New Compounds, Novel Strategies Reported at NCDEU

November 1, 2006

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.

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
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
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.

Flaxseed oil
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.

Drugs for anxiety
Studies of two investigational com pounds for generalized anxiety disorder were presented. Sanjay Mathew, MD, of the Mount Sinai School of Medicine in New York, reported on a study of a novel non-azapirone, serotonin (5HT)1A-selective antagonist (PRX00023, EPIX Pharmaceuticals). The compound was tested in open-label design in 21 patients over 4 weeks, with daily dosing titrated from 40 to 120 mg. Mathew indicated that the agent appeared effective in reducing anxiety symptoms on Hamilton Anxiety (HAM-A) scale ratings. No withdrawal or serious adverse effects were ob served, nor were there discontinuations because of adverse effects. Mathew an tic ipated that larger, placebo-controlled studies of the compound will follow.

Pregabalin (Lyrica) is an antiepileptic agent structurally related to, but without the actions of naturally occurring g-aminobutyric acid. It has been found to be useful in clinical trials for neuropathic pain, and has appeared to exert anxiolytic activity in animal models and in limited, short-term clinical trials. Pfizer researcher Jeri Brock, MS, de scribed a 1-year open-label study of pregabalin for generalized anxiety disorder involving 265 patients, with 140 completing 36 weeks and 68 completing the year. Brock reported anxiolytic effect and good tolerability, which appeared to be maintained over the course of the study. Dizziness and somnolence were among the most common adverse events, with 11% discontinuation be cause of adverse reactions.

Antipsychotics for depression or anxiety
Several studies evaluated the effectiveness of second-generation antipsychotics as adjunctive or monotherapy for nonpsychotic illnesses, such as major depression, bipolar depression, and anxiety. David Solomon, MD, of Brown University in Providence, RI, described a 4-week placebo-controlled trial of risperidone (Risperdal) 0.5 to 3 mg daily as augmentation for 97 patients who had not responded ade quately to a 5-week open-label antidepressant regimen.

Solomon reported reductions in Montgomery-Asberg Depression Rat ing Scale (MADRS) scores in both the antidepressant-risperidone group and the antidepressant-placebo group from the level seen after 5 weeks of treatment with the antidepressant alone. Remission from depression (MADRS score of 10 or lower) was achieved by 52% of the risperidone augmentation group and 24% of those continuing the antidepressant along with placebo.

Another study assessed quetiapine (Seroquel) augmentation for major depression in 32 patients in an 8-week, placebo-controlled design. Gregory W. Mattingly, MD, of St Charles (Mo) Psychiatric Associates, reported on the addition of 200 to 400 mg of quetiapine daily for 21 of the patients whose baseline HAM-D17 scores had remained at 20 or higher after 8 weeks' treatment with an antidepressant. Patients receiving the augmentation had a significantly lower HAM-D score (mean, 8.3) than those receiving the antidepressant-placebo combination (mean, 14.7).

Mattingly noted that 67% of patients receiving an antidepressant with quetiapine met the "responder" criterion of 50% or greater reduction in HAM-D, compared with 27% on the antidepressant-placebo combination; and 43% of the quetiapine group achieved the remission criterion of a HAM-D score of 7 or less, compared with 15% of those on the antidepressant without active augmentation.

Quetiapine was also studied as monotherapy for bipolar depression. Trisha Suppes, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas, summarized the results of 2 8-week clinical trials in volving 351 patients receiving 300 or 600 mg of quetiapine daily. The patients had exhibited moderate to severe de pression at baseline, but had significantly greater improvement in mean MADRS total scores with either dosage of quetiapine than those taking pla cebo, from the first to the eighth weekly assessment.

