Flexible-dose Study Research Articles

Safety and effectiveness of vortioxetine in patients with major depressive disorder in a real-life clinical setting in India: results from an interventional, flexible-dose study

Objective Vortioxetine has demonstrated safety and efficacy in improving symptoms of major depressive disorder (MDD), including overall functioning in real-world settings. This is the first study in a real-life clinical setting in India to evaluate effectiveness and safety of vortioxetine in patients with MDD. Methods This interventional, open-label study consisted of a 12-week treatment period with flexible doses of vortioxetine (5–20 mg/day) in adult patients (aged 18–65 years) with a confirmed MDD diagnosis. Effectiveness outcomes included change from baseline to week 12 in Patient Health Questionnaire-9 (PHQ-9) and Clinical Global Impression–Severity (CGI-S) scores, along with CGI-Improvement (CGI-I) scores at week 12, using a mixed model for repeated measures. Adverse events (AEs) were recorded for safety outcome assessments. Results Of 395 patients who received vortioxetine, 42.3% were women mean age 38.9 years; 322 patients completed the study. Significant improvement in depressive symptoms was observed in change from baseline to week 12 least squares (LS) mean (SE) PHQ-9 total score (−9.36 [0.276]; p<.0001) and CGI-S score (−2.14 [0.065]; p<.0001). LS mean (SE) CGI-I score showed significant improvement at week 12 (1.93 [0.067]; p<.0001). Subgroup analysis across age, sex, disease severity, and body mass index showed significant improvements in depression symptoms and severity. A total of 35.4% (n = 140) of patients experienced treatment-emergent AEs (mostly mild-moderate); nausea and pruritus were the most frequent (6.6%, n = 26 each). Conclusion Safety and effectiveness of vortioxetine in improving symptoms of MDD over a 12-week period was demonstrated in a real-life clinical setting in India. Clinical trial registration information Open-label, flexible-dose study of vortioxetine in patients with major depressive disorder in India; Clinical Trials.gov ID: NCT04288895; https://www.clinicaltrials.gov/study/NCT04288895

Can Adverse Event Patterns Inform Shared Decision-Making in ADHD Treatment? A Systematic Review of Evidence From Registration Trials for FDA-Approved Treatments in Adults.

Adult patients and clinicians are faced with several pharmacological options to manage attention-deficit/hyperactivity disorder (ADHD). If types or rates of adverse experiences vary among these options, these differences could inform the shared decision-making process. To discern differentiating evidence-based patterns of risk, we analyzed data from FDA package labels for drugs approved to treat adult ADHD and reports from the registration trials used to create these labels. Three analyses of adverse effects were conducted: placebo-corrected occurrence at rates of 1 in 5, 10, and 20 participants, association with discontinuation, and uniqueness of occurrence within the treatment options. Among the 7 agents approved to treat adult ADHD, the number of types of side effects experienced during a mix of fixed and flexible-dose studies was greatest among the nonstimulant medications, but the stimulant medications had higher rates of occurrence of side effects. The minimum frequency at which all medications had adverse events was 1 in 10 participants. Overall discontinuation rates did not differ among the stimulant medications nor between stimulants and nonstimulants. To our knowledge, this is the first study to compile and compare data from all FDA registration trials for medications approved to treat adult ADHD. This article describes a process by which readily available adverse event reporting data can be used as a tool to inform shared clinical decision-making. While differences in the methodology and outcome reporting of the trials included may limit generalizability, the number of individual patients included and the completeness of the discontinuation data can be used to inform discussions with patients about the relative likelihood of adverse experiences and other patient concerns.

Safety and tolerability of cariprazine for the adjunctive treatment of major depressive disorder: a pooled analysis of phase 2b/phase 3 clinical trials.

To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d [approved doses for MDD]). In a separate safety analysis, cariprazine 0.1-4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.

