(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
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.