Leading Agents Compared; Innovations Assessed at NCDEU

October 1, 2001

In the first of this series of articles, some of the innovative research and technologies presented at the 41st annual New Clinical Drug Evaluation Unit meeting in Phoenix in May are discussed.

(This is the first installment in a series of articles on the 2001 meeting of the New Clinical Drug Evaluation Unit [NCDEU]-Ed.)

Risperidone (Risperdal) and olanzapine (Zyprexa) were directly compared for several populations in studies reported at the 41st annual NCDEU Meeting of the National Institute of Mental Health in Phoenix, May 28-31.

In a double-blind study sponsored by risperidone manufacturer Janssen Pharmaceutica, 377 patients with schizophrenia or schizoaffective disorder were randomly assigned to receive eight weeks of treatment with either risperidone 2 mg to 6 mg daily (mean dose 4.8 mg) or 5 mg to 20 mg of olanzapine (mean dose 12.4 mg). The groups were similar in the number of patients who dropped from the study and in the number experiencing extrapyramidal side effects (EPS), as well as in the severity of their EPS. The researchers reported greater improvement with risperidone on the Positive and Negative Syndrome Scale (PANSS) anxiety/depression cluster and the depression and grandiosity items, but they found no significant differences between groups on individual factors.

In another Janssen-sponsored study, 176 elderly patients with schizophrenia were treated with either 1 mg to 3 mg of risperidone daily (mean 2 mg) or 5 mg to 20 mg olanzapine (mean 10 mg). While there was greater reduction in PANSS scores with risperidone at study midpoint, there were no significant between-group differences at eight weeks on this or the secondary efficacy measures, and the groups had a similar incidence of common adverse events.

In an assessment of the level of functioning of 30 patients with schizophrenia receiving eight weeks of treatment with either risperidone or olanzapine, researchers at University of California, San Diego, reported comparable improvement, measured with the Scale of Functioning (SOF). The SOF total scores increased 4.7% for 15 patients on risperidone and 6.5% for those on olanzapine, although the final analysis did not significantly differentiate the groups.

Both olanzapine and risperidone, as well as haloperidol (Haldol), appeared less effective than clozapine (Clozaril) in specifically reducing hostility symptoms in 157 treatment-resistant patients, in a study conducted by researchers at the Nathan Kline Institute at New York University and others. Patients were randomly assigned to 14 weeks of treatment with one of the four agents. The researchers reported that patients receiving clozapine evidenced greater improvement on the PANSS hostility item and that this difference was independent of antipsychotic effect. Neither risperidone nor olanzapine showed superiority over haloperidol on this measure.

An additional comparison of olanzapine and risperidone with a traditional neuroleptic was conducted in a naturalistic setting by University of Pittsburgh researchers. They commented that although the efficacy of atypical antipsychotics has been well-established, "the comparative effectiveness between agents is less clear. We set out to evaluate treatment effectiveness of olanzapine, risperidone and the conventional agent, perphenazine [Etrafon, Triavil, Trilafon]."

The researchers conducted a retrospective review of 386 patients discharged on one of these agents between January 1997 and June 1998. They found no statistical differences in one-year readmission rates between the groups nor in time to first admission. Other measures of drug effectiveness such as functioning were not applied nor were measures of how the drugs were tolerated.

Olanzapine was also compared to ziprasidone (Geodon) in a study sponsored by ziprasidone manufacturer Pfizer Inc. In the six-week assessment, 268 patients were randomized to receive either 5 mg to 15 mg olanzapine daily or 40 mg to 80 mg ziprasidone twice daily. The groups demonstrated comparable improvement on efficacy measures, as well as on movement disorder ratings. Although there were no significant differences on these measures, the researchers noted differences favoring ziprasidone on "health parameters" of weight gain and cholesterol level increase.

Addressing the issue of weight gain, Eli Lilly and Company researchers reported administering the histamine H2 blocker nizatidine (Axiol), a putative appetite suppressant, in combination with olanzapine in an effort to mitigate associated weight gain. In comparison to an olanzapine and placebo combination, there was significantly less weight gain in patients receiving 300 mg nizatidine twice daily, but not in those receiving 150 mg. In the 16-week treatment period, olanzapine with placebo was associated with an average body weight increase of 12.15 lbs; patients receiving nizatidine 150 mg twice daily with olanzapine gained an average of 9.72 lbs, and those receiving 300 mg twice daily with olanzapine gained 6.08 lbs.

Comparing Antidepressants

Most antidepressant comparisons pitted a selective serotonin reuptake inhibitor antidepressant against a non-SSRI. In one comparative study sponsored by Wyeth-Ayerst, the rate of remission from depression in patients receiving its antidepressant, venlafaxine (Effexor), was compared to that in patients treated with the SSRI paroxetine (Paxil). In another Wyeth-sponsored study, the emergence of suicidal ideation was assessed in patients treated with either venlafaxine or one of several SSRIs.

In the first investigation, pooled original data from studies involving 1,108 patients with depression treated for eight weeks with venlafaxine, paroxetine or placebo were analyzed for achievement of remission, defined as a Hamilton Rating Scale for Depression (HAM-D-17) score of less than 7. The researchers reported a significantly greater remission rate at weeks 6 and 8 with venlafaxine (45%) than paroxetine (38%) and a significantly greater number of patients with an absence of symptoms (HAM-D-17 score of 0). They noted, however, that no significant treatment differences were discerned with the Montgomery-Asberg Depression Rating Scale (MADRS).

