Kenneth S. Koblan

Dasotraline for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial in Adults

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity associated with clinically significant impairment in functioning. ADHD has an early onset, but frequently persists, with a prevalence estimate of 4% in adults. Dasotraline is a novel compound that is a potent inhibitor of dopamine and norepinephrine transporters that achieves stable plasma concentrations with once-daily dosing. In this study, adult outpatients meeting DSM-IV-TR criteria for ADHD were randomized to 4 weeks of double-blind, once-daily treatment with dasotraline 4 and 8 mg/day or placebo. The primary efficacy end point was change from baseline at week 4 in the ADHD Rating Scale, Version IV (ADHD RS-IV) total score. Secondary efficacy end points included the Clinical Global Impression, Severity (CGI-S) scale, modified for ADHD symptoms. Least squares (LS) mean improvements at week 4 in ADHD RS-IV total score were significantly greater for dasotraline 8 mg/day vs placebo (−13.9 vs −9.7; P=0.019), and nonsignificantly greater for 4 mg/day (−12.4; P=0.076). The LS mean improvements in modified CGI-S were significantly greater at week 4 for dasotraline 8 mg/day vs placebo (−1.1 vs −0.7; P=0.013), and for 4 mg/day vs placebo (−1.1 vs −0.7; P=0.021). The most frequent adverse events reported were insomnia, decreased appetite, nausea, and dry mouth. Discontinuations due to treatment-emergent adverse events were 10.3% and 27.8% of patients in 4 and 8 mg/day treatment groups, respectively. This study provides preliminary evidence that once-daily dosing with dasotraline, a long-acting, dual monoamine reuptake inhibitor, may be a safe and efficacious treatment for adult ADHD.

Catechol-O-methyltransferase genotype as modifier of superior responses to venlafaxine treatment in major depressive disorder.

Responses to venlafaxine treatment in major depressive disorder were stratified by COMT genotypes (Val158Met, rs4680) in a randomized, double-blind, placebo-controlled clinical trial. Improvements in depression scores among subjects with Val/Val genotypes were larger than those in Met/Met genotypes, suggesting that venlafaxine may alter noradrenergic flux differentially according to COMT activity.

Assessment of human abuse potential of dasotraline compared to methylphenidate and placebo in recreational stimulant users

AIMS The aim of this study was to evaluate the abuse potential of dasotraline, a novel dopamine and norepinephrine reuptake inhibitor with slow absorption (tmax, 10-12h) and elimination (t1/2=47-77 h) that is in development for the treatment of attention deficit hyperactivity disorder (ADHD). METHODS Recreational stimulant users (N=48) who had specific experience with cocaine, and who were able to distinguish methylphenidate (60 mg) versus placebo in a qualification session, were randomized, in a 6-period, double-blind, crossover design, to receive single doses of dasotraline 8 mg, 16 mg, and 36 mg, methylphenidate (MPH) 40 mg and 80 mg, and placebo. The primary endpoint was the Drug Liking Visual Analog Scale (VAS) score at the time of peak effect (Emax). RESULTS There were no significant differences between the 3 doses of dasotraline and placebo on the drug liking VAS at Emax, and on most secondary endpoints. Both doses of MPH had significantly higher VAS-drug liking scores at Emax relative to both placebo (P<0.001 for all comparisons) and dasotraline 8 mg (P<0.001), 16 mg (P<0.001) and 36 mg (P<0.01). The increase in heart rate for MPH and dasotraline 36 mg showed a time-course that closely matched subject-rated measures such as Any Effects VAS. CONCLUSIONS In this study, dasotraline was found to have low potential for abuse, which may be, in part, related to its established pharmacokinetics (PK) profile, which is characterized by slow absorption and gradual elimination.

Differences in memory function between 5-HT1A receptor genotypes in patients with major depressive disorder

BACKGROUND While extensive literature on the role of the serotonin receptor 1A (5-HT1A-R) in cognition exists, the findings are largely from animal studies. There has been little research conducted into 5-HT1A-R genotypes and cognitive function in humans. This article evaluates the role of 5-HT1A-R genotypes on the profile of cognitive function in patients with major depressive disorder (MDD). METHODS The study sample was 455 MDD patients aged between 18 and 55 years. They had enrolled into a clinical trial and were tested prior to dosing on the baseline study day using the CDR System, an integrated set of 3 attention tests, 2 working memory tests, and 4 episodic memory tests. 5-HT1A-R genotyping for (SNP ID rs6295) had been conducted during the study screening period. RESULTS Validated factor scores were derived from the 9 tests. It was found that patients with the C/C genotype for the C(1019)G polymorphism of the 5-HT1A-R were significantly superior in retaining and retrieving information, in both working and episodic memory, than those with either the C/G or the G/G genotypes. No differences were found in measures of attention or in the speed of retrieval of information from memory. CONCLUSIONS This is, to our knowledge, the first relationship found between objective tests of cognitive function and 5-HT1A-R genotypes in MDD.