Personality traits predict treatment outcome of an antidepressant in untreated adolescents with depression: An 8-week, open-label, flexible-dose study

BackgroundAntidepressant response in adults with major depressive disorder (MDD) is probably influenced by personality dimensions. However, personality dimensions in depression and their association with antidepressant treatment in adolescents are relatively unknown. We sought to investigate whether personality traits (PTs) can influence antidepressant treatment response in adolescents with depression. MethodsEighty-two adolescents with MDD who had completed the 8 weeks of treatment with selective serotonin reuptake inhibitors (SSRI) were enrolled. The Revised NEO Five-Factor Inventory (NEO-FFI-R) was used to measure their personality at baseline, and the 17-item Hamilton Depression Rating Scale (HAMD-17) and Children's Depression Rating Scale-Revised (CDRS-R) were used to evaluate depressive symptoms at baseline and 8 weeks. Moreover, logistic regression was performed to investigate the relationship between personality dimensions and antidepressant response. Receiver operating characteristic analyses were employed to determine the accuracy of a PT-based model in predicting the antidepressant response rate. ResultsAdolescents with MDD had significantly different PTs at baseline. Multivariable logistic regression analysis showed that extroversion scores were associated with response to antidepressant treatment, the lower the extroversion score, the better the response to antidepressant treatment, after correcting for variables with significant differences and trends or all potential confounding variables. It was also found that the combination of disease duration, extraversion-gregariousness, and agreeableness-trust effectively predicted antidepressant response in adolescents with MDD, with a sensitivity of 79.4 % and specificity of 68.7 %. ConclusionPersonality dysfunction in adolescents is associated with MDD. The antidepressant treatment response is influenced by the degree of extroversion in adolescents with MDD.

Safety and Tolerability of Cariprazine for the Adjunctive Treatment of Major Depressive Disorder: A Pooled Analysis of Phase 2B and 3 Clinical Trials

AbstractBackgroundCariprazine has been shown to be efficacious in placebo-controlled clinical trials. In this pooled analysis, the safety of cariprazine in patients with major depressive disorder (MDD) with inadequate response to antidepressants was evaluated using data from placebo-controlled studies of up to 8 weeks’ duration and a long-term open-label safety study.MethodsThe safety, tolerability, and efficacy of cariprazine as an adjunctive treatment for patients with MDD with inadequate response to antidepressant alone was assessed in five placebo-controlled studies (two 6-week fixed-dose studies [NCT03738215; NCT03739203] and three 8-week flexible-dose studies [NCT00854100; NCT01715805; NCT01469377]) and one 26-week open-label flexible-dose study (NCT01838876). Fixed doses of cariprazine 1.5 and 3 mg/d and flexible doses of 0.1-4.5 mg/d were evaluated. Safety assessments included adverse event (AE) reporting, clinical laboratory tests, weight and other vital signs, and suicide evaluation with Columbia-Suicide Severity Rating Scale (C-SSRS). Pooled analyses of the incidence of safety endpoints overall and within each treatment arm were performed using the most frequent (modal) daily dose taken by patients during the study.ResultsA total of 2,222 MDD patients with an ongoing antidepressant received treatment with cariprazine, representing 370 patient-years of exposure in placebo-controlled and open-label studies. In the placebo-controlled studies, 1,969 patients were randomized to cariprazine (dose range, 0.1–4.5 mg/d) and 1,108 patients were randomized to placebo. Overall, treatment-emergent AEs occurred in 61% of cariprazine- and 48% of placebo-treated patients; discontinuation due to an AE occurred with 6% of cariprazine- and 2% of placebo-treated patients. The 2 AEs that occurred in at least 5% of cariprazine-treated patients and at a rate at least twice the rate in placebo-treated patients were akathisia (cariprazine=11%; placebo=2%) and restlessness (cariprazine=6%; placebo=2%). Changes in metabolic parameters, including shifts in fasting glucose and lipid parameters, were similar in cariprazine- and placebo-treated patients. In the long-term safety study, mean weight change was 1.6 kg over 6 months. In the placebo-controlled and long-term studies, other safety endpoints including laboratory and C-SSRS assessments of suicidality were generally consistent with the safety profile of cariprazine in approved indications of bipolar disorder and schizophrenia.ConclusionCariprazine is generally safe and well-tolerated in MDD patients with inadequate response to antidepressant monotherapy. Safety analysis of 2,222 cariprazine-treated patients with MDD revealed no new safety signals, and the data is consistent with the currently approved prescribing information.FundingAbbVie

