Two-Year Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study.

BACKGROUND: Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical remission at week 12 (W12) and maintaining clinical remission at W52 in patients with moderately to severely active ulcerative colitis. Results are presented from the open-label extension study through W104. METHODS: Clinical, symptomatic, quality-of-life, and adverse event outcomes are reported for mirikizumab induction responders and extended induction responders, including biologic-failed patients, who entered LUCENT-3, with data shown for W52 maintenance responders or remitters. Discontinuations or missing data were handled by nonresponder imputation (NRI), modified NRI (mNRI), and observed case (OC). RESULTS: Among W52 mirikizumab responders, clinical response at W104 was 74.5%, 87.2%, and 96.7% and clinical remission was 76.6%, 89.0%, and 98.3% for NRI, mNRI, and OC, respectively. Among W52 mirikizumab remitters, clinical response at W104 was 54.0%, 62.8%, and 70.1% and clinical remission was 65.6%, 76.1%, and 84.2%. Using mNRI, remission rates at W104 for W52 clinical remitters were 74.7% corticosteroid-free, 79.5% endoscopic, 63.9% histologic-endoscopic mucosal remission, 85.9% symptomatic, 59.8% bowel urgency, 80.5% Inflammatory Bowel Disease Questionnaire (using NRI), 71.2% histologic-endoscopic mucosal improvement, and 77.5% bowel urgency improvement. Previous biologic-failed vs not-biologic-failed patient data were generally similar. Extended induction mNRI clinical response was 81.9%. Serious adverse events were reported in 5.2% of patients; 2.8% discontinued treatment due to adverse events. CONCLUSIONS: Endoscopic, histologic, symptomatic, and quality-of-life outcomes support the long-term benefit of mirikizumab treatment up to 104 weeks in patients with ulcerative colitis, including biologic-failed patients, with no new safety concerns.

Long-term clinical response/remission, endoscopic, histologic, and symptomatic data from an open-label study in patients with moderately to severely active ulcerative colitis demonstrate that 2-year continuous mirikizumab treatment maintained clinical remission in a majority of induction clinical responders, regardless of previous biologic failure status.

Clinical Effect of Mirikizumab Treatment on Bowel Urgency in Patients with Moderately to Severely Active Ulcerative Colitis and the Clinical Relevance of Bowel Urgency Improvement for Disease Remission.

Background: Bowel urgency reduces ulcerative colitis patients' quality of life. Mirikizumab, a p19-directed anti-IL-23 antibody, demonstrates ulcerative colitis efficacy. Mirikizumab efficacy to reduce bowel urgency and bowel urgency association with other endpoints were analyzed in 2 Phase 3 trials. Methods: LUCENT-1 (Induction): 1162 patients randomized 3:1 to intravenous 300 mg mirikizumab or placebo every 4 weeks for 12 weeks. LUCENT-2 (Maintenance): 544 mirikizumab responders during induction were re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo every 4 weeks for 40 weeks (52 weeks of continuous treatment). Bowel urgency was measured using the Urgency Numeric Rating Scale (0-10); for patients with LUCENT-1 baseline score ≥3, bowel urgency clinically meaningful improvement (≥3-point decrease) and remission (score ≤1) rates in mirikizumab versus placebo groups were compared at Weeks 12 and 52. Associations between bowel urgency and other efficacy endpoints were assessed at Weeks 12 and 52. Results: A significantly higher proportion of mirikizumab patients versus placebo achieved clinically meaningful improvement in bowel urgency and remission at Weeks 12 and 52. Significantly higher percentages of patients achieving bowel urgency clinically meaningful improvement or remission, compared with those who did not, also achieved endpoints for clinical, corticosteroid-free, endoscopic, and symptomatic remission; clinical response; normalized fecal calprotectin and C-reactive protein; and improved quality of life. Conclusions: In patients with ulcerative colitis, bowel urgency improvement was associated with better clinical outcomes than in patients without improvement during induction and maintenance. A greater proportion of mirikizumab patients achieved sustainable bowel urgency improvement and remission compared to placebo patients.

Effect of a change in lasmiditan dose on efficacy and safety in patients with migraine.

Background: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.Objective: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.Methods: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50-100, 50-200, 100-100, 100-200, 200-100, 200-200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar's test.Results: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings.Conclusion: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients.Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186).

Lasmiditan in patients with common migraine comorbidities: a post hoc efficacy and safety analysis of two phase 3 randomized clinical trials.

OBJECTIVE: Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT1F receptor agonist approved in the United States for the acute treatment of migraine. METHODS: In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). RESULTS: Across all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments. CONCLUSIONS: The efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.

Lasmiditan mechanism of action - review of a selective 5-HT1F agonist.

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

Medical Writing Competency Model - Section 1: Functions, Tasks, and Activities.

This article provides Section 1 of the 2017 Edition 2 Medical Writing Competency Model that describes the core work functions and associated tasks and activities related to professional medical writing within the life sciences industry. The functions in the Model are scientific communication strategy; document preparation, development, and finalization; document project management; document template, standard, format, and style development and maintenance; outsourcing, alliance partner, and client management; knowledge, skill, ability, and behavior development and sharing; and process improvement. The full Model also includes Section 2, which covers the knowledge, skills, abilities, and behaviors needed for medical writers to be effective in their roles; Section 2 is presented in a companion article. Regulatory, publication, and other scientific writing as well as management of writing activities are covered. The Model was developed to aid medical writers and managers within the life sciences industry regarding medical writing hiring, training, expectation and goal setting, performance evaluation, career development, retention, and role value sharing to cross-functional partners.

Medical Writing Competency Model - Section 2: Knowledge, Skills, Abilities, and Behaviors.

This article provides Section 2 of the 2017 Edition 2 Medical Writing Competency Model that describes the knowledge, skills, abilities, and behaviors that professional medical writers need in order to perform effectively within the life sciences industry. What a medical writer should know, what they should be able to do, and how they should use this knowledge and these skills to facilitate their primary work function is a focus. Regulatory, publication, and other scientific writing as well as management of writing activities are covered. The full Model also includes Section 1, which covers the core work functions and associated tasks and activities related to professional medical writing within the life sciences industry; Section 1 is included in a companion article. The Model was developed to aid medical writers and managers within the life sciences industry regarding medical writing hiring, training, expectation and goal setting, performance evaluation, career development, retention, and role value sharing to cross-functional partners.

A review of the efficacy of atomoxetine in the treatment of attention-deficit hyperactivity disorder in children and adult patients with common comorbidities.

Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder that is often diagnosed during childhood, but has also increasingly been recognized to occur in adults. Importantly, up to 52% of children (including adolescents) and 87% of adults with ADHD also have a comorbid psychiatric disorder. The presence of a comorbid disorder has the potential to impact diagnosis and could affect treatment outcomes. Atomoxetine is a nonstimulant treatment for ADHD. Despite numerous published studies regarding efficacy of atomoxetine in the treatment of ADHD in patients with comorbid disorders, there is limited information about the impact of individual common comorbid disorders on the efficacy of atomoxetine for ADHD, especially with regard to adults. Moreover, a cumulative review and assessment of these studies has not been conducted. For this reason, we performed a literature review to find, identify, and cumulatively review clinical studies that examined the efficacy of atomoxetine in the treatment of patients with ADHD and comorbid psychiatric disorders. We found a total of 50 clinical studies (37 in children; 13 in adults) that examined the efficacy of atomoxetine in patients with ADHD and a comorbid disorder. The comorbidities that were studied in children or in adults included anxiety, depression, and substance use disorder. Overall, the presence of comorbidity did not adversely impact the efficacy of atomoxetine in treatment of ADHD symptoms in both patient populations. In the studies identified and assessed in this review, atomoxetine did not appear to exacerbate any of the comorbid conditions and could, therefore, be an important therapy choice for the treatment of ADHD in the presence of comorbid disorders.

Misuse of Methylphenidate.

