Report on the 1998 American College of Neuropsychopharmacology Annual Meeting

(This is the first in a series of articles summarizing research presented at the 1998 American College of Neuropsychopharmacology Annual Meeting-Ed.)

Single Bedtime Dose
Divalproex Therapy

Inherent in divalproex (Depakote) treatment for bipolar patients are problems with compliance and sleep enhancement. Hence, to see if compliance, efficacy, tolerability and possible sleep enhancement might result, single nightly dosing with divalproex was investigated. Ten patients who were initially treated with divided dose divalproex therapy participated in a study utilizing two regimens of divalproex treatment: divided dose and a single nightly dose. The results showed a 20% average increase of valproic acid levels with the once-nightly dosing, which was well tolerated by all patients. All patients who were switched from divided doses to single nightly doses either maintained their previous level of clinical response to divided doses or had further improvement in their symptomatology. Increased compliance and sleep enhancement accounted for the benefits of single nightly dosing.

Atypical Antipsychotics Versus Depot Neuroleptics/Rehospitalization Rates

A comparison of rehospitalization rates among patients discharged from Maryland's mental hygiene facilities while receiving clozapine (Clozaril), risperidone (Risperdal) or depot neuroleptics was conducted by researchers at the Maryland Psychiatric Research Center and the University of Maryland School of Pharmacy. Their findings revealed that the probability of readmission within the first year after discharge was 17% for risperidone (n=75), 13% for clozapine (n=49) and 26% for haloperidol (Haldol) and fluphenazine decanoate depot formulations. These data, verifying that atypical antipsychotics have lower readmission rates than depot neuroleptic injections, suggest that the effectiveness of atypical antipsychotics in preventing rehospitalizations may be due to reasons other than simply improved compliance with therapy.

Repetitive Transcranial Magnetic Stimulation: Neuropsychological Effects

A study of repetitive transcranial magnetic stimulation (rTMS) was done to assess its neuropsychological effects when applied to the dorsolateral prefrontal cortex in 36 normal volunteers. Subjects were randomized to receive right (n=12), left (n=12) or sham (n=12) rTMS to the dorsolateral prefrontal region at 1 Hz frequency, two minutes duration and intensity, 20% above motor threshold. They were assessed before and after rTMS by a computerized neuropsychological battery that measured attention, short-term visual and spatial memory, calculation, and reaction time.

A preliminary analysis of the results of this study, which is still in progress, does not show any major group differences when the effects of right, left and sham rTMS were compared. These preliminary results suggest that low-frequency rTMS as given in this study does not significantly interfere with general cognitive functions in normal volunteers. The results are in accord with the lack of reported cognitive effects in depressed subjects treated under the same protocol. This report was presented by the research psychiatrists at Rambam Medical Center, Haifa, Israel.

Intramuscular Olanzapine Therapy

An intramuscular (IM) formulation of olanzapine (Zyprexa) has been tested in 31 healthy subjects and in 26 patients with acute nonorganic psychosis. Eli Lilly and Company employees in the United Kingdom reported that, in the latter, administration of 2.5 mg, 5 mg, 7.5 mg or 10 mg IM olanzapine for two days followed by oral olanzapine (10 mg or higher) reduced Brief Psychiatric Rating Scale scores by 10 points during the first 24 hours of treatment and by 18 points from baseline to day 5. Almost 50% of patients were mildly or borderline ill at day 5 by Clinical Global Improvement-Severity criteria. Side effects were mild and transient. These results suggest that IM olanzapine may be safe and efficacious in patients with acute nonorganic psychosis. IM olanzapine was also found safe and well-tolerated in healthy subjects, with a low incidence of postural hypotension.

Olanzapine Combined With Fluoxetine Therapy

Based on the hypothesis that a combination of olanzapine and fluoxetine (Prozac) would create a broad pharmacological and therapeutic spectrum that may provide greater efficacy in treatment-resistant depressed patients, Eli Lilly and Company sponsored a two-center, eight-week, double-blind comparison of olanzapine monotherapy, fluoxetine monotherapy and combined olanzapine/fluoxetine in 28 patients with DSM-IV criteria for recurrent, treatment-resistant major depressive disorder without psychosis. The olanzapine/fluoxetine group experienced a statistically greater improvement on the Hamilton Rating Scale for Depression (HAM-D-21) total score than either the olanzapine or fluoxetine monotherapy groups. There were no statistically significant differences between any of the treatment groups on any measures of parkinsonism or akathisia. There were no significant adverse interactions between olanzapine and fluoxetine given in combination.

Topiramate Plus Lithium

Anticonvulsants are often co-prescribed with lithium for the treatment of bipolar disorders. Hence, in an open-label, sequential crossover study design, the comparative steady-state pharmacokinetics of lithium before and after multiple oral daily topiramate (Topamax) dosing was evaluated in 12 healthy adult volunteers. Subjects received lithium 300 mg every eight hours for 14 days.

Topiramate dosing (50 mg every 12 hours) began on the ninth day of lithium dosing. This was followed by titration of topiramate dose to 75 mg every 12 hours on the 10th day and 100 mg every 12 hours from the 11th to the 14th day of lithium dosing. Lithium serum concentrations were measured on days 4 through 7 (before topiramate) and days 9 through 13 (after topiramate). Lithium serum concentrations were slightly reduced following six days of topiramate dosing. Mean lithium serum concentrations ranged from 0.6 mEq/L to 0.9 mEq/L before topiramate dosing and from 0.5 mEq/L to 0.8 mEq/L after topiramate dosing.

