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P.1 Affectioe disorders and antidepressants
brains were dissected, and the neuropeptide extracted and measured by radioimmunoassays. Results and Comments: The main findings were: (1) the phase of the oesWas cycle does not affect the regional brain NPY-LI concentrations, and (2) baseline NPY-LI concentrations are lower in female "depressed" rats, compared to FRL and SD strains, reaching statistical significance in hypothalamus and in hipoccampus. The results demonstrate significant NPY gender differences. Decreased NPY-LI levels were particularly pronounced in female FSL "depressed" animals vs. FRL control rats; these changes may constitute a clue to the markedly higher incidence of affective disorders in females. Supported by the Swedish Medical Research Council grant 10414, Karolinska Institute.
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neurolmaging shows antidepressant binding pdmadly at serotonin uptake sites in the dorsomedlal thalamus of "higher" animals
D.E Smith 1'2, A.D. Gee2, E. Danielsen2, K. Ishizu2, M. Sakoh2, J. Scheel-Kriiger a, A. Gjedde2. 1Dept. of Biological Psychiatry, Psychi-
atn'c Hospital, 8240 Risskov; 2PET Center, Aarhus University Hosp., Norrebrogade 44, 8000 Aarhus C; 3R&D, NeuroSearch, Glostrup, Denmark Introduction: Selective serotonin reuptake inhibitors (SSRIs) are used widely for treating depressive disorders. At present, however, there are many unanswered questions concerning the cerebral sites and mechanisms of action of these drugs. Some SSRIs have been radiolabelled for PET and SPECT, but none has proven to be ideal for imaging of neuronal serotonin uptake sites. Here, we present findings on a new, preclinical SSRI, NS2381, that we have used for neuroimaging of serotonin uptake sites in living brain. Methods: NS2381 (3-(4-trifluoromethyl-phenyl)-8-azabicyclo[3.2.1]oct-2-ene) was IN-methyl llC] radiolabelled, either as racemic compound or as (+)- and (-)-enantiomer. All procedures involving animals were approved by the Danish National Committee for ethics in biomedical research. Female domestic pigs weighing 35--45 kg were anesthetized with midazolam and ketamine HC1 followed by isoflourane in O2/N20. Catheters were surgically installed in a femoral artery and vein. A Siemens ECAT EXACT HR was used for scanning. The pigs received intravenous bolus injections of [HC] NS2381 (760-1025 MBq), once under baseline conditions and once during continuous i.v. infusion of citalopram HBr (racemate). Estimation of pharmacokinetic parameters was done by graphical analysis using multilinear regression and a onecompartment model with pools of free and bound radioligand. Results: The following table shows kinetic parameters of racemic [11C] NS2381 in selected regions of living porcine brain under baseline conditions and during infusion of citalopram, a potent SSRI. The data for the enantiomers are already available and will appear on the poster. Treatment
Baseline
Citalopram
Brain region
Cerebellum Thalamus Raph6 Frontal Cortex Cerebellum Thalamus Raph~ Frontal Cortex
K~
k~
V~
(ml/cm3/min) (mill-1)
(ml/cm3)
2.13 4- 0.33 2.12 4- 0.07 2.70 4- 0.12 1.50 4- 0.09 1.32 4- 0.02 1.37 4- 0.09 1.50 4- 0.02 1.13 4- 0.04
95.0 -4- 14.9 160.0 4- 17.3 128.5 4- 6.9 127.0 -4- 27.8 56.5 4- 4.5 110.9 4- 21.6 79.9 4- 9.4 80.1 4- 18.6
0.024-4-0.007 0.014-4-0.002 0.0214- 0.002 0.013-4-0.003 0.024-4-0.002 0.0134- 0.003 0.0194- 0.003 0.0154- 0.004
Discussion: The PET findings obtained with [1]C] NS2381 support our hypothesis that the dorsomedial thalamus plays a key role in the pathophysiology of affeetive disease and in therapeutic actions of SSRIs.
Alpha-l-acid giycoprotein in major depressive disorder E. Nieto, E. Vieta, L. Alvarez, M. Torra, E Colom, C. Gastt. Hospital
Clinic and University of Barcelona. C/Villarroel 170, Barcelona 08036, Spain Objective: Increased plasma levels of alfa-l-acid glycoprotein (AGP) were reported in major depressive disorder. This study examined the relationships between AGP levels and severity, treatment response and antidepressant levels of depressed patients. Methods: Plasma AGP levels were measured in 36 subjects with major depressive disorder before and after 6-week treatment with imipramine and in 30 age- and sex-matched controls. Free imipmmine plasma levels of depressed patients were measured at 6 weeks. Comparative analysis between depressed patients and controls, between nonresponders (N = 12) and responders (N = 24), and between severely depressed patients (N = 14) and moderately depressed patients (N = 22) were made. Statistics: Before comparative analysis test of homogeneity of variances and analysis of normality (Kolmogorov-Smirnov) were performed. Comparative analysis of normal variables between two groups was performed by means of unpaired two-tailod Student t-test. Correlation between AGP measures and baseline HDRS scores and free imipramine plasma levels were made by means of Spearman's rank correlation coefficient. Results: Depressed patients had significantly higher mean values of AGP than control subjects. Imipramine non-responders and specially severe depressed patients had significantly higher increase of AGP levels during treatment than other depressed subgroups. There was no correlation between baseline AGP levels and severity of depression or free imiprarnine levels. Conclusions: Depressed patients showed high baseline concentrations of AGP. AGP levels did no predict neither free imipmmine plasma levels nor differential response after 6 weeks of treatment with imipramine. Higher increase of AGP during treatment was associated with severity of depression and treatment non-response.