This chapter reviews methylphenidate misuse, abuse, dependence, diversion, and malingering associated with its use as a prescription medication for attention-deficit/hyperactivity disorder and the nonmedical use linked to its stimulant effects. Methylphenidate-induced regional elevations in brain dopamine appear to be integral to both efficacy in attention-deficit/hyperactivity disorder and potential for abuse, raising potential concerns for drug safety and prescription drug diversion costs associated with nonmedical use. Regardless, methylphenidate is an important treatment option, and detecting malingering for the purpose of illicit access to methylphenidate for subsequent misuse or diversion is a difficult challenge. Also discussed are the effects of methylphenidate in patients with comorbid substance use disorder and the potential linkage of methylphenidate use with subsequent substance abuse. The current data suggest that methylphenidate misuse and diversion are common health-care problems with a stimulant prescription drug diversion prevalence of approximately 5-10 % of high school students and 5-35 % of college students. The effectiveness and speed of action of methylphenidate are deemed desirable to enhance attention and focus performance for activities such as studying for exams, but methylphenidate is also misused recreationally. These data suggest a need for close screening and therapeutic monitoring of methylphenidate use in the treatment of attention-deficit/hyperactivity disorder.

Clinical Impact of Not Achieving Recommended Dose on Duration of Atomoxetine Treatment in Adults with Attention-Deficit/Hyperactivity Disorder.

AIM: To compare atomoxetine (ATX) length of therapy (LoT) among adults with ADHD who reached the recommended dose of 80 mg/day (ATX ≥ 80) versus those who did not (ATX < 80) analyzed separately in patients prescribed ATX as monotherapy (mono) and in combination with other ADHD medications (combo). METHODS: This was a retrospective observational cohort study of the Truven Health Marketscan Commercial Claims Database from January 1, 2006-September 30, 2013, with a 6-month preindex period free of ATX (1st ATX claim as index event) and a 1-year follow-up. LoT during follow-up was calculated using prescription claim fill dates and included all days with medication on hand regardless of treatment gaps. RESULTS: Only 45.0% of the 36,076 mono and 77.9% of the 1548 combo patients reached an ATX dose of ≥80 mg/day in 1-year follow-up. When patients filled at least one 80 mg prescription, their total days of therapy over the course of a year were significantly greater than if they did not (mono: 159.3 vs. 65.6 days; combo: 237.4 vs. 172.0; P < 0.0001). Across all timepoints examined (Day 14, 30, 60, 90, 210) for mono and combo, ATX ≥ 80 versus ATX < 80 patients had greater mean doses (P < 0.0001). Combo patients had longer ATX LoT than mono patients regardless if they reached 80 mg or not (P < 0.0001), but mono patients LoT was 93.8 days longer for ATX ≥ 80 versus ATX < 80 patients compared to 65.5 days for combo patients. Of patients reaching 80 mg/day, 71.7% of mono and 62.8% of combo patients did so by Day 30. For mono ATX ≥ 80 and ATX < 80 patients, LoT was significantly (P < 0.0001) less in previously treated patients compared to naive patients. CONCLUSION: Ensuring adult ADHD patients are treated with ATX at a target dose of 80 mg/day is an important clinical consideration for maximizing patient days on therapy, which can be important for treatment optimization.

Atomoxetine Increased Effect over Time in Adults with Attention-Deficit/Hyperactivity Disorder Treated for up to 6 Months: Pooled Analysis of Two Double-Blind, Placebo-Controlled, Randomized Trials.

INTRODUCTION: Changes in the magnitude of efficacy throughout 26 weeks of atomoxetine treatment, along with impact of dosing, were evaluated in adults with ADHD from two randomized, double-blind, placebo-controlled studies. AIMS: Pooled placebo (n = 485) and atomoxetine (n = 518) patients, dosed 25, 40, 60, 80 (target dose), or 100 mg daily, were assessed. Change from baseline in Conners' Adult ADHD Rating Scale-Investigator Rated Scale: Screening Version (CAARS) total ADHD symptoms score and Adult ADHD Investigator Symptom Rating Scale (AISRS) total score were analyzed using mixed-model repeated measures, with least squares mean change, effect size, and response rate calculated at 1, 2, 4, 8, 12, 16, 22, and 26 weeks. RESULTS: Decreases on CAARS for atomoxetine- versus placebo-treated patients were consistently statistically significantly greater at every time point beginning at one week (P ≤ 0.006, 0.28 effect size). By 4 weeks, comparison was -13.19 compared with -8.84 (P < 0.0001, 0.45 effect size). By 26 weeks, mean change was -15.42 versus -9.71 (0.52 effect size); increase in effect size over time was most pronounced in the 80 mg group (0.82 effect size). AISRS demonstrated similar results. Atomoxetine response rate (CAARS 50% decrease) continued to increase throughout 26 weeks. CONCLUSIONS: Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment. The data support increased effect size and response rate over time during longer-term treatment at target dose.

