blinded placebo, etanercept (50 mg twice weekly) or 80 mg ixekizumab every 2 weeks (IXEQ2W) or every 4 weeks (IXEQ4W) for 12 weeks. At week 12, all patients were assigned to open-label ixekizumab 80 mg every 4 weeks through week 60. In this 60-week post hoc subset analysis, we evaluated only those patients with significant baseline nail involvement, defined as fingernail NAPSI ≥16 and at least 4 fingernails involved.
RESULTS: Ixekizumab Q2W or Q4W resulted in greater improvement in nail psoriasis than placebo or etanercept by week 12 of administration, as measured by percent NAPSI reduction (IXEQ2W 39% improvement, IXEQ4W 40%, etanercept 28%, placebo -4.7%). At week 24, significantly more patients receiving ixekizumab exhibited no signs of nail involvement (IXEQ2W/Q4W 34%, IXEQ4W/Q4W 30%). Similar gains were observed at 60 weeks in all treatment groups.
CONCLUSION: Ixekizumab led to improvement in fingernail psoriasis by week 12 compared with placebo. Continued improvement in fingernail psoriasis with ixekizumab was observed, with >50% of patients achieving complete fingernail psoriasis resolution (NAPSI=0) at week 60.

J Drugs Dermatol. 2016;15(8):958-961.

The importance of unresolved fatigue in depression: costs and comorbidities.

OBJECTIVE: To assess the cost outcomes of patients with a history of depression and clinically significant fatigue. METHODS: Adults with ≥ 2 claims with depression diagnosis codes identified from the HealthCore Integrated Research Database were invited to participate in this study linking survey data with retrospective claims data (12-mo presurvey and postsurvey periods). Patient surveys included measures for depression (Quick Inventory of Depressive Symptomatology), fatigue (Fatigue Associated with Depression Questionnaire), anxiety (7-item Generalized Anxiety Disorder scale), sleep difficulty (Athens Insomnia Scale), and pain (Brief Pain Inventory). After adjusting for demographic and clinical characteristics using propensity scores, postsurvey costs were compared between patients with and without fatigue using nonparametric bootstrapping methods. RESULTS: Of the 1982 patients who had completed the survey and had complete claims data, 653 patients had significant levels of fatigue. Patients with fatigue reported significantly higher scores, indicating greater severity, on measures of depression, pain, sleep difficulty, and anxiety (all p < 0.05). These patients also had higher levels of overall medication use and were more likely to have lower measures of socioeconomic status than patients without significant levels of fatigue (all p < 0.05). Mean annual total costs were greater for patients with fatigue than those without fatigue ($14,462 vs $9971, respectively, p < 0.001). These cost differences remained statistically significant after adjusting for clinical and demographic differences. CONCLUSIONS: Clinically significant fatigue appears to add to the economic burden of depression. This reinforces the need for aggressive treatment of all symptoms and further examination of the variability of this relationship as patients approach remission.

What happens next?: a claims database study of second-line pharmacotherapy in patients with major depressive disorder (MDD) who initiate selective serotonin reuptake inhibitor (SSRI) treatment.

