Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial.

Background: Like other alpha-2-adrenergic receptor agonists, dexmedetomidine may reduce the severity of opioid withdrawal but with fewer adverse cardiovascular effects.Objective: This study assessed the safety of sublingual dexmedetomidine (BXCL501) and its preliminary efficacy in treating opioid withdrawal (ClinicalTrials.gov: NCT04470050).Methods: Withdrawal was induced among individuals with physiological dependence on opioids via discontinuation of oral morphine (Days 1-5). Participants were randomized to receive placebo or active BXCL501: 30, 60, 90, 120, 180, and 240 µg twice daily (Days 6-12). Treatment-emergent adverse events (TEAEs) were the primary outcome measure. Secondary outcomes included the Clinical and Subjective Opiate Withdrawal Scales (COWS and SOWS-Gossop, respectively), and the Agitation and Calmness Evaluation Scale (ACES).Results: Of 225 participants enrolled, 90 discontinued during morphine stabilization. Post-BXCL501 randomization (Day 6) data were available from 135 participants (73% male), with 33% completing thru Day 12. In total, 36 subjects reported 1 or more TEAE. Higher doses of BXCL501 (i.e. 180 and 240 µg, twice daily) increased the frequency of: hypotension, orthostatic hypotension, and somnolence. TEAEs related to BXCL501 were mild or moderate in severity, except for one participant in the 120 µg condition whose orthostatic hypotension and bradycardia were classified as severe. Higher BXCL501 dose conditions (120, 180, and 240 µg) resulted in statistically significant reductions in COWS & SOWS scores. Mean ratings on the ACES were between 3 (mild), 4 (normal), and 5 (mild calmness), with few significant differences as a function of dose.Conclusions: These findings support the continued development of BXCL501 for the management of opioid withdrawal.

Sublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial.

Objective: Determine if sublingual dexmedetomidine, a selective α2 adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder.Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 µg, 120 µg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose.Results: Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African American) were randomized; 380 (100%) self-administered study medication, and 372 (97.9%) completed the study. The mean PEC total score at baseline (17.6) indicated mild to moderate agitation. At 2 hours postdose, the least squares mean changes (SE) from baseline were -10.3 (0.4) for sublingual dexmedetomidine 180 µg, -8.5 (0.4) for 120 µg, and -4.8 (0.4) for placebo. Least squares mean differences (97.5% confidence intervals) in the sublingual dexmedetomidine groups were -5.5 (-6.7 to -4.3) for 180 µg and -3.7 (-4.9 to -2.5) for 120 µg (both P < .001 vs placebo). The most commonly encountered adverse events with dexmedetomidine (incidence ≥ 5% and ≥ 2× rate observed with placebo) were somnolence, dry mouth, and hypotension for the 120 µg dose, and somnolence, dizziness, orthostatic hypotension, and oral hypoesthesia for the 180 µg dose.Conclusions: Treatment with sublingual dexmedetomidine 180 µg or 120 µg was more efficacious than placebo in reducing acute agitation associated with schizophrenia as measured by PEC scores at 2 hours postdose.Trial Registration: ClinicalTrials.gov identifier: NCT04268303.

Sublingual Dexmedetomidine for Agitation Associated with Schizophrenia or Bipolar Disorder: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed.

INTRODUCTION: The objective was to use the evidence-based medicine metrics of number needed to treat, number needed to harm, and likelihood to be helped or harmed to appraise the clinical efficacy and tolerability of sublingual dexmedetomidine in adults with agitation associated with schizophrenia or bipolar disorder. METHODS: Sublingual dexmedetomidine data for this post hoc analysis were obtained from two similarly designed, double-blind, randomized, placebo-controlled studies of adults with schizophrenia or bipolar disorder. Response to treatment was defined as a ≥ 40% reduction from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC). Tolerability was assessed by evaluating rates of adverse events. RESULTS: The number needed to treat (95% confidence interval) estimate versus placebo for PEC response at 2 h post-dose was 3 (2, 3) for the sublingual dexmedetomidine 180-µg group (n = 125) and 3 (3, 4) for the 120-µg group (n = 129) in the study of patients with schizophrenia and 3 (2, 3) for the sublingual dexmedetomidine 180-µg group (n = 126) and 4 (3, 6) for the 120-µg group (n = 126) in the study of patients with bipolar disorder. Number needed to harm values versus placebo were greater than 10 for all adverse events except somnolence, where the number needed to harm (95% confidence interval) was 7 (5, 10) for all doses pooled from both studies. In all instances, likelihood to be helped or harmed values were greater than 1 for efficacy versus applicable tolerability outcomes. CONCLUSIONS: The number needed to treat, number needed to harm, and likelihood to be helped or harmed of sublingual dexmedetomidine support a favorable benefit-risk profile in adults with acute agitation associated with schizophrenia or bipolar disorder. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT04268303 , NCT04268303. CLINICALTRIALS: gov, https://clinicaltrials.gov/ct2/show/NCT04276883 , NCT04276883.