Predicting efficacy of viloxazine extended-release treatment in adults with ADHD using an early change in ADHD symptoms: Machine learning Post Hoc analysis of a phase 3 clinical trial

Early response to viloxazine extended-release (viloxazine ER, Qelbree®) treatment predicted efficacy outcome in pediatric subjects with attention-deficit/hyperactivity disorder (ADHD). This study sought to determine whether the machine learning lasso model used in the pediatric study would predict response to viloxazine ER in an adult population based on early improvements in ADHD symptoms. We used data from a double-blind, placebo-controlled, flexible-dose (200–600 mg) study of viloxazine ER (N = 354; 18 to 60 years old). Area under the Receiver Operating Characteristic Curve (ROC AUC) statistics were computed using the lasso model from pediatric data to predict responder status in adults. Response was defined as ≥50% reduction from baseline in the Adult ADHD Investigator Symptoms Rating Scale (AISRS) Total score at Week 6. The adult study sample included 127 viloxazine ER-treated subjects with Week 6 data. Fifty-one subjects (40.2%) were categorized as responders. The ROC curves indicated that data collected up to Week 2 were sufficient to accurately predict treatment response at Week 6 with 68% positive predictive power, 80% sensitivity, and 74% specificity. This analysis demonstrated that the predictive model estimated from the child data generalizes to adults with ADHD, further supporting the consistency of viloxazine ER treatment across age groups.

Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder

BackgroundSertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. MethodThis naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7–18 years) within the prospective multicenter “TDM-VIGIL” project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. ResultsA strong linear positive dose–serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. ConclusionsThis TDM–flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug–drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry.

Vortioxetine 20 mg/day in patients with major depressive disorder: updated analysis of efficacy, safety, and optimal timing of dose adjustment.

Analysis of efficacy and tolerability of vortioxetine 20mg/day, and optimal timing of dose adjustment, in patients with major depressive disorder (MDD). Pooled analysis of six randomized, fixed-dose studies of vortioxetine 5 to 20mg/day. Mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was analyzed by vortioxetine dose using a mixed model for repeated measures. Tolerability was assessed over the 8-week treatment period and from day8 (ie, following dose increase to 20mg/day). Data from three randomized, flexible-dose studies were examined for frequency and timing of dose adjustment. A clear dose-response relationship for vortioxetine was confirmed in terms of improvement in MADRS total score. Significant differences vs placebo were seen for vortioxetine 20mg/day from week2 onwards; vortioxetine 10mg did not separate from placebo until week4. At week8, mean change in MADRS total score from baseline was significantly greater for vortioxetine 20mg/day vs 10mg/day (difference, -1.03 points; P<.05). Incidence of adverse events was not increased in patients who received vortioxetine 20mg/day vs 10mg/day. In flexible-dose studies, dosage was increased to 20mg/day after 1week in 48.0% of patients; final dosage was 20mg/day in 64.3% of patients. Vortioxetine 20mg is significantly more effective than vortioxetine 10mg in patients with MDD, with a similar tolerability profile. In flexible-dose studies, almost half of all patients received 20mg/day after 1week and two-thirds received 20mg/day as their final dosage.

Safety and Effectiveness of SEP−363856 in Schizophrenia: Results of a 6-Month, Open-Label Extension Study

SEP-363856 is a novel psychotropic agent without dopamine D2 receptor occupancy. Although its mechanism of action has not been fully elucidated, preclinical data suggest that agonism at trace amine receptor 1 (TAAR1) and the serotonin 5-H1A receptor contributes to its efficacy. In a double-blind (DB), placebo-controlled study, SEP-363856 demonstrated significant efficacy in the treatment of an exacerbation of schizophrenia (Koblan et al, NEJM 2020; 82:1497-1506). We present results of a 6-month extension study whose aim was to evaluate the safety and effectiveness of longer-term treatment with SEP-363856. Patients with an acute exacerbation of schizophrenia who completed a 4-week, DB, placebo-controlled, flexible-dose (50 or 75 mg) study of SEP-363856 were given the option to enroll in an extension study in which they were treated, open-label (OL), with flexible doses (25/50/75 mg/d) of SEP-363856 for 26-weeks. The primary outcomes were safety measures; effectiveness outcomes were secondary and included the PANSS total score and the Brief Negative Symptom Scale (BNSS) total score. A total of 193 patients completed the 4-week DB study, and 156 (80.8%) were dosed in the OL extension study and received at least one dose of SEP-363856 (safety population). Study completer rate was 66.9%; reasons for discontinuation consisted of adverse event (11.5%), withdrawal of consent (10.2%), lack of efficacy (5.1%), and other (6.4%). 15 patients experienced an SAE: schizophrenia (n=11); acute psychosis (N=1); uterine hemorrhage and suicidal ideation (N=1 each); there were no deaths in the study. Individual AEs with an incidence =2% were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decreased (3.2%), and prolactin increased (2.6%). On movement scales, minimal mean change from OL-baseline to Week 26 occurred on the Barnes total score (-0.1), AIMS total score (0.0) and SAS score (-0.1). Mean month 6 change from DB baseline in weight was -0.3 kg. No clinically meaningful median changes were observed at week 26 in metabolic laboratory parameters (total and LDL cholesterol, triglycerides, hemoglobin A1c) or in prolactin levels. During 6 months of OL treatment, one patient had an increase in QTcF =60 msec; no patients had a QTcF interval =480 msec. Treatment with SEP-363856 was associated with significant improvement from OL baseline to week 26 in PANSS total score (-22.6) and BNSS total score (-11.3). Treatment with SEP-363856 was associated with continued improvement from open-label baseline in the PANSS total (-22.6) and BNSS total (-11.3) scores. The most frequently reported adverse events (= 5%) were schizophrenia, headache, insomnia and anxiety. SEP-363856 had minimal effects on weight, lipids, glycemic indices, prolactin, and was associated with minimal risk of extrapyramidal symptom. Sunovion Pharmaceuticals Inc.

Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania.

Background:Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants).Aims:This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083).Methods:ST studies were three-week randomized, double-blind, flexible dose (2–4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2–4 mg/day) study for patients completing the ST studies.Results:A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (−1.74, 2.03), p = 0.8797; study 081: −1.62 (−3.56, 0.32), p = 0.1011. OL study patients (n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients).Conclusions:Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

Lurasidone switching in patients with schizophrenia who showed suboptimal effect and/or intolerability to current antipsychotics: A multi-center, open-label, single-arm, flexible dose study

Objective: In this study, we intended to evaluate the effectiveness and safety of switching to lurasidone in patients with schizophrenia and to get clinical experiences of real-world practice in those who showed suboptimal therapeutic effect and/or intolerability to lurasidone in Taiwan. Methods: We enrolled adult patients (aged 20–75 years) with schizophrenia who had been receiving antipsychotic medications but still continued to show mild-to-moderate symptoms or intolerability, for switching switch to an open-label lurasidone 40–160 mg daily for six weeks. The primary end point of the study was to assess the time to treatment failure, defined as any occurrence of insufficient clinical response, worsen underlying symptoms, or discontinuation due to adverse events. Secondary efficacy measures of the study included decreased scores in the positive and negative syndrome scale (PANSS) total and the clinical global impression-severity scale.(CGI-S), as well as increased clinical global impression-improvement scale (CGI-I). Safety measures included occurrences of treatment-emergent adverse events (TEAEs), abnormal vital signs, Electrocardiogram (ECG), and laboratory parameters. Results: We enrolled 54 patients with 51 completing the study. One patient terminated early due to adverse events and two patients had insufficient therapeutic efficacy. Mean ± standard deviation (SD) time to treatment failure was 27.7 ± 13.1 days. Mean ± SD changes from baseline to six weeks on PANSS, CGI-S, and were −16.8 ± 14.4, −0.6 ± 0.59, and −1.1 ± 1.0, respectively . The most common TEAE was hyperprolactinemia. Furthermore, body weight was significantly decreased from baseline to the end of the study by 0.83 ± 1.96 kg (p

A phase 3 multicenter open-label maintenance study to investigate the long-term safety of sodium zirconium cyclosilicate in Japanese subjects with hyperkalemia

BackgroundHyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia.MethodsThis phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702).ResultsOverall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase.ConclusionAfter a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

Efficacy and safety of dasotraline in adults with binge-eating disorder: a randomized, placebo-controlled, fixed-dose clinical trial.

The aim of this fixed-dose study was to evaluate the efficacy and safety of dasotraline in the treatment of patients with binge-eating disorder (BED). Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for BED were randomized to 12weeks of double-blind treatment with fixed doses of dasotraline (4 and 6mg/d), or placebo. The primary efficacy endpoint was change in number of binge-eating (BE) days per week at week 12. Secondary efficacy endpoints included week 12 change on the BE CGI-Severity Scale (BE-CGI-S) and the Yale-Brown Obsessive-Compulsive Scale Modified for BE (YBOCS-BE). At week 12, treatment with dasotraline was associated with significant improvement in number of BE days per week on the dose of 6mg/d (N=162) vs placebo (N=162; -3.47 vs -2.92; P=.0045), but not 4mg/d (N=161; -3.21). Improvement vs placebo was observed for dasotraline 6 and 4mg/d, respectively, on the BE-CGI-S (effect size [ES]: 0.37 and 0.27) and on the YBOCS-BE total score (ES: 0.43 and 0.29). The most common adverse events on dasotraline were insomnia, dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in blood pressure and pulse were minimal. Treatment with dasotraline 6mg/d (but not 4mg/d) was associated with significantly greater reduction in BE days per week. Both doses of dasotraline were generally safe and well-tolerated and resulted in global improvement on the BE-CGI-S, as well as improvement in BE related obsessional thoughts and compulsive behaviors on the YBOCS-BE. These results confirm the findings of a previous flexible dose study.

Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed

IntroductionThis post hoc study assessed the evidence-base for esketamine nasal spray for management of treatment-resistant depression (TRD) using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). MethodsData sources were four phase III randomized, double-blind studies including two positive studies (acute flexible-dose; maintenance) in patients with TRD. Key efficacy study outcomes: acute response (≥50% decrease from baseline on Montgomery–Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12). NNT, NNH were calculated for esketamine nasal spray+newly initiated oral antidepressant (esketamine+AD) vs. placebo+AD. ResultsIn the pivotal acute flexible-dose study, MADRS response (63.4% vs. 49.5%) and remission (48.2% vs. 30.3%) at 4 weeks resulted in NNT of 8 and 6 for esketamine+AD vs. placebo+AD. NNH values <10 included dissociation (26.1% vs. 3.7%), vertigo (26.1% vs. 2.8%), nausea (26.1% vs. 6.4%), dizziness (20.9% vs. 4.6%), and dysgeusia (24.3% vs. 11.9%). Discontinuation rates due to adverse events (AE) (7.0% vs. 0.9%) yielded NNH=17. LHH comparing MADRS remission vs. discontinuation due to AE was 17 vs. 6. Maintenance use of esketamine+AD demonstrated NNT values<10 for relapse and/or maintenance of remission. In maintenance study, discontinuation due to AE (2.6% vs. 2.1%) yielded NNH=178 (non-significant). LimitationsOnly dichotomous outcomes were included. ConclusionNNT<10 for efficacy outcomes suggests potential benefit of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times likely to result in acute remission vs. discontinuations due to AE.