Suppes noted that quetiapine was generally well tolerated in both studies; and that it is one of the first agents to demonstrate efficacy as monotherapy for this condition. "This analysis of 2 major randomized, controlled trials is, to our knowledge, the largest evaluation to date of an atypical [antipsychotic] as monotherapy for bipolar II depression," Suppes indicated.A comparison of low and high doses of olanzapine or risperidone as adjunctive treatment for resistant depression was reported by Lakshmi Ravindran, MD, of the University of Toronto. Ravindran characterized the study as one of the few head-to-head comparisons of atypical antipsychotics as ad junctive treatment for treatment-resis tant depression.

Forty-three patients were selected for failing to benefit from an adequate trial of either an SSRI or the SNRI antidepressant venlafaxine. The patients were randomized to receive add-on treatment with either 0.5 to 1 mg or 2 to 3 mg daily risperidone; or olanzapine 2.5 to 5 mg or 10 to 15 mg daily. Ravindran reported that the antipsychotics were comparable as adjunctive treatments; and the addition of either antipsychotic in low dose was more effective than in high dose, or than the antidepressant alone, in reducing depressive symptom severity as measured on the HAM-D.

The utility of second-generation antipsychotics for generalized anxiety disorder was explored in a placebo-controlled trial of adjunctive risperidone, and in a trial of quetiapine monotherapy. Janssen Pharmaceutica re search er Gahan Pandina, PhD, described adding 6 weeks of either low-dose risperidone (mean, 0.9 mg daily) or placebo for 390 patients who re mained symptomatic after at least 8 weeks of anxiolytic treatment.

Although both groups were rated on the Most Troubling Symptom scale as significantly improved over baseline after 4 weeks, Pandina related post hoc analysis evidencing greater change from baseline with risperidone in the symptoms that were most severe at baseline: excessive anxiety or worry, restlessness, difficulty in sleeping, and being easily tired. Improvement in the secondary measure of the patient-rated Global Improvement Scale also favored adjunctive risperidone statistically sig nificantly over placebo add-on.

Quetiapine was provided for 6 weeks in daily doses of 25 to 300 mg to 38 patients with generalized anxiety disorder, after a 1-week placebo run-in peri od. Olga Brawman-Mintzer, MD, of the Medical University of South Carolina, Charleston, reported that there was no significant difference in reduction of HAM-A scores between the medicated and placebo groups. While these two trials would suggest that the agents are more likely to benefit patients with generalized anxiety disorder as adjunctive treatments than as monotherapy, Brawman-Mintzer indicated that additional studies with quetiapine as monotherapy are warranted.

Methylphenidate for depression
Methylphenidate, an agent for attention-deficit/hyperactivity disorder (ADHD), was studied for treatment-resistant depression in one report, while risperidone augmentation was evaluated for persistent aggression in ADHD in another. Prakash Masand, MD, described a 4-week placebo-controlled trial with the addition of an extended-release methylphenidate (Ritalin, Con certa, Metadate) 18 to 54 mg daily (mean, 34.2 mg) to a preexisting antidepressant regimen.

At end point, there was no significant difference between the addition of methylphenidate or placebo in re ducing depressive symptom severity. Masand acknowledged this apparent outcome, but also suggested that the results could reflect an inadequate power for statistical analysis, suboptimal dosing, and/or failure to account for comorbid ADHD.

Risperidone for ADHD
An evaluation of risperidone in 25 children with ADHD and aggressive behavior was reported by John Lewis, PhD, of the University of Miami. Patients re ceived either risperidone 0.5 to 2 mg (mean, 1.125 mg) daily or placebo in addition to their ADHD regimen. All 13 patients receiving risperidone dem onstrated at least a 30% improvement on the Children's Aggression Scale-Parent total score, as did a reported 77% of the patients receiving placebo add-on. Lewis indicated that risperidone was well tolerated, and characterized it as a "moderately effective" augmenting strategy for treatment-resistant aggression in children with ADHD.

This is part 2 of the 2-part coverage of the 2006 NCDEU meeting. Part 1 appeared in the October issue of Psychiatric Times.