Effect of Sublingual Dexmedetomidine vs Placebo on Acute Agitation Associated With Bipolar Disorder: A Randomized Clinical Trial.

Importance: Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior. Objective: To evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study. Interventions: Participants were randomized to 3 groups: sublingual dexmedetomidine 180 µg (n = 127), sublingual dexmedetomidine 120 µg (n = 127), or placebo (n = 126). Main Outcomes and Measures: The primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025. Results: Of 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were -10.4 for sublingual dexmedetomidine 180 µg, -9.0 for sublingual dexmedetomidine 120 µg, and -4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were -5.4 (97.5% CI, -6.6 to -4.2) for 180 µg and -4.1 (97.5% CI, -5.3 to -2.9) for 120 µg (both doses P < .001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 µg, -1.1 [97.5% CI, -2.0 to -0.2]; P = .007; for 120 µg, -1.0 [97.5% CI, -1.9 to -0.1]; P = .009). Adverse events occurred in 35.7% of patients taking 180 µg of dexmedetomidine, 34.9% taking 120 µg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 µg, 120 µg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%). Conclusions and Relevance: Among patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 µg or 180 µg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size. Trial Registration: ClinicalTrials.gov Identifier: NCT04276883.

Effect of aripiprazole lauroxil in patients with acute schizophrenia as assessed by the Positive and Negative Syndrome Scale-supportive analyses from a Phase 3 study.

OBJECTIVE: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints. METHODS: Patients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression-Improvement (CGI-I) scale score, was also analyzed. RESULTS: Of 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92-94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo. CONCLUSION: AL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.

Durability of Therapeutic Response With Long-Term Aripiprazole Lauroxil Treatment Following Successful Resolution of an Acute Episode of Schizophrenia.

OBJECTIVE: To evaluate durability of therapeutic effect of long-term treatment with aripiprazole lauroxil in patients with schizophrenia following successful treatment of an acute psychotic episode. METHODS: This post hoc analysis assessed long-term outcomes for a subgroup of patients who entered a 52-week extension study after being successfully stabilized with one of 2 doses of aripiprazole lauroxil (441 or 882 mg) in a pivotal 12-week, placebo-controlled, randomized clinical trial. Durability of therapeutic effect was measured by the proportion of patients completing the 1-year course of aripiprazole lauroxil, the trajectories of the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity (CGI-S) item scores beyond the first 12 weeks, and the likelihood of remission at any follow-up point. RESULTS: In total, 181 patients treated with aripiprazole lauroxil entered the extension study; 73% and 66% of patients from the 441 mg and 882 mg groups, respectively, completed all 13 aripiprazole lauroxil treatments scheduled every 4 weeks over 52 weeks. Both groups continued on a positive trajectory of symptom improvements (P < .0001 for reductions in PANSS total and CGI-S scores from week 12 to end of follow-up). Most patients (74% and 68% in the aripiprazole lauroxil 441 mg and 882 mg groups, respectively) achieved remission during follow-up. CONCLUSIONS: These post hoc analyses of a subgroup of patients demonstrate the continued therapeutic efficacy of aripiprazole lauroxil after successful treatment of an acute episode of schizophrenia. Both the 441 mg and 882 mg groups had similar retention rates, degree of symptom improvement, and likelihood of remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; European Clinical Trials Database (EudraCT) numbers: 2012-003445-15 and 2012-003996-20​​​​.

A Phase-1 Study Comparing Pharmacokinetic and Safety Profiles of Three Different Dose Intervals of Aripiprazole Lauroxil.