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Gender differences in the prognosis of anxiety and depression - a follow-up study
I. Kecskts, E. Szfidtczky, Z. Rihmer, J. Fiiredi. National Institute for
Psychiatry and Neurology, Budapest, Hungary In our follow-up study, we investigated the gender differences in the prognosis of anxiety and depression. Method: We have followed the state of our patients who were admitted to our inpatient psychiatric ward between 1991 and 1996 with a DSM III-R diagnosis major depressive episode. Patients had received an antidepressive medication (TCA-s, SSRI-s and RIMA-s) with or without anxiolytics. The state of the patients were followed by the 21 item Hamilton Depression Rating Scale (HDRS, day 0 and week 6), Zung Self-Rating Depression Scale (SDS, day 0 and end) and the Spielberger State-Trait Anxiety Inventory (STAI, day 0 and end). Results: Ninety-three patients attended the study (25 male and 68 female), with no significant gender differences in age (mean: 43.1 years), follow-up duration (mean: 2.95 years), anxiolytic usage (mean: 75%), prior hospitalisation (mean: 1.04), severity of depression (HDRS mean: 25.8) and state anxiety (STAI-S: 59.7). Indicating woman's more anxious personality the difference in trait anxiety (female: 63.2, male 56.1, p = 0.008) and in SDS scores (female: 58.4, male 53.3, p = 0.019) was significant. Females had a higher response rate (regarding their depressive symptoms, by HDRS, 65% vs 50%, NS). All types of anxiety decreased in both gender by the end of follow-up, but significant changes were only in females (STAI-S from 60.3 to 55.5, p = 0.017, STAI-T from 63.2 to 59.0, p = 0.024). The same tendency have been seen in SDS scores (mean: from 57.1 to 50.0, males: from 53.3 to 48.6, NS, females: from 58.4 to 50.6, p < 0.001). Females had significantly fewer hospitalisation during the follow-up (0.34 vs 0.68, p = 0.020).
P1 Affectioe disorders and antidepressants Conclusion: Even in case of equally severe depression, females have more anxious symptoms. Antidepressive medication significantly reduce woman's anxiety and depression, therefore they have a better prognosis than males.
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Open-label study of fluoxeUne in civilian post-traumatic stress disorder
M. De Clereq, PH. Hoyois, E. Vermeiren. Psychiatry Department,
University of Louuain, Saint-Luc Academic Clinics, Brussels, Belgium Objective: To examine the efficacy of fluoxetine in treating civilian patients with post-traumatic stress disorder (PTSD). Methods: Outpatients (N = 31) were treated at the Crisis and Psychiatric Emergencies Unit of the Saint-Luc Academic Clinic, Brussels. Patients over 14 years of age were eligible to participate if they met DSM-IV criteria A-F for PTSD, including clinically significant suffering for more than one month. Patients with schizophrenia, psychotic disorder, oligophrania, or who were currently taking a tricyclic or serotonin reuptake inhibitor were excluded from the study. Eligible patients initiated open-label fluoxetine 40 mg daily for 60 days and received weekly supportive consultation. Patients were evaluated following 30 and 60 days of treatment. Treatment efficacy on anxiety and depressive symptoms was determined using the Hamilton Anxiety Rating Scale (HAS), Hamilton Depression Rating Scale (HDRS), and Montgomery-Asberg Depression Rating Scale (MADRS). Efficacy on PTSD symptomatology was measured with the Impact of Event Scale (IES) and the IES subscores for intrusion and avoidance. Statistical methods included analysis of variance for repeated measures on total scores at TO (baseline), T30 (30 days of treatment) and T60 (60 days of treatment), and systemic two times mean comparisons using a two-tailed t test. Results: Mean patient age was 41 years (range 18-68 years) and 59% of the patients were male. Patient trauma consisted of assault with a gun (41%), robbery (19%), rape (11%), car accident (11%), and l patient each experienced a hostage situation, bomb attack, fire, war zone escape, or a witnessed suicide. Two-thirds of the patients experienced the trauma within the past 3 months. At endpoint, the HAS, HDRS, MADRS, IES-global, and IES-intrusion scores had decreased significantly from baseline, with 50% decreases in HAS, HDRS and MADRS scores occurring in 27%, 33% and 48% of patients, respectively. The IESavoidance subscore remained stable over time, showing no significant increase or decrease. Conclusion: Anxious, depressive and intrusion symptoms associated with PTSD showed improvement after two months of treatment with fluoxetine, with the most significant improvement occurring after the first 30 days of treatment. The persistence of avoidant behavior is of interest. This study demonstrates the benefits of fluoxetine pharmacotherapy on PTSD associated anxiety and depression.
