Imipramine plasma concentrations and response in panic disorder

FRIDAY, MAY 20

BIOL PSYCHIATRY 677 1994;35:615-747

223. A DOUBLE-BLIND STUDY WITH PAROXETINE VS FLUOXETINE IN DEPRESSIVE PATIENTS

gently used. Our results need to be corroborated in other double-blind placebo controlled studies.

A. Ontiveros I & C. Garcia-Barriga2

225. OPEN CROSS-OVER STUDY WITH FLUOXETINE AND DESIPRAMINE IN MAJOR DEPRESSION

t Department of Psychiatry, University Hospital Jose E. Gonza|ez Monterrey, N.L., 64461 Mexico. 2 Fray Bemardino Alvarez Psychiatric Hospital, Mexico City, Mexico Paroxetine is a potent novel selective serotonin (5-HT) reuptake inhibitor antidepressant (SSRI). As in other SSR! its antidepressant efficacy was tested against placebo and tricyclic antidepressants. This randomized double-blind study was carried out to evaluate the efficacy and safety of peroxetine (PAR) and fiuoxetine (FIX) in a 6.week treatment of depressed outpatients who met DSM-ill-R criteria for major depressive disorder. Inclusion criteria required patients to be of both sexes, 18 to 65 years old and have a HAM-D score > 18 in the first 17 items. Exclusion criteria were: other psychiatric disorders, relevant medical diseases, pregnancy or lactation, other psychopharmacological treatment and/or being in psychotherapy. After a one week washout period, patients were randomized to 20 mg of PAR (N.,60) or FIX (N,,60). Efficacy and safety were assessed with HAM-D, and Clinical Global Impression (CGi) scales. Patients on PAR were older (43 + DS ! !.0 years) than those on FIX (38+ 10.9 years). The analysis of changes in the HAM-D and CG! showed, in both groups of patients, a significant improvement from day 14, with an even greater improvement until day 42 of treatment (p¢0.05). However, at day 14 patients on PAR showed a decrease in 50% of HAM-D scale items against only 13% for patients on FIX (lg0.05). Six patients (20%) on FLX and 3(10%) on PAR finished the treatment prematurely. Even though PAR and FIX were equally effective antidepressant treatments in this study, depressive outpatients seemed to improve faster with PAR. Other studies comparing SSRI need to be done to corroborate our results.

224. A DOUBLE-BLIND PLACEBO CONTROLLED STUDY WITH CLONAZEPAM IN SOCIAL PHOBIA A. Ontiveros & A. Rojas Department of Psychiatry, University Hospital Jose E. Gonzalez, Monterrey N.L. Mexico CP 64461 Case reports and open studies suggest the efficacy of benzodiazepines alprazolam and clonazepam (CLZ) in social phobia (SP). In order to further study this action we carried out a double-blind placebo controlled study with CLZ in patients with SP. We studied 50 consecutive SP patients (DSM-Ili-R) of both sexes, 18 to 65 years of age, with a disorder of at least moderate severity. The exclusion criteria were: relevant medical disorder, other psychopharmacological treatment (except antidepressants currently used) and/or being currently in psychotherapy. After a singleblind week of placebo, patients were randomized to clonazepam (N-25) or placebo (N.,25) in a double-blind treatment for six weeks. CLZ dosage was increased !.0 rag/day each week. Efficacy and safety were assessed weekly [HAM-A and HAM-D scales, CGi 8 points, Fear Questionnaire and Liebowitz Social Phobia Scale]. Both groups of patients on CLZ or placebo were no different in age, sex distribution, age onset and length of disease nor in several measures of severity. An End-point analysis showed that patients on CLZ improved more than those on placebo (p<0.005) with changes since the second week of treatment (p
A. Ontiveros, J. Lugoleos, & A. Rojas Department of Psychiatry, University Hospital Jose E. Gonzalez, Monterrey N.L. Mexico CP 64461 Biological models of"depression could be better understood studying the clinical action of antidepressants. We compared in an open cross-over study two selective reuptake inhibitors: desipramine (DMI) on norepinephrine (NE) vs fluoxetine (FI.,X) on semtonin (5-HT). We studied consecutive patientS with major depression (DSM-lli-R) of both sexes, 18 to 65 years old, with a HAM-D~IS. Exclusion criteria were: other psychiatric disorders and other psychopharmacological treatment. Patients were assigned to two sequences of treatment: I.FLX-DMI (N-8) or li.DMI. FLX (N-8). Patients received a single-blind week of placebo followed by 12 weeks of treatment (6 weeks of DMi and FIX). Both groups of patients were similar in age, sex distribution and final dosage of DM! (!: 194 + DS 32.0 vs !i: 206 :!: DS 43.8 mgr/day). After one week of placebo, patients on sequence ! were more depressed (HAM-D) (26.2 +SD 3.88) than those on sequence !! (21.5 +SD 3.74) (p<0.05). We found no differences in tolerance nor in final HAM-D and CG! scores, after FIX or DMI; and there were no effects due to treatment sequence. Nine (57%) patients improved markedly with FIX and DMI, 3 (! 8%) with FIX, 3 (i 8%) with DM! and only I patient (6%) was resistant to both drugs. A unified 5-HT/ NE model of antidepressant action could be sustained in most of our depressive patients. However, 36% of patients responded preferentially to only one selective reuptake 5-EIT or NE inhibitor, implying a selective response to their action. The findings in this study are relevant to the psychopharmacological treatment of depression.