In the second study, emergence of suicidal ideation was defined as a change in HAM-D suicide item score at baseline from 0 or 1 to a score of 2 or more. Suicidal ideation was then found in 6%, 9.5% and 13.7%, respectively, of patients receiving venlafaxine, an SSRI or placebo. The differences on both the HAM-D and MADRS suicide items between venlafaxine and the SSRIs, and between venlafaxine and placebo, were significant, as were the differences between SSRIs and placebo.

Mirtazapine (Remeron) was compared with the SSRI sertraline (Zoloft) in patients who had not improved with another SSRI. In this study, which was sponsored by Organon, 119 patients were treated for eight weeks with mirtazapine (mean dose 30.4 mg) and 124 patients with sertraline (mean dose of 120.2 mg). The discontinuation rate due to adverse events was twice as high with mirtaza-pine (18.5%) as sertraline (9.5%). Antidepressant response on day 28, defined as a 50% reduction from baseline of HAM-D score, was demonstrated by 40.3% of patients receiving mirtazapine, compared to 27.4% of those on sertraline. Remission rates, however, were approximately 50% in both groups by day 56. Although this population had previously demonstrated resistance to an SSRI, these results were offered as evidence of earlier onset of action with mirtazapine.

In a retrospective analysis of pooled data from two eight-week trials, the effectiveness of bupropion sustained release (Wellbutrin SR) was compared to that of sertraline for alleviating anxiety symptoms in patients with depression. This GlaxoSmithKline-sponsored assessment determined that the antidepressants were similar in their antidepressant and anxiolytic effects. The researchers concluded, "Selection between these agents cannot be based on anticipation of differential anxiolytic effects."

Investigating Innovations

With reversible monoamine oxidase-A inhibitor antidepressants such as moclobemide not yet available in the United States, there is interest in the selective monoamine oxidase-B inhibitor approved for Parkinson's disease, selegiline (Eldepryl), as a possible alternative for depression with less liability than the monoamine oxidase inhibitor antidepressants for hypertensive drug interactions. A transdermal delivery system for selegiline was investigated by manufacturer Somerset Pharmaceuticals to ascertain whether circumventing the "first-pass" hepatic metabolism of oral administration and delivering higher selegiline levels to the central nervous system also reduced potential for adverse interaction with co-administered pressor drugs or with dietary tyramine.

In the first safety study, 10 healthy volunteers received the selegiline transdermal system (STS) with 20 mg/20 cm2 alone and with pseudoephedrine (Sudafed) in increasing dosage over two weeks. Tolerance of the combination was ascertained through monitoring of vital signs, electrocardiograms (EKGs), physical examinations and clinical laboratory results. Administration of the STS alone had little effect on blood pressure or heart rate, while pseudoephedrine alone raised both. Addition of pseudoephedrine to steady-state administration of STS, however, caused minimal changes in the pressor response indicators; and there were no clinically meaningful changes in other monitored parameters.

In another manufacturer-sponsored safety study, 301 patients with major depression were randomized to receive either the STS or topical placebo over an eight-week period without dietary tyramine restrictions. Safety monitoring revealed adverse effects, most of mild to moderate intensity, in 82.6% of patients with the STS and 77.6% of those with placebo; a statistically insignificant difference. There were no statistically significant differences between the groups in vital signs, physical examination, laboratory or EKG.

A separately reported kinetics study indicated that the STS provided higher and more sustained selegiline blood levels than oral administration, with significantly less metabolite formation. The researchers concluded that the transdermal administration of selegiline is safe for adults with major depression, and they anticipate future trials of efficacy.

The administration of rapid transcranial magnetic stimulation (rTMS) as a possible adjunct or alternative to electroconvulsive therapy (ECT) for major depression has been investigated in a number of open-label and sham-controlled trials. In a study sponsored by the Pritzker Foundation, the treatment was provided to 24 patients with treatment-resistant depression who had failed at least two adequate antidepressant trials and exhibited a HAM-D-17 total score of at least 18.

In the 21 patients completing the trial, involving a total of 120 stimulations over a two-week period, there was a 26% mean improvement in HAM-D total scores and a 37% mean improvement in the Beck Depression Inventory (BDI). In addition, 10 of the 21 patients rated themselves as much or very much improved on the Clinical Global Impression scale (CGI). Response was particularly prominent in women, with 53% having greater than 50% reduction in HAM-D or BDI, while no males achieved this level of response.

Vagus nerve stimulation (VNS), a procedure now indicated for treating severe epileptic seizures, also appeared safe and effective for patients with treatment-resistant depression in a study sponsored by the device manufacturer, Cyberonics. In 60 patients receiving the VNS implant device who completed eight weeks of the procedure while continuing antidepressant medication, 31% demonstrated a 50% reduction on the 28-item HAM-D. Twenty-seven percent had a 25% to 49% reduction, and 15% of patients met criteria for remission at the end of the study. There was congruence between the HAM-D-28 and the MADRS results.

The patients with most severe treatment resistance, indicated by failure to respond in seven or more adequate trials of antidepressant treatment, had a response rate of 6% with VNS, compared to 40% of patients who had failed two to six antidepressant trials. The researchers concluded, "VNS seems to be an effective treatment in patients with moderate treatment resistance and was well-tolerated by a majority of the patients."

This novel procedure, referred to as a "pacemaker for the brain" in some press coverage at the earlier American Psychiatric Association meeting in May, was approved for treatment of resistant depression in Canada in April and in Europe several weeks earlier. The first controlled study of VNS for depression (with implanted but inactivated devices in half of the 210 patients) is being conducted at 21 sites in the United States and Canada and is anticipated to be completed by mid-2002.