This is the second of a two-part special edition of Med Check, featuring new research abstracts presented at APA's 157th Annual Meeting in New York City in May. New research abstracts are predominantly preliminary reports of research that has not been peer reviewed and may involve use of medications for purposes the FDA has not approved. Reports are usually funded by the products' manufacturers. This part covers uses of medications for depression and anxiety disorders, psychotic disorders, and sleep disorders.

• Escitalopram may be an effective choice for patients who fail to respond to an adequate trial of another SSRI. A study followed 515 adults who had major depression and had not achieved an optimal response with another SSRI. Patients had been on flexible doses of citalopram, sertraline, paroxetine, or fluoxetine for eight weeks. Patients who had not responded to the initial drug were then switched to open-label escitalopram. About 60 percent of patients who had not met response criteria on their first SSRI went on to meet response criteria on escitalopram, defined as a 50 percent reduction in symptoms as measured on the Montgomery-Asberg Depression Rating Scale (MADRS). More than 40 percent achieved remission of depression symptoms on escitalopram (defined as a score of 10 or less on the MADRS). The most common side effect was headache. APA: NR 758. Presented May 5, 2004.

• Mirtazapine may have significant advantages over standard SSRI antidepressant therapy, according to a pair of studies. The first, a meta-analysis of randomized controlled trials in which mirtazapine was compared with an SSRI, indicated that the combined serotonin-norepinephrine reuptake inhibitor has a quicker onset of action compared with fluoxetine, paroxetine, citalopram, sertraline, or fluvoxamine. A data analysis from more than 2,800 patients in 12 trials showed patients taking mirtazapine were 49 percent more likely to achieve a 50 percent reduction in symptoms (measured with either the Hamilton Depression Rating Scale or the MADRS) than patients on any of the other antidepressants studied.FIG1

A second abstract presented a meta-analysis of remission rates in the same 12 trials with the same 2,800 patients. Patients taking mirtazapine in the trials were 67 percent more likely than patients taking an SSRI to achieve remission (defined as a total HAMD-17 score of less than 7 or a MADRS score of less than 12) within the first 21 days of the trial. Patients treated with mirtazapine were 68 percent more likely to achieve sustained remission as well, compared with those taking an SSRI.

APA: NR 388, NR 386. Presented May 4, 2004.

• Paroxetine—controlled release may be associated with a significantly increased likelihood of patients staying on their treatment regimen, resulting in overall decreases in monthly costs compared with patients taking immediate-release formulations of paroxetine. An analysis of 36 million individuals from 61 health plans determined that patients who were prescribed paroxetine—controlled release for depression, social anxiety, or panic disorder were 40 percent less likely to stop taking their medication than those taking an immediate-release formulation. When researchers looked at medical and prescription costs for those taking controlled release, they found that the increased compliance was associated with a $109 a month decrease in costs compared with those taking immediate-release paroxetine.

APA: NR 809, NR 816. Presented May 5, 2004.

• Sustained duloxetine therapy helps patients with major depression avoid relapse and can successfully "rescue" those whose symptoms do reappear. In a relapse-prevention study, patients who achieved remission on 60 mg duloxetine per day were less likely to relapse if they continued taking the drug, compared with those who stopped taking medication once symptoms remitted. At the end of the 38-week trial, just under 80 percent of patients who continued to take medication remained free of both emotional and somatic symptoms of their depression. In the small subgroup whose symptoms did return, in spite of the 60 mg per day of duloxetine, increasing the dose to 120 mg per day when symptoms reappeared was successful in suppressing the relapse in the majority of patients. APA: NR 712. Presented May 5, 2004.

• The SSRI sertraline appears to be as effective at promoting response and remission in depression as the SNRI venlafaxine—extended release. Some researchers have asserted that the combined serotonin-norepinephrine antidepressants are more efficacious due to their dual mechanism. However, in a randomized, controlled, head-to-head comparison, 163 patients were treated with either 50 mg to 150 mg of sertraline or 75 mg to 225 mg of venlafaxine—extended release for eight weeks, followed by a two-week taper. By the end of the eighth week, patients taking sertraline and venlafaxine—extended release had comparable improvement in scores on the Quality of Life and Enjoyment Questionnaire, Hamilton Depression Rating Scale, and Clinical Global Impression—Improvement scale.

Both treatments were generally well tolerated, but twice as many patients discontinued treatment due to side effects in the venlafaxine group (7 percent) as in the sertraline group (3 percent). The most common side effects with sertraline were nausea, diarrhea, insomnia, and headache; with venlafaxine they were dizziness, insomnia, and headache.

APA: NR 380. Presented May 4, 2004.

• Venlafaxine—extended release may not be effective in depressed children, but may be somewhat effective in adolescents with depression. Combined results from two eight-week, multicenter trials involving 137 patients indicated that children taking venlafaxine—extended release saw a 24-point improvement on the Children's Depression Rating Scale—Revised (CDRS—R), compared with a 22.7-point improvement for children taking placebo, a difference that was not statistically significant. The pooled analysis showed that adolescents in the venlafaxine group had an average improvement of 24.4 points on the CDRS-R, compared with an improvement of 19.9 points for those on placebo. This small difference, however, was statistically significant.

Serious adverse events occurred in 8 percent of subjects taking venlafaxine and 3 percent of those on placebo. Serious adverse events included suicidal ideation, suicide attempt, agitation/hostility, and manic reaction. No suicides or deaths occurred. The most common treatment-emergent adverse events in the venlafaxine group were anorexia, abdominal pain, dizziness, and headache.

APA: NR 470. Presented May 4, 2004.

