I?6 Other topics
(P.6.0431 Hypothalamic-pituitary-adrenocortical-system alterations in aging and depression: Contribution of vasopressln to underlying pathophysiology
M. Hatzinger, C.T. Wotjak’, M.E. Keck’, R. Landgraf’,U. Hemmeter, E. Holsboer-Trachsler, F. Holsboer', I. Neumann’. Psychiatric University Clinic, Depression Research Unit, 4025 Basel, Switzerland ‘Max Planck Institute of Psychiaq, 80804 Munich, Germany
Hypothalamic-pituitary-adrenocortical (HPA)-system alterations are common in human aging as well as in psychiatric disorders like depression. Among the various neuroendocrine function tests, the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test, in which DEX-pretreated individuals receive a single dose of CRH, has proved to be the most sensitive measure of subtle changes in HPA system regulation*. Using this test we showed that basal hormone levels after DEX-pretreatment (t = 2.1, p < 0.05) (DEX non-suppression) as well as hormone release after the additional CRH stimulation (t = 2.7, p < 0.01) were increased in depressed patients (n = 14) as compared to age-matched controls (n = 14). In aging these findings were accentuated (t = -2.98, p < 0.01). We concluded that (1) DEX non-suppression indicates feedback disturbances, and (2) the increased hormone release after additional CRH stimulation suggests alterations in endogenous synergisms of CRH with other ACTH secretagogues, e.g. argininevasopressin (AVP). To further investigate the underlying mechanisms the DEX/CRH test was established in aged male Wistar rats, in which increased basal hormone levels after DEX-pretreatment and elevated hormone release after additional CRH stimulation were demonstrated as well’. To test the hypothesis of AVP being the responsible co-factor in HPA system dysregulation, the DEX/CRH test was conducted in aging rats which were treated with an AVP receptor antagonist (VI) 15 min before CRH injection. The application prevented the CRH-induced hormone release (area under the curve of ACTH: 2896 +/- 759 vs. 699 +/- 479; p < 0.01). In addition, comparing young and aged rats, in situ hybridization revealed an enhanced CRH and AVP mRNA expression within the parvocellular part of the paraventricular nucleus (PVN) in DEX-pretreated aged animals (p < 0.05). Thus, we conclude that an increased AVP synthesis in and secretion from PVN neurons may play a major role in the age-associated and probably also the depression-related HPA system overactivity.
References Hatzineer. M.. Reul. J.M.H.M..Landmaf. R.. Holsboer, F., and Neumann, L ’ I. (1992)CoAbinedhexametha~one/&H&t ‘inrats: bypothalamo-pituitaryIll
antidepressant effect. Furthermore, studies comparing SSRIs with noradrenergic and dopaminergic agents provide additional evidence for the role of serotonergic functioning in the etiology or mediation of PMDD. These studies have shown greater efficacy with serotonergic than nonserotonergic compounds. Method: We reviewed the published literature for controlled (7) and open (4) clinical trials of the SSRI fluoxetine in the treatment of PMDD. Due to the evolving nosology, the studies presented refer to subjects with late luteal phase dysphoric disorder (LLPDD), PMDD, or severe premenstrual syndrome (PMS). Diagnostically, all subjects presented with symptoms consistent with the clinical syndrome of PMDD (with all 7 studies referring to DSM-III-R-defined LLPDD or DSM-IV-defined PMDD for study inclusion). Results: These trials demonstrate an early, robust response of PMDD symptomatology with fluoxetine 20 mg/day. Improvement is often seen in the first cycle of treatment; this response is noticeably quicker in onset than in patients being treated for depression. This may be explained by a unique mechanism of action of fluoxetine, possibly to increase the biosynthesis of allopregnanolone, a neurosteroid metabolite of progesterone. Preliminary data, such as the relatively rapid onset of improvement in some patients initiating treatment with fluoxetine, suggest that intermittent luteal phase fluoxetine dosing may be a suitable treatment strategy for select patients with PMDD. Adverse events, usually transient and rarely leading to discontinuation, were consistent with fluoxetine’s known safety profile. Conclusion: SSFUs are emerging as the drugs of choice in the treatment of PMDD in women who have failed more conservative measures. More double-blind placebo-controlled studies are available for fluoxetine than for any other SSRI. Fluoxetine 20 mg/day is an effective and welltolerated treatment for the whole range of symptoms (psychological and physical) in women with PMDD. More work is needed to precisely determine the mechanism and spectrum of fluoxetine’s action in PMDD and to determine the necessary length of treatment for PMDD. Anecdotal reports suggests that some symptoms return shortly following treatment discontinuation and that restarting fluoxetine is an effective management strategy. Because substantial clinical experience indicates that fluoxetine use in pregnancy does not increase the risk of fetal malformations, and such information is not available for the other SSRIs, fluoxetine should be the first-line treatment option in women with PMDD.
system alterations in aging. Neuroendocrinology
Heuser,I.J., YassouridisA., and Holsboer,F.(1994)The combineddexamethasone/CRH test: A refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28: 341-356.