BACKGROUND: The objective of this research was to examine treatment patterns and health-care costs associated with second-step pharmacotherapy in patients with major depressive disorder (MDD) who initiated monotherapy with a selective serotonin reuptake inhibitor (SSRI) in 2010. METHODS: This claims database study analyzed patients diagnosed with MDD who were prescribed a monotherapy SSRI, with the first prescription identified as the index date. Patients were required to be ≥18 years old, to have continuous insurance coverage from 1 year prior (pre-index) through 1 year post (post-index) from the index date, and to have not received an antidepressant in the pre-index period. The analyses are descriptive of the patient characteristics, initial SSRI prescribed, most commonly prescribed second-step therapies, and annualized health-care costs. RESULTS: The identified patients (N = 5,012) were predominantly female (65.2%) with a mean age of 41.9 years. The most frequent index SSRIs were citalopram (30.1%) and sertraline (27.5%), and 52.9% of patients were prescribed a second-step pharmacotherapy during the post-index period. Add-on therapy occurred twice more frequently than switching treatments, with either anxiolytics (40.2%) or antidepressants (37.1%) as the most common classes of add-on pharmacological therapies. Patients who added a second medication or switched therapies had higher annualized medical costs compared with patients who continued their index SSRI or discontinued treatment. CONCLUSIONS: For patients who were initially treated with an SSRI therapy, approximately half were prescribed a second-step treatment. In this comprehensive claims analysis, many of these patients experienced the addition of second medication, rather than switching to a new therapy. Given the type of medications used, it is possible that second-step interventions were targeted toward resolution of residual symptoms; however, this work is limited by the use of claims data without information on dosing or clinical symptoms, side effects, or response. Findings from this study set the expectation that physicians and patients will most likely need to partner for additional interventions in order to achieve remission.

Understanding the impact of slowing disease progression for individuals with biomarker-confirmed early symptomatic Alzheimer's disease.

Recent advances in development of amyloid-targeting therapies support the potential to slow the rate of progression of Alzheimer's disease. We conducted a narrative review of published evidence identified through a targeted search of the MEDLINE and EMBASE databases (2020-2023), recent presentations at disease-specific conferences, and data updates from cohort studies in Alzheimer's disease to describe the trajectory of the progression of Alzheimer's disease. Our findings enable the interpretation of clinical trial results and the value associated with slowing disease progression across outcomes of relevance to patients, care partners, clinicians, researchers and policymakers. Even at the earliest stages, Alzheimer's disease imposes a substantial burden on individuals, care partners, and healthcare systems. The magnitude of the burden increases with the rate of disease progression and symptom severity, as worsening cognitive decline and physical impairment result in loss of functional independence. Data from cohort studies also indicate that slowing disease progression is associated with decreased likelihood of needing extensive clinical care over at least 5 years, decreased care partner burden, and substantial individual and societal cost savings. Slowed disease progression is of significant benefit to individuals with Alzheimer's disease, their loved ones, and the healthcare system. As clinicians and policymakers devise strategies to improve access to treatment earlier in the disease spectrum, they should carefully weigh the benefits of slowing progression early in the disease (e.g. preservation of cognitive and functional abilities, as well as relative independence) to individuals, their loved ones, and broader society.

Subscale validation of the neuropsychiatric inventory questionnaire: comparison of Alzheimer's disease neuroimaging initiative and national Alzheimer's coordinating center cohorts.

OBJECTIVE: Neuropsychiatric symptoms are prevalent in mild cognitive impairment (MCI) and Alzheimer disease (AD) and commonly measured using the Neuropsychiatric Inventory (NPI). Based on existing exploratory literature, we report preliminary validation of three NPI Questionnaire (NPI-Q-10) subscales that measure clinically meaningful symptom clusters. METHODS: Cross-sectional results for three subscales (NPI-Q-4-Frontal, NPI-Q-4-Agitation/Aggression, NPI-Q-3-Mood) in amnestic MCI and AD dementia cases from the National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) databases were analyzed using confirmatory unrotated principal component analysis. RESULTS: ADNI contributed 103 MCI, 90 MCI converters, and 112 AD dementia cases, whereas NACC contributed 1,042 MCI, 763 MCI converters, and 3,048 AD dementia cases. NACC had higher baseline mean age (75.7 versus 74.6), and more impaired mean scores (at month 24) on Mini-Mental State Exam (19.5 versus 22.4) and NPI-Q-10 (5.0 versus 4.3), and all NPI-Q subscales than ADNI. Medians were not different between cohorts for NPI-Q-4-Agitation/Aggression, and NPI-Q-3-Mood, however. Each item on all scales/subscales contributed variance in principal component analysis Pareto plots. All items in Factor (F) 1 for each scale/subscale projected in a positive direction on biplots (revealing coherence), whereas F2 and F3 items showed more spatial separation (revealing independence). There were remarkable similarities between cohorts for factor loadings and spatial patterns of item projections, although factor item identities varied somewhat, especially beyond F1. CONCLUSION: The similar pattern of results across two cohorts support validity of these subscales, which are worthy of further psychometric evaluation in MCI and AD patients and preliminary application in clinical settings.