Transformed PANSS Factors Intended to Reduce Pseudospecificity Among Symptom Domains and Enhance Understanding of Symptom Change in Antipsychotic-Treated Patients With Schizophrenia

Abstract Positive and Negative Syndrome Scale (PANSS) total score is the standard primary efficacy measure in acute treatment studies of schizophrenia. However, PANSS factors that have been derived from factor analytic approaches over the past several decades have uncertain clinical and regulatory status as they are, to varying degrees, intercorrelated. As a consequence of cross-factor correlations, the apparent improvement in key clinical domains (eg, negative symptoms, disorganized thinking/behavior) may largely be attributable to improvement in a related clinical domain, such as positive symptoms, a problem often referred to as pseudospecificity. Here, we analyzed correlations among PANSS items, at baseline and change post-baseline, in a pooled sample of 5 placebo-controlled clinical trials (N = 1710 patients), using clustering and factor analysis to identify an uncorrelated PANSS score matrix (UPSM) that minimized the degree of correlation between each resulting transformed PANSS factor. The transformed PANSS factors corresponded well with discrete symptom domains described by prior factor analyses, but between-factor change-scores correlations were markedly lower. We then used the UPSM to transform PANSS in data from 4657 unique schizophrenia patients included in 12 additional lurasidone clinical trials. The results confirmed that transformed PANSS factors retained a high degree of specificity, thus validating that low between-factor correlations are a reliable property of the USPM when transforming PANSS data from a variety of clinical trial data sets. These results provide a more robust understanding of the structure of symptom change in schizophrenia and suggest a means to evaluate the specificity of antipsychotic treatment effects.

T109. CLUSTERING OF SCHIZOPHRENIA PATIENT SUBTYPES BY SPECIFIC SYMPTOM DIMENSIONS USING AN UNCORRELATED PANSS SCORE MATRIX (UPSM)

Abstract Background Interpretation of the efficacy of antipsychotic agents in treating schizophrenia using standard (Marder) Positive and Negative Syndrome Scale (PANSS) factors is confounded by moderate-to-high between-factor correlations. In previous pooled analyses of short-term, placebo-controlled lurasidone clinical trials, clustering and factor analysis identified an uncorrelated PANSS score matrix (UPSM) that generated transformed PANSS factor scores with high face validity (good correlation with standard [Marder] PANSS factors), and high specificity/orthogonality (low levels of between-factor correlation) at both baseline, and when measuring change during short-term treatment. In a validation analysis using 12 separate clinical trials, we previously confirmed that the weighted UPSM coefficients had generalizable utility, yielding transformed PANSS factors with high specificity while retaining good levels of correlation with standard PANSS factors. The aim of the current analysis was to determine whether distinct clinical subtypes of schizophrenia could be empirically derived from the transformed PANSS factor scores at baseline. Methods In a new analysis of a pooled sample of 5 placebo-controlled trials (N=1,710 patients), K-means clustering of baseline UPSM factor scores in MATLAB was used to identify whether clinical sub-groups could be empirically derived that were characterized by predominant symptom severity in one or more of the transformed PANSS factor domains. For each empirically derived domain thus identified, key demographic and clinical variables were examined, including baseline transformed PANSS factor severity scores [note: the weighted UPSM coefficient yields factor scores with numerical values that are much smaller than are observed with standard Marder factor scores]; and Montgomery-Åsberg Depression Rating Scale (MADRS) and Negative Symptom Assessment Scale (NSA) scores. Results Cluster analysis using the UPSM transformed PANSS Factor scores identified 5 distinct clinical subtypes defined by the severity of the UPSM Factor score relative to the mean score for all patients on the respective transformed PANSS factors. For the predominant positive cluster, the mean transformed PANSS positive factor score was 3.9 (vs. a mean score of 2.9 ± 0.9 SD for all patients); for the predominant hostile cluster, the hostility factor score was 2.6 (vs. a mean score of 1.4 ± 1.1); for the predominant disorganized cluster, the disorganized factor score was 3.0 (vs. 2.5 ± 1.0); for the affective cluster, the anxiety and depression factors, respectively, were 2.3 (vs. 1.8 ± 0.9) and 2.7 (vs. 1.7 ± 1.0); and for the predominant negative cluster, the apathy/avolition and deficit of expression factors, respectively, were 3.1 (vs. 2.5 ± 0.9) and 2.5 (vs. 1.8 ± 0.9). Patients in the predominant negative cluster had the highest NSA score (61 vs. a mean score overall of 53); and patients in the predominant affective cluster had the highest MADRS score (16 vs. a mean score overall of 11). Discussion These results provide evidence for a consistent underlying schizophrenia symptom structure and suggest the utility of UPSM transformed PANSS factors for characterizing clinical differences among clearly delineated clinical subpopulations, even within a clinical trial population of acute schizophrenia.

