A double-blind, randomized study of the efficacy and safety of venlafaxine extended release (ER) versus fluoxetine in outpatients with major depression

P.1. ,~ffective disorders and antidepressants reported in seasonal and non-seasonal affective disorder. A singlenucleotide polymorphism (C825T) in the G protein beta3-subunit gene has been shown to infuence intracellular response to G protein coupled stimuli, and the T-allele of this polymorphism has been associated with hypertension and major depression. We conducted a genetic association study to investigate a possible association of the G-beta3 C825T polymorphism with seasonal affective disorder, winter type (SAD). Patients were diagnosed according to Rosenthal and DSM-IV criteria for SAD, healthy controls were screened using a structured interview guide for DSM-IV diagnoses (SCID-IV). We genotyped 173 patients with SAD and 143 healthy controls for the T825C polymorphism of the G-beta3 subunit using standard PCR procedures. Patients with SAD were significantly more likely to be either homo- or heterozygous for the G-beta3 T-allele when compared to healthy control subjects (p=0.001), and they displayed a higher frequency of the G-beta3 C825T T-allele (p=0.022). Though, the polymorphism was not associated with seasonality, which is the tendency to experience variations in mood and behavior with changing of the seasons. The G-beta3 C825T polymorphism was clearly associated with SAD in our study sample, however, a replication in an independent study sample is needed. The association of this polymorphism with seasonal and non-seasonal depression strengthens the evidence for the involvement of G protein coupled signal transduction in the pathogenesis of affective disorder.

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double-blind, randomized study of the efficacy and safety of venlafaxine extended release (ER) versus fluoxetine in outpatients with major depression

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Results: Significant differences were not seen regarding changes in HAM-D or CGI Severity of illness from baseline until day 56. However, there were some significant changes with regard to the following: Primary Efficacy: HAM-D from baseline until day 56 had a mean value for fluoxetine of 13.9 versus 14.8 for venlafaxine based on a 95% confidence interval for a treatment difference having a p-value of 0.59. CGI Global severity of illness on day 56 for people who were "Mildly, Moderately and Severely ill" had a total score of 57.1% for fluoxetine and 46% for venlafaxine. The secondary objective was to compare safety: Safety was determined by adverse events, vital signs and weight. All adverse events was recorded. The most common adverse events related to fuoxetine and venlafaxine was listed the UKU rating scale. A brief summary of the adverse event for fluoxetine was that 40 patients had at least one adverse event and 0 serious adverse event. For venlafaxine was these figures 47 patients with at least one adverse event and 2 serious adverse events. Conclusion: Although significant differences were not seen regarding changes in HAM-D or CGI from baseline until day 56, these data show that venlafaxine has a higher response trend level for both primary and secondary efficacy.

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Cellular localization of neurotransmitter receptors involved in the local control of serotonergic neurons: A double in situ hybridization study throughout the midbrain raph(~ nuclei

O.-E Mehtonen. Wyeth Lederle Nordiska AB, Solna, Sweden

J. Serrats, G. Mengod, R. Cort6s. Department of Neurochemistry, Institut d'Investigacions Biomkdiques de Barcelona, CSIC (ID1BAPS), Barcelona, Spain

Objective: The primary objective was to compare the efficacy of venlafaxine ER with the efficacy of fluoxetine in outpatients with moderate to severe depression. The secondary objective was to compare safety. Method: 20 General Practitioners (GPs) and in Finland enrolled 102 patients in this 10-11 week, double-blind study. Efficacy data were available for 99 outpatients (50 on venlafaxine extended release and 49 on fluoxetine) with major depression. The dose of venlafaxine ranged from 75 to 150 mg. HAM-D was measured during the screening visit and baseline visit, and the total score was used as an inclusion criterion. To be eligible for the study, patients had to have a minimum score of 20 and no more than a 20% decrease between screening and baseline. Primary Efficacy: This was determined by observing a) change in HAM-D from baseline until day 56 and b) CGI Severity of illness on day 56. If the HAM-D total score decreased by at least 50% since baseline, the patient was considered a clinical responder. If the CGI Severity of the illness on day 56 was scored as 1 (very much improved) or 2 (much improved), the patient was considered a clinical responder. All efficacy variables were evaluated at screening time, on study day-1 and on study days 7, 14, 21, 28, 42, 56 and 70. Secondary objective was to compare safety: Safety was determined at routine physical examination (including height and weight) on day 56, but adverse events during the course of the study and the post-study visit, by vital signs and UKU Side effect Rating Scale measurements. Vital signs and UKU were determined at baseline and on study Days 7,14, 21,28,42,56 and 70. Vital signs were also measured at the post-study visit.

We have investigated the cellular localization of mRNAs coding for different neurotransmitter receptors involved in the control of serotonergic neurons in the dorsal raph6 nucleus (DR), median raph6 nucleus (MnR) and raph6 magnus (RMg). These studies were performed using double in situ hybridization histochemistry, combining non-radioactively and radioactively labeled oligonucleotide probes, and were done at different brain levels to determine the regional degree of co-expression of several neurotransmitter receptors within the raph6 nuclei. Serotonergic and GABAergic cell bodies were labeled using oligonucleotides complementary to the mRNAs encoding the serotonin transporter (5-HTT) and glutamic acid decarboxylase (GAD) respectively. In order to find out which receptors were expressed in serotonergic and GABAergic cells, we carried out double in situ hybridization histochemistry experiments combining the aforementioned probes with oligonucleotides complementary to the mRNA coding for 5-HT1A, 5-HT]B, 5-HT2c, 5-HT2A, 5-HTsB, ~t-opioid, GABA B, and cqB-adrenergic receptors. From our extensive analyses of mRNAs coding for receptors expressed in midbrain raph~ nuclei, we will show different examples. For instance, we observed the presence of GABAB receptor mRNA in GABAergic as well as in serotonergic cells, confirming the hypothesis of the presence of GABAB receptor in these two neuronal populations. We also demonstrate that 5-HT2c and g-opioid receptor mRNAs are present in GABAergic cells, but they seem to be absent in serotonergic cell bodies. Furthermore, we have analyzed the cellular localization of the mRNA encoding the 5-HT5B receptor, whose functional characterization is still limited. We demonstrate its presence in serotonergic cell bodies located in the midline