Derivation of a brief measure of agitation and aggression in Alzheimer's disease.

OBJECTIVE: Neuropsychiatric symptoms, including agitation and aggression (A/A), are highly prevalent in Alzheimer's disease (AD) and are associated with increased disability, functional impairment, caregiver distress, and institutionalization. Previous psychometric work suggests that individual items of agitation, irritability, disinhibition, and aberrant motor behavior from the Neuropsychiatric Inventory (NPI) may be a valid measure of A/A in AD. We provide additional confirmation of this subscale, as well as preliminary validation of it as a measure of A/A (the NPI-4-A/A). METHODS: The sample included 641 individuals identified from the South Carolina Alzheimer's Disease Registry and assessed to be at a nursing home level of care. Demographic and medical data were extracted from the Registry, and phone interviews were conducted with caregivers to collect additional information not included in the Registry. The primary statistical analysis was confirmatory factor analysis of the NPI-12 factor structure. RESULTS: The standardized root mean residual and root mean square error of approximation (90% CI) values of 0.060 and 0.043 (0.030, 0.057), respectively suggest adequate model fit of the data, whereas the Tucker-Lewis index estimate of 0.779 is below the criteria for adequate model fit. All but two normalized residuals (NR) suggested adequate model fit of the data (|NR| < 2.58). NPI-4-A/A scores were higher in patients residing in nursing homes and were correlated with caregiver burden. CONCLUSIONS: The NPI-4-A/A is proposed as a measure of A/A in AD. The utility and validity of this measure should be explored further. Improved measurement and focus on subgroups of neuropsychiatric symptoms should be integrated into interventions for AD.

Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease.

BACKGROUND: Mibampator, an amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor potentiator, was evaluated for treatment of agitation and aggression (A/A) in Alzheimer's disease (AD). METHODS: Outpatients (n = 132) with probable AD and A/A randomized to 12 weeks of double-blind treatment with 3-mg po mibampator or placebo were assessed using the 4-domain A/A subscale of the Neuropsychiatric Inventory (NPI-4-A/A) derived from the Neuropsychiatric Inventory. Secondary measures included the Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior Inventory (FrSBe), and Alzheimer's Disease Assessment Scale-Cognitive. Efficacy was analyzed using mixed-effects model repeated measures from baseline to endpoint. Adverse events (AEs), labs, vital signs, and electrocardiograms were monitored. RESULTS: Baseline characteristics were comparable between groups. Both groups improved on the NPI-4-A/A, but without group differences. Among secondaries, mibampator was significantly better (p = 0.007) than placebo only on the FrSBe. AEs were similar between groups. One death occurred in the placebo group. CONCLUSION: Possible explanations for no significant group differences include caregiver, drug target engagement, and design issues. This trial is registered on ClinicalTrials.gov; ID: NCT00843518.

Meaningful Clinical Changes in Alzheimer Disease Measured With the iADRS and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings.

Purpose of Review: To provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ study. Recent Findings: The iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months (p = 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months. Summary: The iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD.

Migraine history and response to lasmiditan across racial and ethnic groups.

