I>'OL PSYCHIATRY 1~~6:39;500-666
IIlong standardized guidelines adapted from DSM·IV criteria. Data were obtained on :1 ronge of clinical-psychopathologic variables, psychotropic medicalions, nnd plasma drug levels, "Recovery" was defined using Clinical Global Improvement scale (CGl) and Global Assessment of Functioning (OAF) ratings by the investigators. Results showed signilicant improvement for all treatment groups, with "recovery" in lIpprox]m:Jtely 40% of both the "mixed" and "pure" cohorts. Patients prescribed lithium, divalproex, or carbama7.cpine all showed significant improvement as compared 10 olher treatment modalities. Preliminary survival analyses demonstrJtcd no significant differences in the time course to recovery tlmong palients laking anticonvul!lants vs. lithium. Dirferentitll response 10 anticonvulsants andlor litl1ium i~ presented as a multivariate function of 2ffective symptoms, comorbiLl subst:mcc abuse. past treatmenl, and adjunctive psychotropic medic:ltiolls. The findinss sugsest that both "pure" and "mixed" slate bipolar patients show significant impro\'ement during naturalistic treatment with anticonvulsants or lithium. Multiple factors may be involved in predicting n superior response to either treatment.
420. A BRIDGING STUDY OF LESOPITRON IN GENERALIZED ANXIETY DISORDER J.1. Sramek'. N.R. Cutler'. G. Marion-Landais 2 , C.M. Jensen2 • N.M. Kurtz3 , & A.T. Carrington 2 ICalifornia Clinical Trials, Beverly Hills, CA 90211: 2Knoll Phnnnaceutical Company, Shreveport, LA 71136; 3Worldwidc Clinical Trials, Beverly Hills. CA 90211 Lcsopitron, il S-HT 1A tlgonist. is a polentialnnxiolytic in the uzapirone class, It has greater potency in llnimlll models of amticty than buspironc. gepirone, or irl.~Elpjrone, untl lacks the anlklopamincrgic and anti3dren· ergie effccts associated with buspironc, This double-blind bridging study assessed the safcty, tolcrnbility, and PK of fixed doses of leslJpitron (20, 25, 30. 40. 45. SO. and 60 mg bid) over u 6 1/2 duy inpatient administralion periotl in 7 panels. E.1ch panel had 6 generalized anxiety disorder (GAD) patients (4 lesopitron/2 placebo). One pi:ltient on 25 mg bid lesopilron voluntarily withdrew due 10 increased anxiety. Another patient experienced severe onhostatic hypotension at 60 mg bid lesopitron on the third day of dosing. The symptoms resotved within lin hour and the patient completed the study. Moderate to severe di7.ziness, Iighl headcdness, nausea, ulldlor hCildilche occurred in 2 other patients at 60 mg bid. Fifty mg bid was lherefore delincd as the maximum toh:mtcd dose (MID). The most commonly reponed adverse events in all the panels were light headedness, dizziness, headilche, and nausea. Absorption of lesopilron wa.~ rapid (Tmux: 0.5 to I hr) nnd independent of the administered dose. Elimination wus nlso rapid. with II half-life of 1.1-5.6 . hours. Plasma concentrations of Lcsopitron were highly variable among imlh'iduals and independent of dose. Cmalt for Illl subjects rangell from 1.3 to 194,2 ng/ml; these 2 vo.lucs, both came from the 40 mg bid pElnel. Cmax of the metabolite S·hydroxylesopitron for all subjects ranged from 6,0 nglml (25 mg bid) to 507,6 nglml (60 mg bid) and was, on average, dose-dependent. Lcsopitronlmc:tlloolite conccntration~ were not notably high in the puti~nt who volunt:trily di~eDntinucti or in lhe p:ltient who experienced orthostatic hypotension. The MTD In GAD patients of 50 mg bid was 100% greater titan the highest dose tested in henlthy volunteers. Bridging studies offer the potential to identify the maximum dose range of the compound cully In development, so thai t1ose-rmtling Phase II studies cnn I'C confidently conduct~d across Ihe tol~rubte nnd safe clinical dose range.