[P.6.044[ The role of fluoxetine in the treatment of premenstrual
R. Judge, S. Romano, J. Dillon. Eli Lilly and Company, Indianapolis, Indiana, USA
Introduction: Many women experience physical and psychological changes associated with the menstrual cycle. These changes may include fatigue, breast tenderness, edema, and irritability. However, for women (3-5%) who meet the DSM-IV criteria for premenstrual dysphoric disorder (PMDD), psychological symptoms are severe and social and occupational functioning is impaired. While the etiology of PMDD is unknown, symptoms of dysphoria, including depression and anxiety, predominate and indicate a link to serotonin dysregulation. Successful treatment of PMDD with sleep deprivation, evening bright light, and tricyclic antidepressants has suggested a pathophysiological link between PMDD and major depression. More recently, research implicating neuroactive steroids in the etiology of premenstrual symptoms has pointed to a mechanism of action of the serotonin reuptake inhibitors (SSRIs) which may be distinct from their
A health economic analysis of pharmacotherapy for major depressive disorder in Europe and the Americas
S.R. Arikian, J.J. Doyle. The Analytica Group, Ltd, Scarsdale; Columbia School of Public Health, New York, Ivr: USA We conducted a multi-national pharmacoeconomic analysis of oral therapies in the management of major depressive disorder (MDD) in ten countries located in Europe, Latin America, and North America. The study was performed by an independent group of researchers under an unrestricted grant from Wyeth-Ayerst International. Data used to populate country-specific decision analytic models were derived from an international meta-analysis, a Delphi panel (conducted in each country to ascertain local practice patterns in depression management), and a financial analysis to valuate resources consumed with local currencies. Local market research data was used to estimate the utilization of antidepressant agents, and health care system information was collected in order to model pharmacoeconomic and net economic endpoints. Major depressive disorder presents a significant clinical and economic burden to societies across the world. According to the WHO, depression is estimated to be present in 10% of all patients seeking care at primary health care facilities worldwide, but it is frequently unrecognized by primary care physicians. In fact, the recent DEPRES study showed that just 41% of patients with MDD received medication in the European community. Greenberg et al estimated in 1993 that the three leading types of depression cost the United States US$ 43.7 billion annually, similar to the cost of heart disease. In the United Kingdom, Kind estimates the annual cost of depression at &420 million.
F6 Other topics A review of 20 epidemiologic studies conducted since 1980 confirms the prevalence of MDD to be significant. The DEPRES study reported a 6-month prevalence of MDD of 6.9%, ranging from 3.8% in Germany to 9.9% in United Kingdom. The 6-month prevalence of MDD in the United States is 2.2% according to 20 the National Institute of Mental Health Epidemiological Catchment Area (ECA) study. We performed a patient-level pharmacoeconomic evaluation of MDD using a decision analytic approach. We then applied the pharmacoeconomic results at the policy-level to calculate the net economic (budgetary) impact of shifting medical prescribing practice to the most costeffective therapy. The perspective for the analysis was that of the public payor (i.e. government) for all countries studied except for the US, where the managed care perspective was evaluated. An expected cost analysis demonstrated that venlafaxine XR utilization consistently yields a lower cost of therapy when compared to SSRIs and TCAs. The expected cost savings attributable to venlafaxine XR range from $16.51 to $2540.00, and are a function of superior efficacy and reduced health care services. A policy level analysis was also performed and demonstrated that a 1% increase in venlafaxine utilization would yield cost savings to the primary payor ranging from US $3,400,000 in Italy to US $24,400.000 in Germany. These results withstand comprehensive multivariate sensitivity analysis.
lP.6.0461 Sertraiine efficacy in the treatment of premenstrual dysphoric
R. Rodriguez Castro, S. Ros Montalban’ *, J.R. Domenech Bisen, J. De la Torre Hemtidez3. ‘Hospital de1 Mal; Servei de Psiquiatria, Unioersitat Autonoma Barcelona; ‘Institut de Psiquiatria Bioltigica Barcelona, Grupo Quit&; ‘Hospital Creu Roja Barcelona, Spain Introduction: PMDD IS characterized by debilating mood and behavioral changes in the Week preceding menstruation that interfere with normal functioning. Objective: Evaluate the significant improvement in symptoms of PMDD after Sertraline treatment Methods: A sample study involving 32 patients wifh diagnostical criteria of PMDD Phase I Two menstrual cycles without pharmacological treatment Phase 11Three menstrual cycles with sertraline 50-150 mg/day The patients were assessed at all visits during the trial using the EEASL, CGI and daily symptoms journal. Results: Sertraline mean daily dose was 65 mg. 28 patients improved in premenstrual symtomatology 75% from baseline and the daily functioning of patients in the EEASL. Conclusion: Sertraline is effective and well tolerated in patients suffering from PMDD.
