New Products, Applications Assessed at NCDEU

(This is the third part of a series on the 2000 New Clinical Drug Evaluation Unit [NCDEU] meeting, held May 30 through June 2 in Boca Raton, Fla. Part I appeared in the September issue of Psychiatric Times, p36 and Part II appeared in October PT, p32-Ed.)

Evaluations of new drugs, new dosage formulations and new applications for currently approved drugs were a substantial portion of the scientific program at the 40th annual NCDEU meeting, which is sponsored by the National Institute of Mental Health.

Extrapolating from the long half-life of fluoxetine (Prozac) and its major active metabolite, norfluoxetine, Eli Lilly and Company researchers reported successfully developing a modified-release, enteric-coated 90 mg formulation for treating depression with a once-weekly administration. An application for the novel formulation was submitted to the U.S. Food and Drug Administration in March.

The effectiveness of the weekly dose for antidepressant maintenance was compared to fluoxetine 20 mg/day in patients with major depression who had improved in a 13-week open trial with the daily regimen. Mark Schmidt, M.D., and colleagues at Lilly continued 189 patients on daily fluoxetine. They converted 190 patients to the weekly formulation and 122 to placebo for 25 weeks in randomized, double-blind fashion. The active treatments were found to be similar in effectiveness and were associated with significantly lower relapse rate than placebo.

In a separate study with Lilly researchers in the United Kingdom, patient compliance with the weekly enteric-coated formulation was compared in 56 patients to compliance with daily fluoxetine in 53 patients over a 12-week study period. In comparison to the 83.2% baseline compliance over a four-week, open-label treatment with daily fluoxetine, the patients converted to weekly dosing were rated 85.9+21.4% compliant, while those continuing with daily dosing decreased to 79.4+16% compliance with their regimen.

An investigational transdermal delivery system for selegiline (Eldepryl), a selective monoamine (MAO)-B inhibitor approved for treatment of Parkinson's disease, was assessed for possible benefit of patients with major depression by Jay Amsterdam, M.D., and Alexander Bodkin, M.D. At six sites, 177 patients with a score of at least 20 on the Hamilton Rating Scale for Depression (HAM-D-17) were randomized in double-blind, parallel-groups to receive either the transdermal system (89 patients), which delivered 20 mg selegiline daily, or a placebo patch.

The investigators reported that their criteria for response of at least 50% reduction in HAM-D score was met in 37% of those receiving medication, compared with 24% of those on placebo. Response on the Clinical Global Impression (CGI) scale was found in 42% of medicated patients and 28% of those on placebo. The statistical separation of drug and placebo was apparent by week 1 on the Montgomery-Asberg Depression Rating Scale (MADRS).

Except for a local application-site rash with the medication patch, there were no differences in adverse reactions between groups. The investigators found that their data, albeit preliminary, suggest that the transdermal delivery of selegiline may be a safe and effective treatment for patients with major depression, and it may have a relatively rapid onset of action.

The kinetics and safety of a new intramuscular (IM) depot formulation of risperidone (Risperdal) were reported by Marielle Eerdekens, M.D., and colleagues at the Janssen Research Foundation. The investigators tapered the oral risperidone regimen of stabilized patients with schizophrenia, while providing depot doses at two-week intervals. They found oral and depot dosing to be equivalent in the total amount of active drug available within the respective dosing periods. As expected, however, peak plasma concentrations were significantly lower with depot injection than after oral dosage. In addition to being bioequivalent to oral dosing, the IM depot was well tolerated.

New Agents Reboxetine and Ziprasidone

Several studies with the selective norepinephrine reuptake inhibitor antidepressant reboxetine (Vestra) were presented. The agent is used clinically in Europe and is pending regulatory approval in Canada and the United States. Maurizio Fava, M.D., and Patrick McGrath, M.D., collaborated with Pharmacia & Upjohn Corp. (now Pharmacia Corp.) researchers in evaluating the efficacy and safety of reboxetine in patients with major depression. These patients had failed to respond to at least six weeks of fluoxetine treatment, with 40 mg daily given for the last three weeks of treatment.

At the time of their report to the NCDEU, the researchers had enrolled 80 outpatients in the study. The patients were started on reboxetine 4 mg twice daily without a washout period and were treated for a total of eight weeks, with option to increase daily dosage to 10 mg after four weeks. Patients were then randomized to a 24-week, placebo-controlled discontinuation phase. The investigators indicated that patients tolerated the switch from fluoxetine to reboxetine, although they experienced more adverse events during the first four weeks than in the second. Preliminary results indicate a statistically significant reduction in the HAM-D-25 scores from the fluoxetine-treatment baseline at both four weeks and end of treatment.

James Ferguson, M.D., and colleagues described changes in suicidal ideation in trials with reboxetine from a review they conducted. Ferguson indicated that they had consistently found significant decreased scores in the suicidal-ideation item 3 and depressed-mood item 1 on the HAM-D from baseline to each assessment, with the depressed mood item score reduction evident in some cases in the second week of treatment.

Intramuscular ziprasidone (Zeldox), an investigational antipsychotic formulated in both a rapid-acting IM and oral dosage form, was evaluated in two 24-hour, double-blind trials in 20 mg, 10 mg and 2 mg for acute agitation and psychosis; and in two open-label, seven-day trials in comparison with IM haloperidol (Haldol), in fixed and flexible dosage.

Dan Zimbroff, M.D., and colleagues reported that IM ziprasidone in 10 mg and 20 mg produced rapid, significant, dose-related reductions in symptoms of agitation, while the 2 mg dose was ineffective. In comparison to IM haloperidol, ziprasidone evidenced significantly greater reduction in the Brief Psychiatric Rating Scale (BPRS) scores, and it was associated with a substantially lower incidence of movement disorders.

Several reports were also presented from an evaluation of oral dosage ziprasidone treatment of patients who had not tolerated, or adequately responded to, either conventional neuroleptics (93 patients), olanzapine (Zyprexa) (88 patients) or risperidone (41 patients). In three separate six-week, multicenter, open-label trials, these patients were randomized to ziprasidone in a variety of dosing schedules from 40 mg/day to 160 mg/day.

Nina Schooler, Ph.D., and Cynthia Siu, Ph.D., of Pfizer Inc., examined the changes in the Positive and Negative Symptom Scale (PANSS) anxiety item score for these patients to ascertain any anxiolytic effect of ziprasidone. They posited that the agent's unique pharmacological profile, which includes serotonin and norepinephrine reuptake inhibition and serotonin 5-HT1A receptor agonism, might have antianxiety properties.

Significant improvement in the PANSS anxiety item score was found to occur with ziprasidone treatment in patients with at least minimal baseline anxiety. This improvement appeared independent of changes in depressive symptoms or somatic concerns. The investigators called for further study of the agent's possible anxiolytic activity, in view of the prevalence of anxiety symptoms in schizophrenia.