421. AN OPEN LABEL TRIAL OF
VENLAFAXINE IN ADULTS WITH ATTENTION DEFICIT DISORDER L.A. Adler, S. Resnick, M. Kunz. & O. Devinsky Psychiatry and Neurology Services. NYU School of Medicine, The Hospital for Joint Diseases and the New York VAMC Tricyclic antidepressants (TeAs).are commonly used to treat adults with 3ttenlion deficit disorder (ADD) and attention deficit hypcmctivity disorder (ADHD) (Wilcns cl al Progress NOles 1994). However. as secn during the treatment of depression, anticholinergic side-effects, orthostatic hypotcnsion and sedalion may be dosc limiting when TeAs arc used 10 treat ADD. Vcnlafaxlne (Effexor) is a recently ma.rketcd antidepressant which is specific for L~c re-uptake of norepinephrine and scrotonin, but rcl:stively free of muscarinic, histaminic and alpha-adrenergic effects of TeAs. We now report data on the first 24 patients enrolled in an open-label pilot lrial of \'enlafaxine 12.5-225 mglday in the treatment of adults with ADD/ADHD. Patients with ADD or ADHD who were candidates for antidepressants were screened for enrollment, The diagnosis of ADD WIIS established by the 25 item Wender Utah Rating Scale (Ward et al Am Jot/mal of Ps)'clllatlJ' 1993). Five of the twenty-four patients were receiving concomitant medications (stimulants: 2: clonazepam: 2; ~odone: I): these patients were stabiiized on the doses of these olher medications prior to, and throughout the course of venlafax· ine trealment. Nineteen of the patients were not receiving mcdicntions other than venlafaxine. P'Jtients were treated with vcnlafaxine over an eight week period. nlC sIllrting dose of vc:nlafaxinc was 12.5 - 37,5 mg/day, with the dose being increased nccording to beneficial effects on ADD or side-effects up tl> a maximal dose of225 mgldny. WURS rntings were repeated every one to two weeks. Five patients discontinued vcnlafultinc within the first wcek of treatmcnt because of sedation. nausea or activation, and therefore their results arc not included in the analyses. The mean dose of venlafaxine was 102.1 :!: 61.3 SO mg/day. WURS scores decreased from a mean of 64.4 :t 20,4 SD at baseline to a mcun of 30,0:t IS.4 SD lifter vcnlnfa:dnc treatment (paired Student's t-lest: t(l8) = 8,31, p
422. PARADOXICAL INVIGORATION THROUGH SLEEP DEPRIVATION M.P. Szuba l • D.F. Dinges', L.R. Baxter~,3, W.A. Ball', & K. O' Sullivan I IUniversity of Pennsylvania School of Medicine, Phihldelphia, PA 19104: 2University of Alabama al Birmingham School of Medicine, Binnlngham, AL 3.5294; JUCLA School of Medicine. Los Angeles, CA 90024
Total sleep deprivlltion (TSD) produces a same.day, but transient, antidepressant eifect in over 60% of depressed patients. In the first siudy, 26 Inpatients with m3jordcprcssion undel'Went one night ofTSD (subject
awake 0700 Day I ulllil 2100 Day 2). Raters completed a modified, validated Hamilton Depression Scale (HAM6) on subjects the day before and day of slecp deprivation, Subjecls completed the Profile of Mood States (POMS) every two hours while awake. In a similar study. 23 controls without medical or psychiatric histories also underwent one night of TSD and completed the POMS every two hours, According to previously published criteria, we classified 12 of the 26 (46%) depressed subjects as "responders" 10 sleep deprivation. Responders' mood improved 55.8 ± 18.3% from pre- 10 post·sleep deprivation while nonresponders improved only 11.1 :!: 34.8% on the HAM6 (one-tailed t "" 4.0, p=O.OOO3). Arter 34 hours of sleep deprivation, POMS-derived fatigue scores dropped from 19,6 ± 7.9 to 14.4 :!:: 9.0 in depressed responders (t = 1.8, dJ. = 11. P = 0,05). However. in nonresponders. fatigue rose from 13.1 ± 10,7 to 18.6 ::!: 9.7 (I"" 1.9, d.f. = 13. P = 0,04', and rose from 2,3 :!:: 3.8to 9.5 ± 6.2 in controls (t =5.7, d.f. = 22, P = 0.000004). Vigor scores rose from 5.1 :!: 6.6 10 11.5 :!:: 9.2 in responders (t = 2.2, d.f. = 11, P = 0.03), dropped from 8,4 ::!:: 8.8 to 5.2 :!:: 4.3 in nonresponders (t "" l.5, d.f. = 13, P = 0.08) and dropped from 10.0 :!: 7.3 104.4 ± 4.7(t=4.4, dJ. =22, p= 0.000 I). Thus. control subjects and a subset of depressed subjects show worsening of vigor and f:ltigue after sleep deprivation, In stark contrnst, sleep deprivation invigorates many depressed subjects. ll1ese seemingly paradoxical results suggest that sleep deprivation exerts different neurobiologic effects on the arousal systems of controls a.~ compared to some depressed subjects.