BACKGROUND: Aripiprazole lauroxil (AL) is an FDA-approved treatment for schizophrenia. AL is a non-ester prodrug of aripiprazole that results in extended systemic release of aripiprazole after intramuscular (IM) administration. This Phase-1 study evaluated the pharmacokinetics (PK) and safety of a new AL dose (1064 mg)* for 2-month dose intervals. The study also evaluated 4- and 6-week dose intervals of AL at the 441 mg and 882 mg doses, respectively. METHODS: A total of 139 patients diagnosed with schizophrenia and stabilized on a first-line antipsychotic (other than aripiprazole) were randomized to one of 3 dose/dose-interval groups: a 4-week interval of AL 441 mg (n = 35), a 6-week interval of AL 882 mg (n = 34), and an 8-week interval of AL 1064 mg IM injection (n = 70). After randomization, AL assignment was open label and administered as gluteal injections over 24 weeks. The total number of injections over this time period was related to the interval: 7 injections for the 441 mg group, 5 for the 882 mg group, and 4 for the 1064 mg group. PK and safety assessments occurred every 2 weeks and extended for an additional 20 weeks after the last injection. Patients continued their prior antipsychotic throughout, such that the safety (but not the PK) findings also reflect a second antipsychotic co-prescribed with AL. RESULTS: PK findings: administration of AL 1064 mg every 8 weeks and AL 882 mg every 6 weeks provided continuous exposure to aripiprazole. Compared with the AL 441 mg every 4 weeks group, the longer dose-interval groups had consistently higher plasma concentrations for the entirety of the 6- and 8-week dose intervals for the 882 mg and 1064 mg dose groups. Safety findings: the overall safety profile of the group randomized to the 8 week/1064 mg combination was comparable to the 6 week/882 mg and 4 week/441 mg groups. The most common adverse event (AE) for all groups was injection-site reaction (pain). There was no apparent dose-AE signal for extrapyramidal symptoms, akathisia, sedation, or weight gain. In particular, there was no other safety signal identified with the longest interval/highest-dose AL group of 8 weeks/1064 mg. CONCLUSION: AL allows for a range of dose/dose-interval combinations. The PK results from this study show that a dosing interval of every 8 weeks for the 1064 mg dose resulted in aripiprazole concentrations within the established therapeutic window for AL. There was no safety signal directing any particular concern to any of the three doses/dose intervals studied. All patients continued their primary antipsychotics without any apparent tolerability issue arising from the addition of the AL injections. The results of this study show that 1064 mg AL may be suitable for a 2-month dose interval. The three doses/dose intervals studied have the potential to help clinicians and patients expand their choice of AL treatment to best meet the needs of the individual patient.

Metabolic and Endocrine Profiles During 1-Year Treatment of Outpatients with Schizophrenia with Aripiprazole Lauroxil.

BACKGROUND: We assessed long-term metabolic and endocrine profiles of outpatients with schizophrenia participating in a one-year open-label extension study of monthly aripiprazole lauroxil (AL), a long-acting injectable antipsychotic. METHODS: Patients (N = 478) were enrolled in a 52-week, open-label extension study of AL monotherapy administered by intramuscular injection every 4 weeks. Of these, most (368) received AL 882 mg and the remainder AL 441 mg as their fixed-dose regimen. Among the patients entering the long-term study, 181 (38%) had already received three prior AL injections. The baseline values for this analysis were obtained from the visit before the first AL injection. Patients were followed for the full year of the extension study unless they discontinued early. Changes in metabolic parameters (weight, fasting blood sugar, lipids) and serum prolactin were assessed over the duration of AL exposure, which could extend to a total of 16 AL injections. Data presented are last observation carried forward from baseline to last visit. RESULTS: Most patients remained for most of the follow-up period, with 409 (86%) remaining at 6 months and 326 (68%) completing the one-year treatment period. The mean (standard deviation) changes from baseline in the overall population were: +1.1 (27.5) mg/dL for glucose, +0.07 (0.6)% for glycated hemoglobin (HbA1c), -3.3 (35.8) mg/dL for total cholesterol and -5.3 (101.9) mg/dL for triglycerides. Prolactin change from baseline was -8.7 ng/mL (14.7) for men and -14.9 (43.4) ng/mL for women. Overall, the mean weight change was +0.8 (5.9) kg. In terms of categorical weight change, 88 patients (18%) gained ≥7% body weight, and 59 (12%) lost ≥7% body weight. Overall, there was no clinically meaningful difference between any of these variables and AL dose. CONCLUSION: Long-term treatment with AL in outpatients with schizophrenia was associated with a modest lowering of serum prolactin for both genders and relatively modest changes in average weight, fasting glucose, and HbA1c values. There appeared to be little net change in lipid parameters. This presentation extends a recently published report on the short-term metabolic and endocrine effects of AL over a period of 12 weeks. The present study increased the follow-up period to more than a year and was careful to use the first exposure to AL as the baseline. Limitations include lack of a comparison group and difficulty disentangling effects of medication treatment versus factors. Overall, the metabolic, weight, and endocrine effects reported here are consistent with other long-term effects of oral aripiprazole treatment. This study was funded by Alkermes, Inc.

Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation.

Aripiprazole lauroxil (AL), a new long-acting injectable antipsychotic, demonstrated safety and efficacy in treating acute exacerbation symptoms of schizophrenia in a 12-week placebo-controlled trial of two doses of AL (441mg and 882mg) administered every 4weeks. We performed a post hoc analysis of this trial to evaluate the efficacy of AL in the subgroup of patients with severe psychotic symptoms, defined as those with baseline Positive and Negative Syndrome Scale (PANSS) Total score above the median score of 92 (n=309). Change from baseline to Day 85 in PANSS Total score; Positive, Negative, and General Psychopathology subscale scores; and overall response rate were assessed. Statistically significant and clinically meaningful improvements in PANSS Total score were demonstrated with AL 441mg and AL 882mg, with placebo-adjusted differences of -14.7 (p<0.0001) and -16.6 (p<0.0001), respectively. Significant and clinically meaningful findings with both doses of AL were also demonstrated for the PANSS subscales and responder rates. Overall responder rates at Day 85 were significantly greater for AL 441mg (49%; p<0.001) and 882 mg (61%; p<0.001) groups vs. placebo (18%). Common adverse events (>5%) were schizophrenia, akathisia, headache, insomnia, and anxiety. AL demonstrated robust efficacy in treatment of the subgroup of patients experiencing severe psychotic symptoms. Both doses (441mg and 882mg) were effective, with numerically greater improvement in symptoms and proportion of responders favoring the higher dose arm. Both doses had a side effect profile consistent with the known safety profile of aripiprazole.

Effect of patient age on treatment response in a study of the acute exacerbation of psychosis in schizophrenia.

Younger patients with schizophrenia have most likely experienced fewer adverse consequences of the illness than older patients who may have experienced a lifetime of treatment as well as socio-economic problems as a consequence of the illness. There is limited information regarding differential efficacy of long-acting injectable (LAI) antipsychotic medications across the age span in patients with schizophrenia. We conducted a post hoc age and gender analysis of treatment response to aripiprazole lauroxil (AL; ARISTADA®; Alkermes, Inc.), in a 12-week, double-blind, placebo-controlled, multinational, Phase 3 study evaluating two doses of AL (441mg and 882mg) versus placebo in adult patients experiencing an acute exacerbation of schizophrenia within the previous 2months. We examined change in the total Positive and Negative Syndrome Scale (PANSS) scores from baseline using analysis of covariance and categorical treatment response (defined as ≥30% total PANSS score improvement from baseline) in the following age groups: <30, 30-39, 40-49, and 50-69years old. Age and gender did not moderate the treatment response in this study. Both AL 441mg and AL 882mg showed an early and significant improvement of the mean total PANSS scores and categorical treatment responses compared to placebo in all four age groups, including younger patients regardless of gender that was sustained over the 85-day treatment period.

Effect of Aripiprazole Lauroxil on Metabolic and Endocrine Profiles and Related Safety Considerations Among Patients With Acute Schizophrenia.

