Investigational drugs and novel applications of established agents for psychiatric illness were described in a number of reports at the 46th annual NIMH-sponsored New Clinical Drug Evaluation Unit (NCDEU) meeting in Boca Raton, Fla, June 12-15, 2006. Some highlights follow.
Paliperidone is a new compound from Janssen Pharmaceutica/Johnson & Johnson in phase 3 clinical trials for antipsychotic efficacy. An assessment by the FDA Psychopharmacologic Drugs Advisory Committee scheduled for September 7 was canceled by the agency's Division of Psychiatry Products, according to the manufacturer, be cause "it had not identified any issues at this time requiring Advisory Committee feedback."
Preclinical studies indicate that paliperidone selectively modulates dopaminergic activity by stimulating or antagonizing dopamine receptors depending on endogenous levels of dopamine activity. Three clinical studies of an extended-release formula for acute schizophrenia were reported at the NCDEU meeting.
Stephen Marder, MD, Veterans Affairs Integrated Service Networks, Los Angeles, described a US-based placebo-controlled trial of paliperidone 6 and 12 mg, and olanzapine (Zyprexa) 10 mg to ensure assay sensitivity, in approximately 400 patients. Paliper i done was significantly more effective than placebo in symptom reduction, as well as in its effect on personal and social functioning and quality of sleep. Extra pyramidal symptoms (EPS) were com parable with paliperidone 6 mg and olanzapine 10 mg but increased with the higher dose of paliperidone.
John Kane, MD, Zucker Hillside Hospital, Glen Oaks, NY, reported on an international arm of this study, involving 6-, 9-, and 12-mg daily paliperidone doses; placebo; or 10 mg of olanzapine in more than 600 patients. Another multicenter international trial assessed daily doses of 3, 9, and 15 mg. The results were similarly favorable relative to placebo, with dose-related increases in EPS observed with paliperidone 9, 12, and 15 mg.
Desvenlafaxine, a derivative of ven lafaxine (Effexor) from Wyeth, was also to be evaluated in the cancelled September advisory committee meeting. The manufacturer announced that "after further review of the data, the FDA decided it was no longer necessary to hold the ad visory com mittee meeting before issuing its action letter." The anticipated deadline for FDA action on the desvenlafaxine New Drug Application (NDA) was extended by 3 months until January 22, 2007, to allow the agency to con sider preclinical data received in the last quarter of the review period.
Two 8-week clinical studies pre sent ed at the NCDEU meeting indicated that desvenlafaxine had good effect on depressive symptoms and was generally well tolerated. Nicholas DeMartinis, MD, of the University of Connecticut, reported that in a trial with 461 patients, the 100- and 400-mg doses, but not the 200-mg dose, reduced scores on the Hamilton Depression Rating Scale (HAM-D) significantly more than placebo. All dose strengths were associated with significantly greater im provement of Clinical Global Impres sion scores.
In a multicenter international trial of the 200- and 400-mg doses in 375 patients, Wyeth researcher Lucia Septien-Velez, MD, reported both doses were associated with significantly greater improvement than placebo in mood symptoms. The most prominent adverse effect in both trials was nausea, and the side-effect profile of desvenlafaxine was considered consistent with that of the serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant class.
Although there have been some evaluations of omega-3 fatty acid (O3FA) supplementation for bipolar disorder and for depression, flaxseed oil, an O3FA source, has not been studied, according to Barbara Gracious, MD, of the University of Rochester (NY) Medical Center. Her group chose to study the product, she indicated, be cause of its "frequent over-the-counter use as an alternative/complementary supplement, and greater acceptance by young patients who often refuse fish oil."
Gracious described the study of flaxseed oil for possible mood-stabilizing effect in 44 children and adolescents with bipolar disorder. The patients were randomly selected to receive 16 weeks of flaxseed oil containing 550 mg of alpha-linoleic acid per gram or an olive oil placebo as adjunctive or monotherapy. Dosing was titrated by 2000 mg on each visit as tolerated, to 12,000 mg daily.
Although the group taking the flaxseed oil continued in the trial for an average 3 weeks longer than the placebo group, there was no statistical difference in mood stability be tween the groups. Gracious suggested that further study focus on fish source O3FAs.