OBJECTIVE: The robust enrollment in SPARTAN and SAMURAI provided the opportunity to present post-hoc descriptive details on migraine disease characteristics and treatment outcomes after treatment with lasmiditan, a selective serotonin (5-HT1F) receptor agonist, in racial and ethnic subgroups. METHODS: Descriptive data from racial (White [W](n = 3471) and Black or African American [AA](n = 792)) and ethnic (Hispanic or Latinx [HL](n = 775) and Non-Hispanic or Latinx [Non-HL](n = 3637)) populations are presented on pooled data from two double-blind, placebo-controlled, randomized Phase 3 studies (SAMURAI [NCT02439320] and SPARTAN [NCT2605174]). Patients were treated with lasmiditan (50 (SPARTAN only), 100, or 200 mg) or placebo for a single migraine attack of moderate-to-severe intensity. Efficacy data were recorded in an electronic diary at baseline, 30, 60, 90, and 120 min. Safety was evaluated and reported by occurrences of adverse events. RESULTS: Clinical characteristics were generally similar across populations. W participants had longer migraine history than AA participants, and Non-HL participants had more migraine disability than HL participants. In the lasmiditan single-attack studies, AA participants waited longer than W participants to take study drug. A higher proportion of HL participants rated baseline migraine severity as severe compared to Non-HL participants. Response to lasmiditan was similar across racial and ethnic groups, including pain response, freedom from most bothersome symptom and migraine-related disability, and safety and tolerability. Across multiple outcomes, AA and HL participants tended to report more positive outcomes. CONCLUSIONS: There were few differences in demographic and clinical characteristics across racial and ethnic groups. Similar lasmiditan efficacy and safety outcomes were observed in AA versus W participants, and in HL versus Non-HL participants. Small observed differences may be driven by a tendency toward a more positive response observed across all treatment groups by AA and HL participants.

Lasmiditan efficacy in migraine attacks with mild vs. moderate or severe pain.

OBJECTIVE: To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity. METHODS: Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher's exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain. RESULTS: In SAMURAI and SPARTAN, most treated attacks were of moderate (N = 2768) or severe (N = 1147) intensity, compared to mild (N = 65). Numerically greater 2-h PF and 24-h SPF response rates were observed in attacks treated at mild compared to moderate or severe pain. Analysis of GLADIATOR data included 273 (1.5%), 11,644 (65.1%), and 5948 (33.3%) attacks treated when pain was mild, moderate, and severe, respectively. In general, a significantly greater proportion of attacks treated at mild pain achieved 2-h PF and MBS freedom, as well as 24-h SPF. The incidence of treatment-emergent adverse events in LTN treatment groups were similar regardless of baseline head pain intensity. CONCLUSIONS: Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

Pharmacokinetics, Safety, and Tolerability of Lasmiditan in Pediatric Patients with Migraine.

INTRODUCTION: Lasmiditan is a selective serotonin (5-HT1F) receptor agonist approved in the US for the acute treatment ofmigraine in adults. This phase I, open-label, two-cohort study assessed the pharmacokinetics (PK), safety, and tolerability of lasmiditan in patients with migraine aged 6 to < 18 years. METHODS: Cohort 1 (15 to ≤ 40 kg) and Cohort 2 (> 40 to ≤ 55 kg) received single oral doses of lasmiditan (100 mg and 200 mg, respectively).Blood samples for the assessment of PK and safety parameters were collected over a 24-h period. Follow-up was approximately 14 days after dosing. RESULTS: Eighteen patients received lasmiditan (11 in Cohort 1, 7 in Cohort 2) and 17 patients completed the study. One patient in Cohort 2 discontinued due to adverse events. Plasma concentrations peaked at 1.5-2 h post dose and then declined, with a terminal half-life of approximately 4 h in both cohorts. While the exposure to lasmiditan was generally similar between cohorts, PK parameters, such as apparent total body clearance and volume of distribution, were greater for the 200 mg cohort relative to the 100 mg cohort. No deaths or serious adverse events were reported. The frequency and severity of adverse events (including somnolence, dizziness, and fatigue) were generally mild and similar to those in adult studies. CONCLUSION: The PK results support weight-based dosing of lasmiditan in pediatric patients with migraine and no new safety or tolerability issues were identified. These findings support further investigation of lasmiditan as a potential treatment in pediatric patients with migraine. Clinical Trial Registration Numbers NCT03988088 and EMEA-002166-PIP01-17M02.