OBJECTIVE: Aripiprazole lauroxil, a long-acting injectable antipsychotic, demonstrated safety and efficacy in treating symptoms of schizophrenia in a double-blind, placebo-controlled trial. Because the metabolic profile of antipsychotics is an important safety feature, the effects of aripiprazole lauroxil on body weight, endocrine and metabolic profiles, and safety were examined in a secondary analysis. METHODS: Patients with schizophrenia (DSM-IV-TR criteria) were randomly assigned to aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo intramuscularly once monthly between December 2011 and March 2014. Changes in body weight, body mass index, fasting blood glucose and serum lipids, glycosylated hemoglobin (HbA1c), and prolactin over 12 weeks were assessed. The incidence of treatment-emergent adverse events (AEs) was evaluated. RESULTS: Among 622 randomized patients, no clinically relevant changes from baseline to week 12 were observed for any serum lipid, lipoprotein, plasma glucose, or HbA1c value with placebo or either dose of aripiprazole lauroxil. Both doses of aripiprazole lauroxil were associated with reductions in mean prolactin levels, whereas placebo treatment was not. The mean (standard deviation) change from baseline for body weight was 0.74 (3.9) kg, 0.86 (3.7) kg, and 0.01 (3.6) kg for aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. AEs related to metabolic parameters were reported in 2.4%, 1.4%, and 2.4% of patients in the aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. CONCLUSIONS: Aripiprazole lauroxil was well tolerated, with a low-risk metabolic profile relative to published data for other antipsychotics. Changes similar to those observed with placebo were observed in the aripiprazole lauroxil groups for metabolic parameters, with modest weight gain in the active treatment groups over the 12-week course. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039.

Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia.

This study aimed to evaluate the effects of aripiprazole lauroxil on hostility and aggressive behavior in patients with schizophrenia. Patients aged 18-70 years with a diagnosis of schizophrenia and currently experiencing an acute exacerbation or relapse were randomized to intramuscular (IM) aripiprazole lauroxil 441 mg (n=207), 882 mg (n=208), or placebo (n=207) for 12 weeks. In post-hoc analyses, hostility and aggression were assessed by the Positive and Negative Syndrome Scale (PANSS) Hostility item (P7) and a specific antihostility effect was assessed by adjusting for positive symptoms of schizophrenia, somnolence, and akathisia. The PANSS excited component score [P4 (Excitement), P7 (Hostility), G4 (Tension), G8 (Uncooperativeness), and G14 (Poor impulse control)], and the Personal and Social Performance scale disturbing and aggressive behavior domain were also assessed. Of the 147 patients who received aripiprazole lauroxil 882 mg and with a baseline PANSS Hostility item P7 more than 1, there was a significant (P<0.05) improvement versus placebo on the PANSS Hostility item P7 score by mixed-model repeated-measures at the end of the study, which remained significant when PANSS-positive symptoms and somnolence or akathisia were included as additional covariates. The proportion with PANSS Hostility item P7 more than 1 at endpoint was significantly (P<0.05) lower with aripiprazole lauroxil versus placebo (53.6, 46.1, and 66.3% for 441, 882 mg, and placebo). A significant (P<0.05) improvement was found with aripiprazole lauroxil versus placebo for change from baseline in the PANSS excited component score. The proportion of patients with aggressive behavior on the Personal and Social Performance scale was significantly (P<0.05) lower for aripiprazole lauroxil: 30.0% for 441 mg versus 44.1% for placebo (P=0.006) and 22.2% for 881 mg (P<0.001 versus placebo). Treatment with aripiprazole lauroxil resulted in decreases in agitation and hostility in patients with schizophrenia and this antihostility effect appears to be independent of a general antipsychotic effect.

A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia.