168 Effect of Dasotraline on Body Weight in Patients with Binge-Eating Disorder

Binge-eating disorder (BED) is associated with obesity (BMI ≥30) in approximately 40-45% of patients. Dasotraline is a long-acting dopamine/norepinephrine reuptake inhibitor with a PK profile characterized by slow absorption and an elimination half-life of 47-77 hours, permitting once-daily dosing. In a recent placebo-controlled, flexible-dose study, dasotraline demonstrated significant efficacy in patients with BED. We now report an analysis from this study of the effect of dasotraline on body weight. Patients with moderate-to-severe BED, based on DSM-5 criteria, were randomized to 12 weeks of double-blind flexible-dose treatment with dasotraline (4-8 mg/d) vs. placebo. The primary efficacy outcome was number of binge-eating days/week. Mean change in body weight at Week 12 (assessed as a safety outcome) was analyzed by baseline body mass index (BMI, kg/m2) category. Inferential statistics were not performed. The safety population consisted of 317 patients (female, 84%; mean age, 38.2 years; mean weight, 97.3 kg). At baseline, the proportions of patients in each BMI category were as follows: normal (<25 kg/m2: 5.7%), overweight (25 to <30 kg/m2: 18.3%), obesity class I (30 to <35 kg/m2: 24.9%), class II (35 to <40 kg/m2: 29.3%), and class III (≥40 kg/m2: 21.8%). For the overall patient sample, treatment with dasotraline significantly reduced the number of binge-eating days per week vs. placebo (-3.74 vs. -2.75; P<0.0001; effect size = 0.74). Mean changes at Week 12 in weight (kg) for completers treated with dasotraline vs. placebo, by baseline BMI category, were as follows: normal weight (-4.6 vs. -0.2), overweight (-5.8 vs. +1.3), and combined obesity classes I-III (-6.2 vs. +0.3). Among obese patients (Class I-III, combined) treated with dasotraline, weight reduction (≥5%) was observed in 45.3% of patients (vs. 4.1% on placebo); and weight reduction ≥10% in approximately 13.7% of patients (vs. none on placebo). Weight-related adverse events, for dasotraline vs. placebo, consisted of decreased appetite (19.7% vs. 6.9%), decreased weight (12.1% vs. 0%), and increased weight (0.6% vs. 1.3%). Among patients completing 12 weeks of treatment with dasotraline, weight reduction ≥5% was observed in 45% of obese patients with a BMI ≥30. The most frequent weight-related adverse event was decreased appetite, reported in approximately one in five patients treated with dasotraline.Clinicaltrials.gov number: NCT02564588. Supported by funding from Sunovion Pharmaceuticals Inc.

Concentration-Effect Relationships of Psychoactive Drugs and the Problem to Calculate Therapeutic Reference Ranges.

Despite the obvious potential of Therapeutic Drug Monitoring (TDM) as a tool to optimize psychopharmacotherapy, especially treatment with mood-stabilizing, antidepressant and antipsychotic drugs, acceptance of TDM as a routine tool is still limited. A serious scientific argument against the regular use of TDM is the lack of evidence for a concentration-dependent clinical effect. The aim of this review was to highlight methodological problems leading to poor or even negative concentration-effect relationships and to show how therapeutically effective concentrations of psychoactive drugs can be determined using routine TDM databases. Reports on concentration-effect relationships of psychoactive drugs were analyzed with regard to applied methods. From routine TDM databases of patients who had been treated with antidepressant or antipsychotic drugs and whose improvement was measured by the clinical global impressions scale, mean and median drug concentrations were calculated and compared with reference ranges recommended by TDM guidelines. Few fixed-dose studies with adequate design and data analysis demonstrated a correlation between drug concentration and clinical effect for psychoactive drugs. Most studies, however, mostly retrospective analyses of TDM databases, failed to find significant concentration-effect relationships because of flexible dosing. They were not suitable for the determination of therapeutically effective drug concentrations. Using TDM databases of antidepressant and antipsychotic drug concentrations in blood of patients who were categorized as responders by the clinical global impressions score, the interquartile ranges of drug concentrations (25th-75th percent range) can be shown to be very close to the therapeutic reference ranges recommended in guidelines for TDM in psychiatry. This review provides a discussion on why simple correlation analyses of psychoactive drug concentrations in blood and clinical effects are obsolete for flexible-dose studies or TDM databases. TDM databases, however, can and should be used to calculate drug concentrations in blood of patients who had responded to the drugs. Interquartile ranges can be regarded and used as preliminary therapeutic reference ranges.