• Aripiprazole, in a new formulation for intramuscular injection, appears to be safe and effective at reducing acute agitation as quickly as 45 minutes after dosing. In a 24-hour, double-blind, placebo-controlled trial, 357 patients with schizophrenia, schizoaffective disorder, or schizophreni-form disorder and acute agitation were randomly assigned to either IM-aripiprazole (1 mg, 5 mg, 10 mg, or 15 mg), IM-haloperidol (7.5 mg), or placebo. Patients were monitored and assessed every 15 minutes for the first two hours, then at four, six, 12, and 24 hours after dosing. IM-aripiprazole at 10 mg showed significant reductions in the Positive and Negative Syndrome Scale—Excited Components (PANSS-EC) at 45 minutes and 60 minutes after dosing. Reductions in scores were maintained throughout the 24-hour period with the 5 mg, 10 mg, and 15 mg doses, though the most robust response was seen with 10 mg. The 15 mg dose was not significantly better than the 10 mg dose.

Patients receiving IM-haloperidol experienced significant reductions in PANSS-EC scores after 104 minutes. No significant improvement in PANSS-EC scores were seen in patients given a placebo injection. Patients treated with aripiprazole also demonstrated significant improvements in scores on the Agitation-Calmness Evaluation Scale, compared with nonsignificant changes for patients treated with IM-haloperidol or placebo. The most common adverse events reported with IM-aripiprazole were headache and minimal pain at the injection site.

APA: NR 612. Presented May 5, 2004.

• Quetiapine monotherapy may be associated with higher rates of patient adherence to antipsychotic medication. A review of managed care claims data on nearly 1,300 patients with bipolar or psychotic disorders treated with quetiapine as monotherapy were compared with matched control groups treated with haloperidol, risperidone, or olanzapine. Persistence was assessed at six, nine, and 12 months. At six months, a significantly greater percentage of patients treated with quetiapine continued to take their medication compared with any other group. At nine months, patients taking quetiapine showed greater persistence than those taking haloperidol or risperidone, but comparable to olanzapine. By 12 months, there was no significant difference between the three second-generation antipsychotics, all of which showed significantly higher rates of persistence than haloperidol.

At six months, 8 percent of patients taking quetiapine had had another antipsychotic added to their medication regimen, and this group increased to 9 percent by 12 months, a higher rate of polypharmacy than associated with either haloperidol or olanzapine, but comparable to risperidone. At all time points in the study, the rate of patients discontinuing quetiapine was significantly lower than that of the other groups. The percentage of patients switching from quetiapine to another antipsychotic due to lack of efficacy or side effects was 4 percent at six months and 6 percent at 12 months. Switching was significantly higher with quetiapine than risperidone, but was not statistically significantly different from switching associated with haloperidol or olanzapine.

APA: NR 562. Presented May 4, 2004.

• Long-acting risperidone injection is costeffective in treating patients with schizophrenia over the course of one year, compared with oral risperidone, oral olanzapine, and haloperidol decanoate injection. Using a decision-tree model based on published literature, a consumer health database, and an expert panel's advice, data on rates of compliance, frequency and duration of relapse, adverse events, resource utilization, and unit cost of health care resources were collected.

The average number of days of relapse requiring hospitalization were predicted to be 28 for haloperidol, 18 for oral risperidone and olanzapine, and 11 for long-acting injectable risperidone. Cost estimates based on modeled number of days of relapse and estimated resources used during relapse calculated savings of $397 per year, $1,742 per year, and $8,328 per year when using injectable risperidone instead of oral risperidone, olanzapine, and haloperidol decanoate, respectively.

APA: NR 658. Presented May 5, 2004.

• Ziprasidone at high doses may be safe and effective for patients who have only partially responded to the drug in doses within the FDA-approved range of 40 mg to 160 mg per day. Previous data had demonstrated more rapid response to doses of the drug between 120 mg and 160 mg in acute psychosis, as well as higher overall response rates. New data indicate that about half of patients with a history of treatment-resistant psychotic or affective disorders who partially respond to ziprasidone at doses up to 160 mg per day see continued improvement at higher doses, up to 480 mg per day. Of 37 patients who received doses greater than 240 mg per day for up to 18 months, six patients reported treatment-emergent adverse events. Sedation accounted for half of reported adverse events, with one patient each reporting restless legs, akathisia, and maxillofacial muscle spasm, described as" sucking."

APA: NR 371. Presented May 4, 2004.

• Eszopiclone decreases time to sleep onset, decreases waking after onset, and improves total sleep time and overall quality of sleep in both adult and elderly patients, according to several studies. Data from four studies involving more than 1,400 patients demonstrated improvement in patient-reported measures of sleep onset, maintenance, total sleep time, and following-day functionality. The studies also measured these variables using objective measures, such as polysomnography.

One study documented long-term safety and efficacy of the investigational nonbenzodiazepine in a double-blind, randomized, placebo-controlled study lasting 12 months. Eszopiclone provided sustained improvement in sleep and daytime function throughout the study. In a cohort of patients who received placebo for the first six months of the study, there were immediate and significant improvements when patients were switched to the active drug treatment. Patients completing the study did not experience significant adverse withdrawal symptoms and did not develop tolerance requiring any increased dosing.

APA: NR 838, NR 848, NR 850. Presented May 6, 2004.

• Indiplon appears to be safe and effective in both immediate-release and modifiedrelease formulations in treating chronic and transient insomnia, according to a series of studies. Data show that indiplon, an investigational selective GABA agonist, is effective across different populations, including elderly patients, at improving quality and length of sleep. The immediate-release formulation is effective at treating insomnia in patients whose main symptom is difficulty falling asleep, while the modified-release formulation is effective for those who have trouble both falling asleep and maintaining sleep. Neither formulation has been associated with evidence of tolerance or with next-day residual effects in trials lasting as long as 35 days.

APA: NR 569, NR 837, NR 568. Presented May 5 and 6, 2004.▪