OBJECTIVE: This study evaluated the efficacy, safety, and tolerability of aripiprazole lauroxil, a novel long-acting injectable atypical antipsychotic, for the treatment of schizophrenia. METHOD: An international multicenter, randomized, double-blind, placebo-controlled trial was conducted between December 2011 and March 2014. Patients (N = 623) aged 18 to 70 years with schizophrenia (DSM-IV-TR criteria), experiencing an acute exacerbation, were randomized in a 1:1:1 ratio to receive gluteal intramuscular injection of aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or matching placebo once monthly for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to day 85. The Clinical Global Impressions-Improvement scale (CGI-I) score at day 85 was the secondary efficacy outcome. Safety and tolerability were assessed. RESULTS: The PANSS total score (mean ± standard error [SE]) improved significantly from baseline to day 85 in the aripiprazole lauroxil 441 mg and 882 mg groups, with placebo-adjusted differences of -10.9 ± 1.8 (P < .001) and -11.9 ± 1.8 (P < .001), respectively. Significant (P ≤ .004) improvements in both active treatment groups were demonstrated as early as day 8 and continued throughout the treatment period. The proportion of patients who were very much or much improved on the CGI-I was significantly greater with aripiprazole lauroxil 441 mg and 882 mg treatment versus placebo (P < .001). The most common treatment-emergent adverse events were insomnia, akathisia, headache, and anxiety. The incidence of injection site reactions was low, predominantly described as injection site pain, and was associated with the first injection. CONCLUSIONS: Aripiprazole lauroxil demonstrated robust efficacy for treatment of patients experiencing acute exacerbation of schizophrenia. The improvement in psychotic symptoms was statistically significant and clinically meaningful. Symptom improvement occurred rapidly after initiation of aripiprazole lauroxil treatment and was maintained throughout the study. Both aripiprazole lauroxil 441 mg and 882 mg doses were well tolerated. These results support aripiprazole lauroxil as an important new treatment option for schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; Clinicaltrialsregister.eu identifier: 2012-003445-15.

Safety, pharmacokinetic, and positron emission tomography evaluation of serotonin and dopamine transporter occupancy following multiple-dose administration of the triple monoamine reuptake inhibitor BMS-820836.

RATIONALE: BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine. OBJECTIVE: This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [(11)C]MADAM or [(11)C]PE2I, respectively. METHODS: Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1-4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4-8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions. RESULTS: Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0-5.5 h post-dose; estimated elimination half-life was 44-74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose. CONCLUSIONS: Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.

Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia.

Aripiprazole lauroxil is a linker lipid ester of aripiprazole for extended-release intramuscular (IM) injection. This multicenter, randomized, open-label study evaluated the pharmacokinetics (PK), relative bioavailability, and tolerability of a single IM deltoid or gluteal injection of aripiprazole lauroxil in adult subjects with chronic stable schizophrenia or schizoaffective disorder. Forty-six subjects were randomized 1:1 to aripiprazole lauroxil 441 mg IM in the deltoid or gluteal muscle. Samples were collected through 89 days post-dose to measure levels of aripiprazole lauroxil, N-hydroxymethyl aripiprazole, aripiprazole, and dehydro-aripiprazole. Forty-three (93.5%) subjects completed all study assessments; most were CYP2D6 extensive or immediate metabolizers (96%); two (4%) were poor metabolizers. The PK of aripiprazole following aripiprazole lauroxil was characterized by a steady rise in plasma concentrations (Tmax 44-50 days), a broad peak, and prolonged exposure attributable to the dissolution of aripiprazole lauroxil and formation rate-limited elimination of aripiprazole (t1/2=15.4-19.2 days). Deltoid vs. gluteal administration resulted in slightly higher Cmax aripiprazole concentrations [1.31 (1.02, 1.67); GMR 90% CI]; total exposure (AUCinf) was similar between sites of administration [0.84 (0.57, 1.24)]. N-hydroxymethyl-aripiprazole and dehydro-aripiprazole exposures were 10% and 33-36%, respectively, of aripiprazole exposure following aripiprazole lauroxil. The most common adverse events were injection site pain in 20 subjects (43.5%) and headache in 6 subjects (13.0%) of mild intensity occurring at a similar rate with deltoid and gluteal administration. Exposure ranges with deltoid and gluteal administration overlapped, suggesting that these sites may be used interchangeably. Despite a higher incidence of adverse events, deltoid muscle provides a more accessible injection site and could facilitate patient acceptance.

Evaluation of safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled, ascending single-dose study.

