euthymia, and for mechanism of action of standard and atypicalantidepressants.

Supported by the VA Medical Research Service and the Pharmacia &Upjohn Corp.

280. OLANZAPINE THERAPY FORPOSTTRAUMATIC STRESS DISORDER

F. Petty (1,4), K. Young (2,4), J. Worchel (2,4),S. Brannan (3,4)

(1) University of Texas Southwestern Medical Center at Dallas, (2)Texas A&M System Health Science Center (3) University of TexasHealth Science Center at San Antonio, (4) “Heart of Texas,” VeteransIntegrated Service Network-VISN 17, Dallas, TX 75216

Posttraumatic stress disorder (PTSD) is a relatively common condition,for which there is no standard of pharmacological treatment. Preclinicalresearch with the learned helplessness animal model of posttraumaticstress disorder, and prior clinical research with nefazodone, suggests thatserotonin 5-HT2 receptor antagonists may successfully treat PTSD,including the “core” or intrusive symptoms. Since the atypical neurolep-tic olanzapine (Zyprexa) has antagonist properties at the 5-HT2 receptor,we undertook a multi-site open label study of olanzapine in veterans withcombat induced PTSD.

Patients are recruited from VA clinics in Dallas, Fort Worth, Waco,Austin, and San Antonio. All procedures have been approved by the relevantethical review committees, and no procedure is performed without fullyinformed, signed, witnessed consent. After evaluation and washout, patientsare titrated up to a maximum dose of 20 mg per day, as tolerated.Primaryoutcome measure is the Clinician Administered PTSD Scale (CAPS), andsecondary measures are the Hamilton Rating Scales for Anxiety and forDepression (HRSA, HRSD). Patients are seen in clinic weekly.

Target enrollment for this ongoing study is 60. We have performed aninterim analysis on the first 14 patients who received an “adequate” trial,defined as 4 weeks of therapy. The most significant improvement overbaseline was seen in the total CAPS score (F5 14.1, p5 0.0001) and inthe Cluster B (core symptoms) subscale score (F5 14.8, p5 0.0001).Significant improvement was also seen on the other CAPS subcales andon the HRSA and HRSD.

If these findings continue in the larger sample, larger scale, randomized,placebo controlled clinical trials should be considered. Also, the efficacy ofolanzapine in civilian PTSD should be tested.

Supported by the VA Medical Research Service and the Eli LillyCorporation.

281. Li1 INHIBITS THE NMDA-INDUCEDCYTOPLASMIC [Ca 21] BUT NOT [Na 1]TRANSIENTS

L. Kiedrowski

Department of Psychiatry, University of Illinois at Chicago, Chicago,IL 60612

It is well recognized that chronic exposure of primary cultures of cerebellargranule cells (CGCs) to 0.5–5 mM lithium inhibits the N-methyl-D-aspartate(NMDA)-induced Ca21 influx, which may be relevant to the mood-stabilizing properties of Li1 therapy. The mechanism(s) by which Li1

inhibits the NMDA-induced Ca21 influx is still obscure. One may envisionthat Li1, directly or indirectly, affects ionic fluxes via the NMDA receptorchannels. If this were the principal mechanism, Li1 should inhibit both theNa1 and Ca21 flow through the NMDA receptor channel. To test thishypothesis, CGCs were exposed to 5 mM Li1 for 8 days, then extracellularLi1 was removed and the effects of NMDA on cytoplasmic [Ca21]([Ca21]c) and [Na1]c transients were compared. As expected, the exposureto Li1 strongly inhibited the NMDA-induced Ca21 influx and preventedmitochondrial Ca21 overload. Surprisingly, Li1 failed to affect the NMDA-induced elevation in [Na1]c. These data may be tentatively interpreted toindicate that chronic Li1 treatment leads to an inhibition of the reverseoperation of the plasma membrane Na1/Ca21 exchanger (NaCaX). Conse-quently, the reverse NaCaX-dependent component of the NMDA-inducedCa21 influx in the Li1-treated CGCs might be downregulated, which wouldexplain the obtained results. The validity of this conclusion as well as themechanism of the inhibition of the NMDA-induced Ca21 influx by Li1 hasto be elucidated further.

Supported by NS-37390.

282. NEW CHOLINERGIC TEST OF SLEEP/MOOD DYSREGULATION IN FAMILIALDEPRESSION

D.E. Giles, M.L. Perlis, H.J. Orff, P.J. Andrews,C.M. McCallum

University of Rochester, Department of Psychiatry, Sleep ResearchLaboratory, Rochester, NY 14642

Major Depression is reliably associated with REM sleep abnormalities,suggesting increased cholinergic activation, enhanced cholinergic sensi-tivity and/or imbalance in cholinergic and monoaminergic tone (e.g.Gillin et al 1991). These findings lead a number of investigators todetermine whether depressed patients and/or family members could bedifferentiated from healthy controls based on response to intravenouslyadministered agents like arecholine and physostigimine. These centrallyactive cholinergic agents preferentially shortened REM latency and/orreduced REM interval times in depression (e.g. Sitaram et al. 1983). Inour study, we tested whether an orally administered cholinergic agonistwould produce similar results and thus serve as a probe of cholinergicabnormalities in our family cohort (e.g. Giles et al 1998). Specifically, weevaluated whether Aricept 10 mg (Donepezil HCI: Pfizer-Eisai) (used totreat Alzheimer’s disease) could be used effectively to alter REM timingpreferentially in depressed patients and, as such, provide a pharmacologicprobe of cholinergic tone.

We age- and sex-matched 8 depressed patients to 8 controls for a3-night sleep laboratory study. The cholinergic challenge distinguishedthe groups. Onset to REM sleep was shorter in depressed patientscompared with controls (47.6 vs. 71.7, p5 .02). REM latency afterAricept in depressed patients was also reduced compared with baseline(47.6 vs. 64.4, p5 .04). Control subjects showed no response: REMlatency after Aricept was virtually identical to baseline REM latency(71.7 vs. 69.3). The three-night protocol and the differential response toa cholinergic challenge in the depressed group strongly support thevalidity of the procedure.

This research was supported by MH39531 and MH56869.

Friday Abstracts 85SBIOL PSYCHIATRY2000;47:1S–173S