C-reactive protein and response to lurasidone in patients with bipolar depression

Prior studies suggest that the inflammatory biomarker c-reactive protein (CRP) holds promise for predicting antidepressant response in patients with major depressive disorder. The objective of this study was to evaluate whether CRP might similarly predict antidepressant responses to lurasidone in patients with bipolar I depression. Serum CRP concentration was measured prior to, and following, 6 weeks of treatment in 485 outpatients with bipolar I depression. Patients were randomized to receive monotherapy with lurasidone 20-60 mg/day (N = 161), lurasidone 80-120 mg/day (N = 162) or placebo (N = 162). CRP was assessed using the wide-range CRP assay (wr-CRP). The primary efficacy endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Mixed models and statistical interaction tests were applied to investigate the moderating effects of pre-treatment wr-CRP on clinical endpoints. CRP was evaluated as a log-transformed continuous variable and by clinically-relevant cut-points. Increasing pre-treatment wr-CRP level predicted a larger overall antidepressant response to lurasidone, as well as an increased response for a number of individual depressive symptoms. These moderating effects of pre-treatment wr-CRP remained significant after adjustment for potential confounds (e.g. baseline BMI and weight change). Treatment with lurasidone did not affect serum concentrations of CRP compared to placebo during the study. Elevated CRP level prior to treatment was associated with an enhanced clinical response to lurasidone in patients with bipolar I depression. If confirmed in future studies, CRP may represent a clinically useful diagnostic and predictive biomarker supporting a precision medicine approach to the treatment of bipolar depression.

Absorption, distribution, metabolism, and excretion of [14C]‐dasotraline in humans

Dasotraline is a dopamine and norepinephrine reuptake inhibitor, and the early clinical trials show a slow absorption and long elimination half‐life. To investigate the absorption, distribution, metabolism, and excretion of dasotraline in humans, a single dose of [14C]‐dasotraline was administered to eight healthy male adult volunteers. At 35 days, 90.7% of the dosed radioactivity was recovered in the urine (68.3%) and feces (22.4%). The major metabolic pathways involved were: (1) amine oxidation to form oxime M41 and sequential sulfation to form M42 or glucuronidation to form M43; (2) N‐hydroxylation and sequential glucuronidation to form M35; (3) oxidative deamination to form (S)‐tetralone; (4) mono‐oxidation of (S)‐tetralone and sequential glucuronidation to form M31A and M32; and (5) N‐acetylation to form (1R,4S)‐acetamide M102. A total of 8 metabolites were detected and structurally elucidated with 4 in plasma (M41, M42, M43, and M35), 7 in urine (M41, M42, M43, M31A, M32, M35, and (S)‐tetralone), and 3 in feces (M41, (S)‐tetralone, and (1R,4S)‐acetamide). The 2 most abundant circulating metabolites were sulfate (M42) and glucuronide (M43) conjugates of the oxime of dasotraline, accounting for 60.1% and 15.0% of the total plasma radioactivity, respectively; unchanged dasotraline accounted for 8.59%. The oxime M41 accounted for only 0.62% of the total plasma radioactivity and was detected only at early time points. M35 was a minor glucuronide metabolite, undetectable by radioactivity but identified by mass spectrometry. The results demonstrate that dasotraline was slowly absorbed, and extensively metabolized by oxidation and subsequent phase II conjugations. The findings from this study also demonstrated that metabolism of dasotraline by humans did not produce metabolites that may cause a safety concern.