lP.6.0471 Quality of life during antihypertensive
of GHQ-12 which is about sleep. Although all the scores were under the treshold for both STAI-1 and STAI-2, the anxiety scores were remarkably lower in Group 6. Conclusion: It was found that hypertension, independently from medication, was appearing to be an important threat against quality of life, itself, even though treated moderately. However, the symptoms in these hypertensive groups did not meet the criteria for depression. Neither p-blockers, nor ACE Inhibitors showed significant effects to cause depression. @-blockers were found to decrease the number of anxiety symptoms when compared with even normotensives.
efficacy A double-blind carbamazepine-controlled and safety study of vaiproate in impuisivity and violence
L.D. Mosca, J.P. Licciardo, J.L. Coppola. Psychiatric Emergency Hospital, “Torcuato de Aluear”, Buenos Aires, Argentina Introduction: Valproate was developed in Europe in 1963 as an antiepileptic and was approved for this use in the United States in 1978. It was first used in the treatment of Bipolar patients in France in 1966. At the present time it is known for its effectiveness as an anti-recurrent. Studies are also being made for its use in controlling impulsivity and violence, panic attacks, addictions and alcoholism, schizoaffective and eating disorders, and neurological disorders, such as migranes and neuropathic pains. One of the daily problems faced in emergency psychiatry is the control of impulsivity and violence, because of that we undertook a study using Valproate. Objective: To determine the effectiveness of Valproate in the reduction of violence and impulsivity in psychiatric patients independently from the basic clinical diagnosis in a double-blind comparison with carbamazepine. Method: 40 inpatients with impulsivity and violent behaviour have been scored using the Modified Overt Aggression Scale (MOAS). An adaptation of Yudofsky’s Overt Aggression Scale. Having access to nursing information and medical instructions They were randomly assigned to twice-daily, double-blind treatment with identical-looding capsules of either valoproate or carbamazepine. The starting doses were Valproate in dosages ranging from 15 to 25 mg/kg or 1&I 5 mg/kg of Carbamazepine over a two months period and were evaluated once a week using MOAS. Results: Repeated MOAS measures revealed reductions in the fiequency of aggressive episodes during Valproate and Carbamazepine treatment, despite Valproate has showed most efficacy and less latency than Carbamazepine. Conclusions: Our results revealed that Valproate is effective in treating aggression. Moreover this treatment appears to be well tolerated and safe.
therapy Membrane-protective peptide
effect of delta-sleep
D.I. Akblylk, E. Giikkurt. Baymdw Medical Center: Ankara; Turkish National Education, Kefiiiren Health Care Center, Ankara, Turkey
Objective: The aim of this study was to compare the effects of two antihypertensive agents; @-blockers and Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors), on the quality of patient’s life and on the scores of depression and anxiety scales. Method: We had three groups of patients with comparable demographic characteristics, 15 patients in each, who were followed in an outpatient clinic; hypertensives under p-blocker treatment (Group @), hypertensives under ACE Inhibitor treatment (Group A) and normotensives who were not under any medication (Group N). They were asked to answer the questions of an information form, a quality of life measure (General Health Questionnaire; GHQ-12), a depression scale (Zung) and an anxiety scale (STAI). The blood pressures were moderately controlled with treatment in hypertensive groups. Results: There was no meaningful difference between all groups for the scores of Zung Depression Scale. GHQ-12 scores were significantly higher in Group A and (3. The difference was striking for first the question
T.I. Bondarenko, LA. Goroshinskaya, 1.1. Mikhaleva, T.A. Shustanova. Department of Biochemishy and Microbiology, Rostou State University. Rostoo-on-Don, Russia Many pathological changes affect cell membranes disturbing their normal molecular organization. If not a reason, it may be an original mechanism of reinforcement of different diseases. Pathogenic role in the development of many mental disordes belongs to stress. Stress induced membrane damage is conditioned by the intensification of free-radical reactions of lipid peroxidation and the deficiency of antioxidant systems. In this come&on the research of the membrane-protective effect of delta-sleep inducing peptide (DSIP) is of interest as DSIP is an antistress and hypnogenic brain modulator. The animals being in stress state in a result of a 3&y exposure under low temperature (0 - +4 “C). Were used as experimental model. We have shown that changes of mitochondrial and lisosomal membrane structure and permeability are observed in