Atomoxetine monotherapy compared with combination therapy for the treatment of ADHD: a retrospective chart review study.

OBJECTIVE: To analyze Clinical Global Impression-Severity (CGI-S) in ADHD patients treated with atomoxetine (ATX) monotherapy versus ATX combination therapy with another ADHD-indicated medication. METHODS: This was a 2-site retrospective observational chart review study of child and adult ADHD patients, not necessarily treatment naïve, but treated ≥50 days post baseline with an endpoint assessment. To adjust for measured confounders, monotherapy (n = 77) versus combination (n = 108) cohort comparisons were performed using propensity score stratification and adjusted ANCOVA. RESULTS: There were no significant baseline cohort differences after propensity stratification. CGI-S scores after a mean 264 days of treatment were not statistically significantly different between cohorts, with no cohort differences observed in any assessed symptom subcategory. The cohorts were similar in discontinuation due to any reason, adverse event, and lack of efficacy. CONCLUSION: ATX combination therapy showed no evidence of additional benefit over ATX monotherapy in the treatment of ADHD in a community-based setting.

Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a CNS disorder that has its onset in childhood, but often persists into adulthood. There is growing recognition that adult ADHD can result in multiple negative consequences for individuals. ADHD is also often associated with a number of comorbid psychiatric disorders. Atomoxetine (ATX), a nonstimulant, selective noradrenergic reuptake inhibitor, was approved in the United States in 2002 for the treatment of ADHD in children and adolescents, as well as adults. We review here the safety and efficacy of ATX in adults with ADHD, including data in special populations, functional outcomes, as well as provider and patient real-world perceptions. METHODS: We searched the databases Embase, MEDLINE and PsycINFO using the terms 'ADHD' and 'adult' and 'ATX' capturing publications from January 1, 1998, to March 27, 2014. Only publications in English were considered. RESULTS: ATX demonstrated significantly greater improvement than placebo (PBO) on the Conners Adult ADHD Rating Scale-Investigator rated:Screening Version (CAARS-Inv:SV) in all trials (N = 6; total score difference ranged from -3.5 to -5.5). For long-term trials using the CAARS-Inv:SV, ATX demonstrated significantly greater improvement than PBO in three of four trials (total score differences ranged from -0.1 to -6.0). In short-term studies, ATX showed significantly greater improvement than PBO on the Adult ADHD Quality-of-Life scale total score in three of three studies, but results were mixed on the Sheehan Disability Scale. Three studies of ATX have reported statistically significant improvement (compared with PBO) on the Behavior Rating Inventory of Executive Function-Adult Version Self Report scale. The most common adverse events (occurring in ≥ 10% of patients taking ATX) were nausea, dry mouth, decreased appetite, insomnia and fatigue. CONCLUSIONS: ATX is an important treatment option for the right patient. ATX can provide long-term, consistent symptom relief and functional improvement for adults with ADHD.

Real-World Dosing Patterns of Atomoxetine in Adults with Attention-Deficit/Hyperactivity Disorder.

AIMS: The aim was to investigate the dosing patterns of atomoxetine monotherapy in adult patients with attention-deficit/hyperactivity disorder (ADHD) in a retrospective analysis. METHODS: Adult (≥ 18 years) patients with ADHD newly initiated on atomoxetine with ≥ 1 outpatient pharmacy claim for atomoxetine between January 2006 and December 2011 were selected from the Truven Health MarketScan(®) Commercial database. After a 30-day titration period, dosing patterns of atomoxetine monotherapy were analyzed in the 12 months following initiation. In addition, patient demographic and clinical characteristics were compared to identify characteristics associated with suboptimal versus recommended dosing. RESULTS: Of the 12,412 adult patients with ADHD newly initiated on atomoxetine, 4548 (36.6%) were suboptimally dosed, whereas 3323 (26.7%) were treated at recommended dose. Overall, study patients were treated at a mean (standard deviation [SD]) dose of 68.5 (44.9) mg/day. The suboptimal dosing cohort included significantly more females (54% vs. 44%, P < 0.001) and had fewer patients with pre-index use of other ADHD medications (17% vs. 20%, P < 0.001) compared with the recommended dosing cohort. CONCLUSIONS: Adult patients with ADHD receiving atomoxetine therapy in a real-world setting are often dosed suboptimally. Increasing the awareness on optimal dosing strategy among clinicians and patients is warranted to maximize the therapeutic benefits of atomoxetine among adult patients with ADHD.