423. COMPARATIVE EFFECTS OF NEFAZODONE & FLUOXETINE ON SLEEP IN OUTPATIENTS WITH MAJOR DEPRESSIVE DISORDER R. Armitage!) A.J. Rush!, le. Gillin2 , & H. MoldofskyJ IUniversity of Te;.als Southweslern Medical Center at Dallas: :lUniversity of California, San Diego School of Medicine; JUniversity of Toronto Centre for Sleep nnd Chronobiology Sleep disturbances are prevalenl in major depressive disorders (MOD). The sleep electroencephalogram (EEG) reveals (I) short rupid·eyemovement (REM) latency «65 min), (2) decreased Siage 314 sleep, (3) increased REM density, nnd (4) reduced sleep continuity (e.g" prolonged sleep latency, reduced sleep efficiency, increased awake and movement time) as charncteristic of patients with MOD. Most antidepressantll, inclUding selective serotonin reuptake inhibitors (SSRls), signilicantly prolong REM latency and suppress total REM time, SSRIs may also increase both awake lime and light non-restorative sleep. By contrast. ~mnl1, open trials indicated that nefazodone. as·HT2 antagonist that also inhibil~ 5-HT rcuptllke, did not prolong REM latency, but did improve sleep continuity. The present study wa.~ undertaken to evaluate the effects of nefazodone and fluoxetine on sleep EEO in a larger sample of patients with MOD. Thi~ multisite, randomized, double-blind, g.week, acutephase treutment trial compared nefazodone (n = 60) with nuoxetine (n = 62) in Ilulpatienls with nonpsychotie MOD and insomnia complaint. Sleep EEO wa~ recorded at baseline (while patients were symptomatic, but unmedicated) and at weeks 2,4, and 8 of treatment, Nefazodone lind fluoxetine were equally effective in reducing depressive symptoms, according 10 the Hamilton Rating Scale for Depression (}IRS-D) total score. Nefllzodone also significantly decreased the HRS-O l;leep faelor score in contmst to fluoxetine. Objective sleep EEG measureS indiented that tteflllodone increa.~l!d sleep efliciency, reduced Siage I sleep, and awake and movement time, whereas fluoxetine had the opposite effect. Fluoxetine also prolonged REM latency lind suppressed REM sleep, while nefazodone did not. In fact nefazodone significnntly increased IotaI
BIOI... PSYCHIATRY 1996:39:500-666
REM time. Subjective sleep quality (patienl report lind clinician ratings) was improved with ncfazodone, but unchanged with fluoxetine. Compared with f1uoxetine, nefazodone was lISsociated with morc "normal" objeclivc and ~ubjective sleep characteristics. Whether these apparent acute-phase benefits are sustained in the longer run, reduce the need for acute-phase ndjunctivc sedative hypnolic agents, or lead to a greater degree of sustained clinical remission in continuation phase or following medication discontinuation deserve study. The differential effecls on REM sleep and REM latency suggest that ncfazodone and fluoxctine may have somewhat different spectra of aClion.
424. ANTIDEPRESSANT RESPONSE TO ORAL PULSE LOAD1NG 'VITH CLOMIPRAMINE S. Dube, J.M. Perel, J. Miewald, & DJ. Kupfer Weslern Psychiatric Institute & Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 We compared the acute antidepressant efficacy of c10miprnmine (eMI) pulse loading in Ihrel! parallel treatment cells in inpatients suffering from major depression: GR I: llingh: amI pulse-loading with 250 mg CMI, followed by twenty-two days placebo, N = 13: OR 2: single oral pulse-loading with 250 mg eMI. followed by seven days placebo, N "" 10; and GR 3: pulse-loading with placebo, followed by seven days placebo. N = 7. Subjects in GR 2 and 3 were assigned to CMI in a double blind manner starting after the 7 day placebo period and continued 011 eMI for the remainder of the study (15 days). Response was defined as HAM·D score :$ 7 after 22 days of treatment. Mean HAM-D scores at the end of the study were significantly different (p<0.OI6) between the three groups (8.23:!:5.34, 6,80±5.31 and 15.71 ±8.44 respectively). A two way ANOVA (response by group) for each raling period revealed that responders in each group had significantly lower HAM-D and MADRS scores than non-responders on days 10 and 17, 19 and 21. On days 18 and 20 after CMI, response was signilicantly related to the group membership. with responders in groups I & 2 showing the lowest HAM-D anti MADRS scores, Comparison of response 10 clinical varinbles. llhowed a significant effect for number of previous episodes and :age at first episode (p< 0.03 each). Plasma levels of CMI and desmethyl CMI were not significantly reltlled to response. The results have implications for efficacy of pulse-loading with eMf in early onset, recurrent depression ami arc discussed in light of the changes in monoamine function.
425. THE ROLE OF THE SEROTONERGIC SYSTEM IN SEASONAL ArrECTIVE DISORDER A. Neumeister', N. Praschak-Rieder', B. Hesselmann I, 1. Tauscher 1t M.L. Rao 2 , & S. Kasper' IDepartmenl of General Psychiatry, University of Vienna, Vienna 1090, Austria; 2Rheinillehe Friedrich-Wilhelms-University, Bonn, Germany Multiple lines of evidence suggest thut the brain serotonergic system is involved into the pathophysiology of seasonal affective disorder (SAD).