A 14 WEEK, RANDOMIZED, PLACEBO-CONTROLLED CROSS-OVER STUDY OF MULTILAYER RELEASE METHYLPHENIDATE CAPSULES (PRC-063) IN ADULT ADHD WITH AND WITHOUT ANXIETY DISORDER COMORBIDITY

Abstract

Background: Psychiatric comorbidity is the rule rather than the exception in adult Attention-deficit Hyperactivity Disorder (ADHD) subjects, with the commonest being anxiety disorders [1]. Anxiety comorbidity has been shown to be associated with greater symptom severity, treatment resistance, and greater functional impairment in ADHD [2]. Stimulant medications have been proven to be effective in improving symptoms of ADHD, however, the data comes from subjects without comorbidity. This trial evaluated the benefit of stimulant medication in ADHD subjects with and without anxiety comorbidity. Aims & Objectives: To evaluate the efficacy and tolerability of multilayer (sustained) release methylphenidate capsules (PRC-063) in adult patients with DSM-5 ADHD with and without anxiety disorder comorbidity. Methods: This was a 14-week, double-blind, placebo-controlled, flexible dose (25-100mg/day), crossover study conducted at 2 sites. Adult ADHD subjects fulfilling DSM5 criteria (N=61) with or without an anxiety disorder comorbidity of panic disorder, agoraphobia, generalized anxiety or social anxiety disorder were included. After 1 week placebo run in, participants were randomized to PRC-063 or placebo; the initial dose was 25mg/day and the dose was titrated up based on efficacy and tolerability to a maximum of 100mg/day over 4 weeks and the maximum dose was maintained for 2 more weeks (Phase 1). At week 7, all subjects were switched to placebo for 1 week before crossing over to the other condition (Phase 2). The ADHD Rating Scale (ADHD-RS-5) total score was the primary efficacy variable and response was defined as >or equal to 30% drop in ADHD-RS-5 plus a Clinical Global Impression- Improvement (CGI-I) score of <than or equal to 2. The secondary measures included CGI-I, CGI-severity (CGI-S), and Hamilton Anxiety Rating Scale (HAM-A). Also, several self-rated measures of symptoms and severity of ADHD, anxiety and comorbid depression were completed, as well as measures of functional impairment and deficits in executive functioning. Results: Comorbid anxiety disorder occurred in 49.2%. At Phase I baseline, there were no significant differences in ADHD-RS-5 or CGI-S between groups, but mean HAM-A score was significantly higher in those with comorbid anxiety (p=.01). The analyses showed that PRC-063 groups had significant improvement in both phases on the ADHD-RS-5 compared to placebo (p<.01). The mean change in ADHD- RS-5 for those who started with PRC-063 in phase 1 was 6.03 ± 2.38 (standard deviation=SD) (D=0.46) and 6.42 ± 2.14 SD (D=0.59) for those who received PRC-063 in phase 2. Also, the proportion of responders in the PRC-063 group was significantly greater than those in the placebo group in both Phase 1 (24.2% vs. 0%; χ2=7.8, df=1 p=.005) and Phase 2 (38.5% vs.3.3%, χ2=10.9, df=1 p<.001). No significant differences were found between those with and without comorbidity on change scores from Phase 1 baseline to end of Phase 1 or between Phase 2 baseline to the end of Phase 2, on either primary or secondary outcomes. Adverse events associated with PRC-063 were decreased appetite, insomnia, nasal congestion, headache, and dry mouth. Discussion & Conclusion: The rates of response to PRC-063 did not differ between ADHD subjects with and without anxiety comorbidity. It is suggested that this agent would be equally effective in the treatment of ADHD with and without anxiety comorbidity. Contrary to common misconception, PRC-063 was not observed to worsen anxiety symptoms. References: [1]Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. American Journal of Psychiatry. 2016;163(4):716-723. [2]Sobanski E, Brü ggemann D, Alm B, et al. Psychiatric comorbidity and functional impairment in a clinically referred sample of adults with attention-deficit/hyperactivity disorder (ADHD). European Archives of Psychiatry and Clinical Neuroscience. 2017;257(7):371-377.