Short-term tolerability of a nonazapirone selective serotonin 1A agonist in adults with generalized anxiety disorder: A 28-day, open-label study

Background: The serotonin 1A (5-hydroxytryptamine 1A [5-HT_1A]) receptor likely plays a critical role in anxiety pathophysiology. Objective: In this proof-of-concept investigation, we tested the short-term tolerability of PRX-00023, a nonazapirone 5-HT_1A selective partial agonist, in outpatients with generalized anxiety disorder (GAD). Methods: Patients with a diagnosis of GAD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Hamilton Anxiety (HAM-A) Rating Scale scores ≥20 were recruited. A 1-week, single-blind placebo run-in was followed by a 28-day,open-label treatment with PRX-00023 QD in a forced-titration protocol: 40 mg (days 1-4), 80 mg (days 5-14), and 120 mg (days 15-28). The primary outcome measures were tolerability and rate of completion of the study. Tolerability was recorded using a table of adverse events (AEs), and measured using laboratory tests, vital signs, and electrocardiogram (ECG) readings. Secondary outcomes included the baseline-to-end point change in HAM-A total score, percentage meeting remission (HAM-A≤7), and response criteria (≥50% reduction in HAM-A total score). Results: Twenty-three patients (56.5% female, 65.2% white; mean age, 37.4 years) were enrolled in the study. A total of 21 patients (91.3%) received study medication and 18 (78.3%) completed the study. Two patients withdrew for personal reasons, 1 was discontinued for noncompliance, and 1 was lost to follow-up. One patient was discontinued from the study due to a history of premature ventricular contractions deemed unrelated to the study drug. AEs were reported in 15 patients, with the most common being back pain (3 patients), influenza-like symptoms (without fever) (2), diarrhea (2), dyspepsia (2), and nausea (2). No serious AEs, withdrawal symptoms, ataxia/ dizziness, or sexual dysfunction were reported; there were no clinically significant laboratory, vital sign, or ECG abnormalities. Mean HAM-A total scores were significantly lower at study end point compared with enrollment (13.9 vs 22.9; P < 0.001), with 32% of patients achieving remission and 52% meeting response criteria. Conclusion: In this preliminary, short-term study, PRX-00023 appeared to be generally well tolerated in this sample of patients with GAD.