Atomoxetine in patients with ADHD: A clinical and pharmacological review of the onset, trajectory, duration of response and implications for patients.

This article reviews data providing new insight into the trajectory of response and maintenance of response of atomoxetine in the treatment of child and adult attention-deficit hyperactivity disorder (ADHD). This nonsystematic review includes: onset of action and duration of effect, response rate, effect size, time to optimal response and norepinephrine transporter blockade biomarker data. Atomoxetine can have an onset of action within 1-2 weeks of starting treatment, but there is an incrementally increasing response for up to 24 weeks or longer. Responder rates and effect sizes are similar to methylphenidate. Upon treatment discontinuation, relapse rates are lower than expected. In adults, 50% maintain their response for at least 6 months after stopping atomoxetine, following 6 months of treatment. Single-dose atomoxetine can provide 24-hour efficacy, despite a 5-hour plasma half-life. Hypotheses can be generated relating to neuroadaptive changes, to explain these findings. Atomoxetine has a trajectory of response that is incremental over a long period of time, with a greater than expected maintenance of response. This has implications for physician atomoxetine dosing and efficacy assessment, patient education and outcomes, and for clinical trial design and assessment of comparative efficacy with stimulant medications.

Medicines in Pregnancy Forum: Proceedings on Ethical and Legal Considerations.

To raise awareness and promote dialogue leading to action, this article provides proceedings on ethical and legal considerations associated with medicine use during pregnancy discussed during the 2014 DIA Medicines and Pregnancy Forum. A key focus of discussion at the forum was "When is it ethically appropriate to include or unethical not to include pregnant patients in clinical studies, and how can ethical barriers be addressed?" Also debated was the question "What are the most appropriate methods to collect and share data on medication use in pregnancy, and what is the best process for sharing such information?" Goals of the forum were to gain participant alignment on answers to these ethical questions, offer rationale for the answers, and provide insight into which stakeholders might be needed to facilitate discussion and action. Participants felt that under the right circumstances, drug research in pregnant women is justified and necessary. Multiple ideas and opinions on the handling of pregnant patients in clinical research, treating pregnant women in clinical practice, and communicating data to physicians and patients are presented.

Suboptimal dosing of Strattera (atomoxetine) for ADHD patients.

To raise awareness, this article provides a commentary on the frequent underdosing of atomoxetine for the treatment of adult attention-deficit/hyperactivity disorder (ADHD) that may be associated with poor patient outcomes. Data suggest an adequate atomoxetine dose for sufficient duration is important for ADHD symptom improvement. Despite the recommended 80 mg/day target dose, real-world data show that an approximately 60 mg/day average adult atomoxetine dose is utilized. This article discusses the factors that may contribute to this suboptimal dosing. Atomoxetine dose titration, setting patient expectations, and the importance of keeping the patient at target dose for an adequate length of time (about 4−6 weeks) prior to judging efficacy are also discussed.

The potential for misuse and abuse of medications in ADHD: a review.

