casopitant and Depressive-Disorder--Major

The difference in location between the receptor occupancy curve of an agonist and its functional response has been described as receptor reserve. This "reserve" for a specific receptor has been found to differ from tissue to tissue and between agonists acting on the same tissue. Recently, two structurally different neurokinin 1 (NK1) receptor antagonists were taken into human and both were tested as antidepressants and for insomnia. Vestipitant and Casopitant both have high affinity for the human NK1 receptor (pKi = 9.4 and 10.2, respectively). In human, at the chosen clinical doses, receptor occupancy was measured in the frontal cortex, at 24 hours post administration, as ∼90% for vestipitant (15 mg) and ∼100% for casopitant (30 mg). In patients with moderate to severe major depression, vestipitant given at 15 mg for 8 weeks showed no statistical significant benefit as measured by change in baseline in HAM-D total score; whereas casopitant at 80 mg achieved statistically significant improvement versus placebo at week 8 (LOCF HAMD17 = -2.7, p = 0.023). A lower dose of 30 mg showed a clear but not significant separation from placebo. However, in acute studies in insomnia, both vestipitant and casopitant at 15 mg and 30 mg, respectively, significantly reduced latency to persistent sleep, wakenings after sleep onset and increased total sleep time by similar amounts. These clinical results suggest that for major depression the receptor occupancy of an NK1 antagonist needs to be very high (almost 100%), whereas, for insomnia a lower occupation is sufficient to give clinical effect.

Topics: Antidepressive Agents; Depressive Disorder, Major; Fluorobenzenes; Humans; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Receptors, Neurokinin-1; Sleep Initiation and Maintenance Disorders; Tissue Distribution

Casopitant, an inhibitor of the neurokinin-1 receptor, and its mesylate salt, are being developed by GlaxoSmithKline plc for the potential treatment of chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), as well as for anxiety, depression and insomnia. Phase II trials are ongoing for anxiety, depression and insomnia, and further results are awaited from phase III trials of CINV and PONV. At the time of publication, it was expected that applications to the FDA for regulatory approval for CINV and PONV would be filed in 2008. Casopitant was previously being developed for the treatment of overactive bladder; however, in September 2007, this indication was no longer listed on the company's product pipeline.

Topics: Animals; Antiemetics; Anxiety Disorders; Clinical Trials as Topic; Contraindications; Depressive Disorder, Major; Drug Evaluation, Preclinical; Female; Fibromyalgia; Humans; Nausea; Neurokinin-1 Receptor Antagonists; Patents as Topic; Piperazines; Piperidines; Postoperative Nausea and Vomiting; Structure-Activity Relationship; Urinary Bladder, Overactive; Vomiting

Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = -2.7; 95% confidence interval, -5.1 to -0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = -1.7; 95% CI, -3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.

Topics: Adult; Antidepressive Agents, Second-Generation; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Paroxetine; Piperazines; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome