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-HT1A]) 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-HT1A 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 > or =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< or =7), and response criteria (> or =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.

Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial.

PRX-00023, a serotonin 1A receptor agonist, was designed to provide high potency and selectivity for its target. To assess the possible therapeutic utility in anxiety, a randomized, double-blind, placebo-controlled trial was conducted in 311 subjects who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for generalized anxiety disorder. All subjects underwent a 1-week placebo run-in and were randomized to receive once-daily capsules containing either PRX-00023 (80 mg/d) or placebo for an additional 8 weeks. The primary outcome measure was the Hamilton Anxiety Scale (HAM-A). The Montgomery-Asberg Depression Rating Scale was used as a secondary endpoint to measure depressive symptoms. Statistical testing was performed with analysis of covariance, between baseline and week 8, with baseline values as a covariate. The anxiolytic effect of PRX-00023, compared with placebo, showed trends across all anxiolytic measures but failed to reach significance on the primary endpoint (HAM-A total score). Among the components of the HAM-A total score, the anxious mood item was significantly different from placebo in the PRX-00023-treated group (-1.015 vs -0.748; P = 0.02). The scores of the Montgomery-Asberg Depression Rating Scale were significantly improved compared with placebo at week 8 (-4.5 vs -1.6; P = 0.0094 in the last observation carried forward analysis). PRX-00023 was well tolerated; of note, there were no drug-related serious adverse events, and more patients discontinued due to adverse events in the placebo group (2.9%) than in the PRX-00023 group (1.4%). The most common adverse event was headache, observed in 15.7% and 10.9% of PRX-00023- and placebo-treated patients, respectively. Furthermore, there was no evidence of impaired sexual function, as measured by the Massachusetts General Hospital Sexual Function Scale. Collectively, these results support further clinical investigation of higher doses of PRX-00023 in anxiety and depression.

Tolerability, pharmacokinetics, and neuroendocrine effects of PRX-00023, a novel 5-HT1A agonist, in healthy subjects.

PRX-00023 is a novel, nonazapirone 5-HT1A agonist in clinical development for treatment of affective disorders. The objectives of the initial clinical phase I studies (a single ascending dose study and multiple dose-ascending and high-dose titration studies) were to measure the pharmacokinetics, pharmacodynamic (neuroendocrine) effects, and tolerability of PRX-00023 in healthy subjects. The studies evaluated 10-mg to 150-mg doses of PRX-00023 in up to 112 healthy male and female subjects aged 18 to 54 years. Single and multiple oral doses of PRX-00023 were found to be safe and well tolerated in healthy subjects. PRX-00023 was absorbed relatively rapidly, with a tmax of 0.5 to 2 hours, and eliminated with a half-life of approximately 12 hours. PRX-00023 treatment transiently increased blood prolactin levels 2 to 3 hours after administration, consistent with its mechanism as a 5-HT1A agonist.

Pharmacological manipulation of brain kynurenine metabolism.

The amino acid tryptophan is a precursor for the neurotransmitter serotonin as well as for kynurenic and quinolinic acids. These latter molecules are antagonists and agonists, respectively, of the excitatory amino acid glutamate and arise through the kynurenine pathway of tryptophan metabolism. Significant differences exist in the sites and physiological control of serotonin versus kynurenine. While serotonin is formed within serotonin neurons (in the brain and intestine) and neuroendocrine cells of the intestine, kynurenine is formed by liver cells (as a precursor to nicotinic acid) and in macrophages, activated by inflammatory cytokines. Our studies are based on the hypothesis that inhibition of kynurenine metabolism (at the kynurenine hydroxylase [KH] step) allows the amino acid to be converted to kynurenic acid, a neuroprotective antagonist of excitatory amino acid receptors. Inhibition of KH also prevents formation of the neurotoxic species 3-hydroxykynurenine and quinolinic acid. To accomplish this end, inhibitors were identified and are described.