The modest mean decrease in lithium serum concentrations with topiramate therapy should be considered if topiramate is coadministered with lithium. As the possibility of an enhanced pharmacodynamic response to lithium with the addition of topiramate exists, lithium dosage adjustment should be taken into consideration as well as serum concentration at both initial concomitant administration and at subsequent administrations.

Effects of Extended Fluoxetine, Sertraline and Paroxetine
Therapy on Weight

A dual-purpose study involving 284 patients with major depression was done to assess the effects of extended selective serotonin reuptake inhibitor (SSRI) treatment on weight and to examine whether different drugs have differential effects. These patients were comparable at baseline for age, sex and body mass index. They were randomly assigned to double-blind treatment with fluoxetine (n=92), sertraline (Zoloft, n=96) or paroxetine (Paxil, n=96). Data were analyzed from 44 fluoxetine patients, 44 sertraline patients and 48 paroxetine patients who completed 26 to 32 weeks of treatment.

Paroxetine-treated patients had a significant weight gain from baseline to endpoint; fluoxetine-treated patients had a modest but nonsignificant decrease in weight; and patients treated with sertraline had a modest but nonsignificant weight increase. These findings indicate that extended treatment with an SSRI (fluoxetine, sertraline or paroxetine) is associated with different risks for weight gain.

Breastfeeding During
Sertraline Treatment

SSRI levels in infants exposed through breastfeeding are reported to be generally low. To assess the safety of breastfeeding during sertraline therapy, Yale University investigators measured whole blood 5-HT in 10 nursing mothers, before and after treatment with sertraline at a maximum dose of 200 mg/day for nine to 12 weeks. Mean age of the infants at the time of initial exposure was 21

14.7 weeks (range two weeks to 12 months).

Marked declines in platelet 5-HT were observed in the mothers after sertraline, but little or no change was seen in infant 5-HT levels. Infant plasma sertraline and desmethylsertraline levels were less than 2.5 ng/mL and less than 5 ng/mL, respectively. The investigators aptly concluded that these findings suggest that women can safely breastfeed an infant while undergoing sertraline treatment but warn that, given the small sample size in their study, cautious interpretation of their findings is warranted.

Reboxetine for Hospitalized Depressed Patients

Reboxetine is a selective noradrenaline reuptake inhibitor that has been marketed for depression in the United Kingdom this past year and is currently in phase III clinical evaluation in the United States. It has negligible affinity for muscarinic, adrenergic and histaminergic receptors. It has been shown to be equieffective with desipramine (Norpramine) and imipramine (Tofranil) in the treatment of mixed populations of patients with mild to severe major depressive disorder.

Reboxetine is an antidepressant that reputedly significantly improves social interaction as indicated by the Social Adaptation Self-evaluation Scale. Its usual therapeutic dose is 4 mg twice daily. The Reboxetine Brazil and Canadian Study Group reported the results of a trial in which reboxetine's efficacy and tolerability (6 mg/day titrated to 10 mg/day over three days) was compared with placebo in a double-blind, six-week study of 52 hospitalized patients. The mean HAM-D-21 total score at baseline was greater than 35 in both groups, indicating severe depression.

After six weeks, 74% of the reboxetine-treated patients and 20% of patients taking placebo had a 50% or more reduction in total HAM-D score (P

Side effects were mild and transient; the most common were dry mouth (57% reboxetine versus 21% placebo) and insomnia (25% reboxetine versus 0% placebo).Prophylactic Reboxetine for Recurrent Major Depression

The International Reboxetine Study Group reported on a study in which reboxetine was shown to be more effective than placebo in preventing relapse in patients with recurrent depression and to be well-tolerated in long-term treatment.

This placebo-controlled, double-blind, parallel-group, 46-week study was conducted to assess the long-term tolerability and efficacy of reboxetine 8 mg/day in 283 depressed patients who had a 50% reduction in HAM-D score following an initial six-week treatment. They were then enrolled in a long-term (46-week) placebo-controlled study.

The relapse rate was much lower in reboxetine-treated patients than in placebo-treated patients (22% versus 56%, PMirtazapine: The First Million Patients

Mirtazapine (Remeron) has been available in the Netherlands since 1994 and marketed in the United States since 1996, providing both pre- and post-marketing data and literature reports of sufficient quantity for a meta-analysis. The meta-analysis was conducted by Davis and Giakas from the department of psychiatry at the University of Illinois Chicago using the Hedges-Olkin and the Mantel-Haenszel methods to quantify efficacy.

This review substantiated that mirtazapine is superior to placebo, comparable to tricyclic antidepressants (TCAs) and at least as effective as fluoxetine for the treatment of major depression. In addition, mirtazapine is substantially safer than the TCAs, does not cause significant overdose toxicity and has a favorable side-effect profile.

In a direct comparison with fluoxetine, mirtazapine did not produce nausea or related gastrointestinal side effects, which are adverse events common to the SSRIs. Post-marketing studies showed mirtazapine to be useful for treating patients intolerant of the SSRIs and verified that it does not produce sexual side effects.

Davis and Giakas also reviewed epidemiologic data on such rare side effects as agranulocytosis. The few reported cases of agranulocytosis associated with mirtazapine usually occurred in patients receiving other drugs known for or suspected of causing agranulocytosis. It is important to note that this research and the report on its findings were not supported by the manufacturer of mirtazapine.