RATIONALE: BMS-820836, a novel triple monoamine reuptake inhibitor, is an experimental monotherapy for sufferers of major depressive disorder who have had an inadequate response to an existing antidepressant treatment. OBJECTIVES: This study was conducted to evaluate the safety and tolerability, pharmacokinetics (PK), and serotonin transporter (SERT) and dopamine transporter (DAT) occupancy for single doses of BMS-820836 in healthy subjects. METHODS: Healthy subjects were assigned to seven BMS-820836 dose panels (0.025, 0.1, 0.5, 1, 2, 3, and 5 mg; n = 8 each), in which subjects were randomly allocated 3:1 to a single BMS-820836 dose or matched placebo. Serial blood samples were collected on Days 1, 2, 3, 4, 7, and 14 to characterize the PK of BMS-820836. Following evaluation of the maximum tolerated dose, SERT occupancy was determined by applying [(11)C]DASB positron emission tomography (PET) after single-dose BMS-820836 (0.5 or 3 mg; n = 3 each) and DAT occupancy by applying [(11)C]PE2I PET after single-dose BMS-820836 (3 mg; n = 6). RESULTS: Single oral doses of BMS-820836 (0.025-3 mg) were generally safe and well tolerated. BMS-820836 had a median T max of 5.0-7.2 h and a mean apparent terminal T 1/2 of 34-57 h. Mean striatal SERT occupancies were 19 ± 9 % and 82 ± 8 % after single doses of 0.5 and 3 mg BMS-820836, respectively. The mean striatal DAT occupancy was 19 ± 9 % after a single 3 mg BMS-820836 dose. CONCLUSIONS: Single doses of BMS-820836 have meaningful SERT and DAT occupancy and demonstrate an acceptable safety and tolerability profile in healthy control subjects.

Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans.

Addiction is a chronic relapsing disorder hypothesized to be produced by drug-induced plasticity that renders individuals vulnerable to craving-inducing stimuli such as re-exposure to the drug of abuse. Drug-induced plasticity that may result in the addiction phenotype includes increased excitatory signaling within corticostriatal pathways that correlates with craving in humans and is necessary for reinstatement in rodents. Reduced cystine-glutamate exchange by system x(c)- appears to contribute to heightened excitatory signaling within the striatum, thereby posing this as a novel target in the treatment of addiction. In the present report, we examined the impact of repeated N-acetyl cysteine, which is commonly used to activate cystine-glutamate exchange, on reinstatement in rodents in a preclinical study and on craving in cocaine-dependent humans in a preliminary, proof-of-concept clinical experiment. Interestingly, repeated administration (7 days) of N-acetyl cysteine (60 mg/kg, IP) produced a significant reduction in cocaine (10 mg/kg, IP)-induced reinstatement, even though rats (N=10-12/group) were tested 24 h after the last administration of N-acetyl cysteine. The reduction in behavior despite the absence of the N-acetyl cysteine indicates that repeated N-acetyl cysteine may have altered drug-induced plasticity that underlies drug-seeking behavior. In parallel, our preliminary clinical data indicate that repeated administration (4 days) of N-acetyl cysteine (1200-2400 mg/day) to cocaine-dependent human subjects (N=4 per group) produced a significant reduction in craving following an experimenter-delivered IV injection of cocaine (20 mg/70 kg/60 s). Collectively, these data demonstrate that N-acetyl cysteine diminishes the motivational qualities of a cocaine challenge injection possibly by altering pathogenic drug-induced plasticity.

Expectation modulates human brain responses to acute cocaine: a functional magnetic resonance imaging study.

BACKGROUND: Human expectation of psychoactive drugs significantly alters drug effects and behavioral responses. However, their neurophysiological mechanisms are not clear. This study investigates how cocaine expectation modulates human brain responses to acute cocaine administration. METHODS: Twenty-six right-handed non-treatment-seeking regular cocaine abusers participated in this study. Changes in blood oxygenation level-dependent (BOLD) signals were measured, and online behavioral ratings during cocaine expectation and acute cocaine administration were recorded. RESULTS: Distinct regional characteristics in BOLD responses to expected and unexpected cocaine infusions were observed in the medial orbitofrontal gyrus (Brodmann area [BA] 11), frontal pole (BA 10), and anterior cingulate gyrus regions. Active engagement in the amygdala and the lateral orbitofrontal cortex (OFC; BA 47) by unexpected but not expected cocaine infusion was discovered. Cocaine expectation did not change BOLD responses to acute cocaine administration in a set of subcortical substrates, the nucleus accumbens, ventral putamen, ventral tegmental area, and thalamus. CONCLUSIONS: These results suggest that cocaine expectation modulates neural-sensitivity adaptation between the expected events and the actual outcomes but did not modulate the pharmacological characteristics of cocaine. In addition, the amygdala-lateral OFC circuitry plays an important role in mediating stimulus-outcome relations and contextual factors of drug abuse.