This article reviews the literature concerning attention-deficit/hyperactivity disorder (ADHD) medication misuse, abuse, dependence, diversion, and malingering. The review covers nonmedical use (NMU) of both stimulant (methylphenidate and amphetamine) and nonstimulant (α-adrenergic agonists and atomoxetine) prescription medications, and provides a discussion on the relevance for ADHD treatment today. The neural basis for ADHD medication mechanisms of action (increased norepinephrine and dopamine signaling) and their neurobiochemical relationship to the abuse potential is explored. Regionally-specific, stimulant-induced elevations in brain dopamine appear to be integral to both efficacy in ADHD and potential for abuse. In addition to the prevalence of misuse and diversion, additional topics discussed include the potential safety concerns associated with NMU of prescription ADHD medications and the cost to payers of prescription drug diversion (eg, increased emergency department visits associated with misuse). The evidence describing the difficulty in detecting malingering for the purpose of illicit access to ADHD medications for subsequent misuse or diversion is also summarized. Moreover, the effect of ADHD medications in patients with comorbid substance use disorder and the controversial potential linkage of stimulant prescription use with subsequent substance use disorder are explored. Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study. Stimulant effectiveness and speed of action are deemed desirable to enhance attention and focus performance for activities like studying, but stimulants are also misused recreationally. Conversely, the data suggest a lack of abuse potential and lack of actual medication misuse for the nonstimulant medications. Although they can be efficacious for the treatment of ADHD, the nonstimulants lack a mechanism of action linked to the abuse potential and they lack the desirable effects (speed of action, stimulant feel) that make stimulants susceptible to NMU. In light of these findings, the data suggest a need for close screening and therapeutic monitoring of ADHD medication use. In addition, nonstimulants might be an appropriate alternative for patients with concern about abuse and physicians concerned with general misuse and diversion.

Atomoxetine effects on executive function as measured by the BRIEF--a in young adults with ADHD: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18-30 years) with ADHD were randomized to receive atomoxetine (20-50 mg BID, N = 220) or placebo (N = 225) for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator). RESULTS: At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T-scores ≥60 (p>.5), with over 92% of patients having composite scores ≥60 (≥60 deemed clinically meaningful for these analyses). At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI) scores, as well as the Inhibit, Self-Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (p<.05), with decreases in scores signifying improvements in executive functioning. Changes in the BRIEF-A Initiate (p = .051), Organization of Materials (p = .051), Shift (p = .090), and Emotional Control (p = .219) subscale scores were not statistically significant. In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity. CONCLUSION: Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales. TRIAL REGISTRATION: ClinicalTrials.gov NCT00510276.

Duloxetine Compared with Pregabalin for Diabetic Peripheral Neuropathic Pain Management in Patients with Suboptimal Pain Response to Gabapentin and Treated with or without Antidepressants: A Post Hoc Analysis.

OBJECTIVE: To examine the efficacy of duloxetine vs. pregabalin in the treatment for diabetic peripheral neuropathic pain (DPNP), comparing patient subgroups with and without concomitant antidepressant use. METHODS: This post hoc analysis assessed data from a randomized 12-week study that confirmed the noninferiority of duloxetine to pregabalin. In the previously published study, patients with DPNP with inadequate response to gabapentin were switched to duloxetine monotherapy, combination therapy of duloxetine plus gabapentin, or pregabalin monotherapy. Current, stable antidepressant use was allowed; 79 patients were concomitantly treated with antidepressants and 328 without antidepressants. In this post hoc analysis, improvement in the weekly mean of diary-based average daily pain ratings (numerical rating scale: 0-10) in antidepressant users and nonusers was analyzed using a longitudinal mixed-models repeated-measures (MMRM) analysis, including a test of the 3-way interaction (antidepressant subgroup by treatment by week) to assess whether the differences among treatment groups over 12 weeks differ between the antidepressant-use subgroups. RESULTS: The 3-way interaction was significant (P = 0.035), demonstrating that treatment-group differences in pain reduction over time differ between the subgroups. Among patients without antidepressant use, patients treated with duloxetine had significantly greater pain reduction than pregabalin at Week 4 and at each successive week up to the 12-week endpoint (-2.8 for duloxetine and -2.1 for pregabalin; P = 0.031); patients treated with duloxetine plus gabapentin had greater pain reduction than pregabalin at Weeks 2, 3, 5, and 7 to 9 (P ≤ 0.05) but not at endpoint (-2.4; P = 0.222). Among concomitant antidepressant users, no treatment-group differences were found. CONCLUSIONS: In patients with DPNP inadequately treated with gabapentin without the concomitant use of antidepressants, switching to duloxetine instead of pregabalin may provide better pain reduction. Conversely, in nonresponders to gabapentin who are concomitantly using an antidepressant, switching to duloxetine or pregabalin may provide similar pain reductions.