Purpose of the Study: To find out more about the development and course of cognitive changes during ECT and their relationship to ECT parameters or depressive illness, we studied 51 depressive patients (ICD 10). After induction of anaesthesia, patients were manually ventilated with pure oxygen. The unilateral ECT stimulus was bidirectional, squarewave, brief pulse with a pulse width of 0.5 ms, delivered by a Thymatron DGx. EEG seizure duration was monitored and recorded, and the degree of postictal EEG suppression computed by the Thymatron DGx. ECG and pulse rate were continuously monitored, blood pressure was taken before treatment, after the end of seizure, and then every minute. The severity of depressive symptomatology was assessed with Hamilton Depression Rating Scale - HAMD - (items 1-17), Clinical Global Impressions (CGI), Hamilton Anxiety Scale (HAMA), Visual Analogue Scale (VAS), Nurses Global Impressions (NGI), and the Selfrating Adjective Checklist (von Zerssen).. To assess cognitive functioning various subtests of the verbal intelligence scale (Lehrl et al.), the Zahlenverbindungstest (Trail Making Test, Oswald and Roth) for the cognitive fastness, the Syndrom-KurzTest (syndrome short test, The SKT neuropsychological test battery, Erzigkeit) for attention and memory function, and other psychological tests for memory, concentration, attention, and learning were used. Ratings and cognition tests were performed before treatment, one day after the third and one day after the last ECT, two weeks and two months after the last ECT. The only concomitant therapy during the course of ECT was chlorprothixene, after the end of ECT patients received paroxetine. Results: The mean HAMD-score was 29.1 before treatment and decreased to 17.1 after the third ECT and 9.9 at the end of the ECT course; two weeks after the end of ECT the mean score was 10.2, and l 1.9 two months later. Similar results were shown in the Zerssen Self rating Scale with 40.1 before treatment, decreasing to 35.7, and 30.9 at end of treatment, 22.2 two weeks and 25.2 two months after end of ECT. For the test for new learning there was an increase of correct items from 61.7 before treatment to 73.4 after the 3rd treatment to 77 at the end of the ECT course, and still an improvement to 86.8 and 91.7 two weeks and two months after the end. For the cognitive rate in the SKT there was a decrease of time needed for the subtest from 57.1 seconds before treatment to 49.5 at the end of treatment, and 42.8 two months after end of ECT course. Similar results are shown in all other cognition tests with an improvement beginning after the third treatment and remaining over the end of the ECT course. Conclusion: Our results show that depressive patients have multiple cognitive disturbances due to depression. Right unilateral ECT improved not only the depressive symptoms but the cognitive disturbances too and did not cause any ECT induced memory loss or other cognitive side effects.
Weight monitoring during two long-term trials of citalopram
References [1] Shalev, AY (1998) Prospective study of posttraumatic stress disorder and depression following trauma. Am J Psychiatry. 155 (5), 630~37. [2] Shalev, AY (1996) Treatment of posttraurnatic stress disorder: a review. Psychosomatic Medicine. 58 (2), 165-182.
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Electroconvulsive Therapy (ECT): therapeutic efficacy and cognitive function
C. Geretsegger1, B. Judendorfer2, P. Weihs 1, W. Aichhorn I , C. Sackel 1, C. Stuppaeck 1. ]Dept. of Psychiatry; 2Dept. of Clinical Psychology,
Christian-Doppler-Clinics, lgnaz-Harrer-S~ 79, A-5020 Salzburg, Austrh~ Introduction: Electroconvulsive therapy is an effective treatment and should no longer be considered a treatment of last resort but as a therapy of first choice in severely ill and certain other depressive patients. The greatest area of concern with ECT has to do with the potential development of adverse cerebral and cognitive changes.
A. Wade, K.E Over~, O. Lemming. Community Pharmacology Services
Ltd, Clydebank, UK Citalopram is a serotonin re-uptake inhibitor with proven efficacy against several psychiatric disorders, including depression and panic disorder. Research into eating disorders indicates that serotonergic neurotransmission may influence food intake; high serotonin levels have been implicated in anorexia nervosa, and low serotonin levels are associated with binge eating. The effect of citalopram on body weight was therefore assessed in two 12-month trials: a double-blind, randomised trial of placebo, citalopram 10-15, 20-30, or 40-60 mg/day, and clomipmmine 60-90 rag/day in 279 patients with panic disorder, and an open trial of citalopram 10-60 mg/day in 541 depressed patients. Body weight was measured at baseline and at regular intervals during treatment. In the panic trial, body weight did not change significantly in patients receiving citalopram or placebo, but weight gain approaching statistical significance was observed with clomipramine (p = 0.078), as is expected with tricyclic antidepressants.