226. IMIPRAMINE PLASMA CONCENTRATIONS AND RESPONSE IN PANIC DISORDER M. Mavissakalian ! & J. Perel 2 tThe Ohio State University College of Medicine, Columbus, OH 43210; 2University of Pittsburgh, Clinical Pharmacology Program, Pittsburgh, PA Plasma concentrations of lmipramine (IMI) and N-desmethylimipramine (DMI) were assessed in 48 rm_n_icdi~rder with agoraphobia patients who completed an 8 week randomized double blind dose ranging study with imipramine hydrochloride: low dose (0.5 mg/kg/day, n-17) medium dose (i.5 mg/kg/day, n-17) and high dose (3 mg/kg/day, n-14). Assessments included patient and clinician rated symptom scales of panic and phobias, as well as operationalized criteria of response, which were based on m 50% change from baseline to signify marked improvement or an absolute cutoff score to signify minimal to absent symptoms. Analysis included correlational and dose-response stratifications with total, IM! and DMi concentrations as well as multiple linear regression and logistic regression analysis with total, IMI and DM! levels as predictors of symptom severity and response. Results revealed a sigmoidal/iinear relationship between total plasma levels and response in panic and a onrvilinear relationship between total plasma level and response in phobias (such that maximal response was achieved in the 75-133 ng/ml range, with diminished response below and above this range). The curvilinearity of phobic response

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BIOL PSYCHIATRY 1994;35:615-747

was associated with the highest concentrations of DM! while the IMIresponse curve remained linear or sigmoidal. The results have practical implications visa vis the selection of optimal plasma levels in the acute tTeatment of panic disorder with agoraphobia and likewise suggest separate and different mechanisms for imipramine's anti-panic and anti-phobic effects.

227. STRESS-INDUCED ALTERATIONS IN PLASMA CORTISOL, NOREPINEPHRINE AND EMOTION R.J. Gruen 1,2, J. Ehrlich 2, R. Silva I, J.W. Schweitzer I, & A.J. Friedhoff I 'Department of Psychiatry, New York University Medical Center. New York, NY; 2Department of Psychology, New York University, New York, NY Naturalistic and laboratory stress has been shown to lead to alterations in plasma cortisol, norepinephrine (NE), and negative emotion, and it has been suggested that dysfunctional attitudes (i.e., rigid, distorted, peffectionistic cognitions) limit an individual's ability to respond to stress adaptively. Stress-induced alterations in plasma glucocorticoids are thought to buffer the effects of stress. The present study then, was designed to examine the relationship between dysfunctional attitudes, and stress-induced alterations in plasma cortisol, NE, and emotion. Subjects: 28 females were divided into 3 groups: controls (n-10); depression in remission subjects (n-9); and actively depressed subjects (n,,,9), ages ranged from 20 to 41 (mean, 27), all healthy and medication free for at least 2 weeks. Methods: Subjects completed the Dysfunctional Attitudes Scale (DAS), re. ceived a physical examination and laboratory workup, and were diagnosed using the SCID. Subjects were then exposed to an induced-failure stressor. Blood samples and mood ratings were obtained at baseline, during stress exposure, and 40 minutes later. Plasma was analyzed for cortisol and NE by HPLC. Statistics: Change in plasma NE, conisol, and emotion were assessed using MANOVA. Relationships between the DAS and stress-induced changes in cortisol, NE, and emotion were assessed using partial correlations. Result: I) induced.failure stress led to a significant increase in both plasma NE and negative emotion during stress egposure. A significantdecrease in cortisol was observed 40 minutes after egposure; 2) Dysfunctional attitudes were significantly and negatively correlated with plasma cortisol and significantlyand positively correlated with negative emotion during stress exposure. Dysfunctional attitudes were significantly and positively correlated with plasma NE 40 minutes after stress exposure. The data support the concept that dysfunctional attitudes play a role in shaping stress-induced alterations in biochemistry and emotion.