Effectiveness of adjunctive antidepressant treatment for bipolar depression.

BACKGROUND: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. METHODS: In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. RESULTS: Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

Acute Migraine Prescription Patterns Vary by Baseline Cardiovascular Risk and Clinical Characteristics: A Real-World Evidence Study.

INTRODUCTION: Migraine is a debilitating neurological disease and one of the most common disorders in the world. Although the triptans, potent 5-HT1B/1D receptor agonists, are an effective and widely used acute treatment of migraine, few studies have assessed how their cardiovascular risk warnings could impact prescription patterns. This study characterized cardiovascular risk factors and other aspects of people with migraine in real-world settings and confirmed patterns of acute migraine care. METHODS: This retrospective study included five cohorts: people with migraine prescribed acute treatments [triptans, opiates, prescription nonsteroidal anti-inflammatory drugs (NSAIDs)], untreated people with migraine, and individuals without migraine diagnosis. Baseline demographic and clinical characteristics were used to develop and validate a 1-year myocardial infarction (MI) risk prediction model among untreated people with migraine. This validated prediction model generated disease risk scores (DRSs) for MI among untreated cohorts. RESULTS: Patients in the study included 436,642 prescribed a triptan, 55,234 prescribed opiates, and 334,152 prescribed NSAIDs; as well as 1,168,212 untreated persons with migraine and 11,735,009 nonmigraine participants. Those prescribed triptans were younger, had fewer cardiovascular risk factors and hospitalizations, and lower concomitant medication use than those in the NSAID and opiate cohorts. The distribution of the DRS showed that compared to patients prescribed NSAIDs (4.2%) or opiates (3.5%), a smaller proportion of patients prescribed triptans (1.3%) were at high risk for MI at 1 year (> 10%). CONCLUSION: People with migraine who had more cardiovascular risk factors and greater 1-year MI risk score were disproportionately prescribed opiates and NSAIDs compared to triptans. Future research should explore unmet needs for patients with disorders for which triptan therapy is contraindicated.

Retrospective age at onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study.

OBJECTIVE: Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms. METHODS: We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Age at illness onset was identified retrospectively by clinician assessment at study entry. RESULTS: Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two-year follow-up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups. CONCLUSION: Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation.

Increasing minority research participation through collaboration with community outpatient clinics: the STEP-BD Community Partners Experience.

BACKGROUND: Minority populations have been under-represented in mental health research studies. The systematic treatment enhancement program for bipolar disorder developed the Community Partners Program (CPP) to address this issue in a large, prospective treatment study of persons with bipolar disorder. PURPOSE: The primary goal of CPP was to develop a community-based infrastructure for studying bipolar disorder that would enhance the ethnic/racial and socioeconomic diversity of participants. METHODS: Selected academic sites partnered with local clinics (n = 6 partnerships in five cities). This report describes the conceptualization, implementation, and qualitative evaluation of CPP, as well as quantitative analysis of clinical and sociodemographic differences between the samples recruited at academic versus community sites. RESULTS: Quantitative analysis of the 155 participants from the six partnerships revealed enrollment of 45% from minority populations (vs. 15% in academic sites). Significant sociodemographic differences were evident not only between academic and community sites, but within minority and non-minority groups across site types. Notably, clinical differences were not evident between participants from academic and community sites. Review of qualitative data suggests that certain factors around implementation of research protocols may enhance community participation. CONCLUSIONS: Moving research recruitment and participation into community sites was more successful in increasing minority enrollment than efforts to attract such individuals to academic sites. Recommendations for creating and maintaining academic/community partnerships are given. LIMITATIONS: Several important variables were not considered including mood severity, hospitalization, or treatment differences. Minority participants were grouped by combining African American and Hispanics, which may have obscured subgroup differences. A derivation of standard qualitative methods was used in this study.