WHAT WE KNOW—AND DON'T KNOW—ABOUT THE PSYCHOSOCIAL IMPACT OF PSYCHIATRIC GENETIC INFORMATION

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1–7 mg/day; morning administration) in children (aged 6–12 years) and adolescents (aged 13–17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p < 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive–impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p < 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p < 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.

Adjunctive Brexpiprazole and Functioning in Major Depressive Disorder: A Pooled Analysis of Six Randomized Studies Using the Sheehan Disability Scale.

BackgroundPatients with major depressive disorder and inadequate response to antidepressant treatments may experience a prolonged loss of functioning. This post hoc analysis aimed to determine the effect of adjunctive brexpiprazole on functioning in such patients.MethodsA pooled analysis of data from the 6-week, randomized, double-blind treatment phases of 6 studies of adjunctive brexpiprazole (2 and 3 mg/d in fixed-dose studies; 1–3 mg/d in flexible-dose studies) vs placebo in patients with major depressive disorder and inadequate response to antidepressant treatments (NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT00797966, NCT01052077). Functioning was measured by change in Sheehan Disability Scale score from baseline to week 6.ResultsConsidering Sheehan Disability Scale mean score across all 6 studies (n = 2066 randomized), the least squares mean difference between antidepressant treatments + brexpiprazole and antidepressant treatments + placebo at week 6 was −0.40 (95% CI: −0.56, −0.23; P < .0001). Antidepressant treatments + brexpiprazole showed a greater benefit than antidepressant treatments + placebo on the social life (−0.45; −0.63, −0.27; P < .001) and family life (−0.50; −0.70, −0.31; P < .001) items but not on the work/studies item (−0.16; −0.38, 0.06; P = .16). Pooled analyses of just the (1) fixed-dose, (2) flexible-dose, and (3) Phase 3 studies showed the same pattern of benefits for antidepressant treatments + brexpiprazole.ConclusionsBrexpiprazole, as adjunct to antidepressant treatments, improved functioning in patients with major depressive disorder and inadequate response to antidepressant treatments.

Effect of Brexpiprazole on Prolactin

Hyperprolactinemia is an undesirable effect of most antipsychotics because of D2-receptor blockade. We assessed the effect of the D2-receptor partial agonist brexpiprazole on prolactin, based on pooled data from three 6-week, randomized, placebo-controlled studies and two open-label extension studies in patients with schizophrenia. In the short-term studies, patients received 0.25, 1, 2, 4 mg brexpiprazole or placebo; or flexible-dose brexpiprazole (2-4 mg/d), placebo, or active reference. The extension studies were 52-week, flexible-dose (1-4 mg/d) studies. We studied changes from baseline and shifts in prolactin status in patients with normal or elevated prolactin levels at baseline, and prolactin-related treatment-emergent adverse events (TEAEs). Median changes from baseline to week 6 in brexpiprazole-treated patients in short-term studies were as follows: 3.63 ng/mL (females), 0.26 ng/mL (males); placebo: -2.15 ng/mL (females), -1.08 ng/mL (males).Median changes from baseline to week 52 in long-term studies were 0.60 ng/mL (females) and 0.18 ng/mL (males). Prolactin levels in patients with baseline values greater than 1× upper limit of normal tended to decrease over time regardless of previous treatment.The proportions of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies were as follows: 1.5% (females), 1.6% (males); placebo: 3.6% (females), 3.4% (males). Corresponding figures in long-term studies were 5.3% (females) and 2.0% (males).In short-term studies, the incidence of prolactin-related TEAEs was 1.8% for brexpiprazole and 0.6% for placebo. In long-term studies, the incidence of prolactin-related TEAEs was 1.7%. Small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, and low incidence of prolactin-related TEAEs were observed after treatment with brexpiprazole.

Distinguishing the efficacy and sedative effects of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1–7 mg/day; morning administration) in children (aged 6–12 years) and adolescents (aged 13–17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p < 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive–impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p < 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p < 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.