228. PROMISING MEDICATIONS NOT AVAILABLE IN THE UNITED STATES I.D. Glick i, O. Vinar2, D.F. Klein 3, W. Z. Potter4, S.A. Montgomery 5, & y. Lecrubier~

FRIDAY,, MAY 20

cations being used outside of the U.S., which may be of interest. Accordingly, the objective of this report is to identify medications not available in the U.S. which are safe and efficacious, and which offer clinically significant advantages over what is now in the armamentarium. An international team was organized to collect data Rom four sources: 1) from the controlled trials literature, 2) from expert psychopharmacologic clinicians, 3) from regulatory agencies in Europe and 4) from the indusu'y. Countries surveyed include England, France, Italy, Sweden, Hungary, Czechoslovakia, Germany, Switzerland and Holland. Conditions covered include Schizophrenia, Mood Disorder, Anxiety Disorder, Eating Disorder, Substance Abuse, and Personality Disorder. A "hot-list" of the 15 most promising medications and their indications will be discussed. There are a number of drugs currently not available in the U.S., which offer significant advantage in terms of safety or efficacy or both, to improve the care of psychiatric patients.

229. PREDICTIVE BIO-CLINICAL PROFILES OF ANTIDEPRESSANT RESPONSES IN DEPRESSION F. Duval 1,2, M.C. Mokrani 2, M.Jautz l, M.A. Crocq t,2, P. Bailey 2, T.S. Diep t, E. E. Andrade l, & J.P. Maehert, 2 1Centre Hospitalier, Rouffach, 68250, France; 2Research Center for Applied Neuroscience in Psychiatry (FORENAP), Rouffach, 68250, France Fifty-seven drag-free inpatients meeting DSM-llI-R criteria for major depressive episode (MDE) were treated for one month with antidepressants and were then classified as full, partial or uon-respondem according to their post-treatment Hamilton Depression Scale score. These three groups were examined for differences in clinical, psychological, and neuroendo. crine (i,e. 8 AM and ! ! PM TRH-TSH tests and dexamethasone suppression test [DST]) variables. Endocrine tests remained abnormal in partial responders (n-.! 2)and non-responders (n=19); they normalized in the re. spender group. However, at baseline the responder group showed a lower incidence of endocrine abnormalities (g2-11,6, dr=2, IgO.003). A facto. rial correspondence analysis was carried out to examine differences at baseline between the three groups. Non-responders were mainly characterized by blunted 8 AM-STSI-i,mood-congruent psychotic features and history of antidepressant nonresponse. Moreover they differed from responders by having increased frequency of blunted 11 PM-STStl and melancholic features. Respenders were characterized by normal ~TSH (difference between I ! PM- and 8 AM-STSH), absence of personality disorder, total duration of illness less than 2 years, presence of psychosocial stressor during the last year, DST-positive (cortisol nonsuppression), and response to serotonin reuptake inhibitors such as fluoxetine. Partial responders were characterized by increased frequency of blunted ~TSH and borderline personality disorder. These findings suggest that patients meeting DSM-IlI-R criteria for MDE are heterogeneous and that a multivariate approach combining clinical, psychological and neuroendocrine variables may define sub-groups with different prognoses.

tStanford University School of Medicine, Stanford, CA 94305; 2Academy of Sci. & State Institute for Drug Control, Czechoslovakia; 3New York State Psychiatry Institute, New York, N.Y. 10032; 4National Institute of Mental Health, ethesda: MA 20892; 5St. Mary's Hospital Medical School, noon, united Kingdom; Htpital de la Salpttri~:re, Paris, France

230. ANTIGLUCOCORTICOID MEDICATION EFFECTS ON SPECIFIC DEPRESSIVE SYMPTOMS

Like clozapine, paroxetine and clomipramine, there are efficacious medi-

O.M. Wolkowitz, V.I. Reus, F. Manfredi, T. Chan, J.Canick, S. Ormiston, J. Ingbar, & L. Brizendine