P.4.c.008 Benzodiazepines and salivary cortisol: the Netherlands study of depression and anxiety (NESDA)

P.4.c Anxiety disorders and anxiolytics - Anxiolytics (clinical)

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variable and presynaptic 5-HTIA BPND of the DRN as regressor, controlling for sex and specific activity of the radiotracer. Results: In healthy subjects parametric analysis showed significant positive associations between pre- and postsynaptic 5-HT IA BPND within the amygdala and throughout most of the cortical regions being strongest in the insula, anterior cingulate and orbitofrontal cortices (p < 0.01 FDR-corrected). However, in the patient group this relationship was reduced within all regions prior to medication. Direct comparison of the patient scans before and after medication revealed a significantly greater association of pre- to postsynaptic 5-HTIA BPND in the right amygdala, bilateral hippocampus, insula and orbitofrontal cortex after SSRI treatment (p < 0.005 uncorr., see Table). Conclusions: This is the first study characterising the relationship between pre- to postsynaptic 5-HTIA receptors in healthy controls and anxiety disorders. Our data suggests that within healthy controls lower serotonin levels caused by higher DRN 5-HTIA autoreceptors are compensated with an upregulation of postsynaptic 5-HTIA receptors. However, this compensatory mechanism seems to be disturbed within anxiety disorders. More importantly, SSRI treatment not only changes pre- and postsynaptic 5-HTIA receptor levels [1] but enhances the association between 5-HTIA receptor binding in the DRN and postsynaptic sites (see Table). Here we identified key regions linked to emotional processing possibly explaining the attenuated activation of the amygdala after SSRI treatment [3]. Table: Correlations between pre- and postsynaptic 5-HTlA BPmJ for clusters, where patients showedsignificantlygreater association after SSRI treabnent (p < 0.005 uncorr.) Region

MNI coordinates x, y,z (left/right)

Amygdala Hippocampus Orbitofrontal cortex Insula

29,-3,-15 -21,-17,-13/21,-9,-19 -11,17,-15/11,17,-15 -35,9,15/37,11,13

Before treabnent After treabnent Pearson's p-value Pearson's p-value r

0.276 0.154 0.464 0.44

r

0.253 0.529 0.046 0.059

0.698 0.596 0.678 0.723

0.0009 0.007 0.0014 0.0005

This work was supported by an unrestricted investigatorinitiated research grant from H Lundbeck A/S to. S. Kasper. The study protocol has been planned by the authors who retained full academic control and are publishing the study independently. References [1] Spinde1eggerC., Lanzenberger R., Wadsak w., et al., 2008. Influence of escitalopram treatment on 5-HTlA receptor binding in limbic regions in patients with anxiety disorders. Molecular Psychiatry 2008 Mar 25 [Epub ahead of print]. [2] Hahn A., Savli M., Stein P., et al., 2009. Serotonin-1A receptor binding potential in dorsal raphe nuclei predicts orbitofronta1 reactivity in healthy subjects. European Neuropsychopharmacology 19 (Suppl. 1): S15-S16. [3] Arce E., Simmons A.N., Lovero K.L., et al., 2008. Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacology 196: 661-72

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Benzodiazepines and salivary cortisol: the Netherlands study of depression and anxiety (NESDA)

L. Manthey 1 " E.J. Giltay 1 , T. Veen1 , S.A. Vreeburg/, EG. Zitman1 , B.WJ.H. Penninx-. 1Leiden University Medical

Centre (LUMC), Psychiatry, Leiden, The Netherlands; 2VU University Medical Center, Psychiatry, Leiden, The Netherlands Background and purpose of the study: Previous intervention studies have shown that benzodiazepines (BZD), drugs commonly used in the treatment of insomnia, anxiety and MDD (Major depressive disorder) act as GABAA agonists in the paraventricular nucleus (PVN) of the hypothalamus, part of the stressregulating hypothalarnic-pituitary-adrenal (HPA) axis. Following administration, BZDs antagonize stress-induced PVN output of corticotrophin releasing hormone, resulting in a decreased release of adrenocorticotropic hormone into the blood circulation, and attenuated stimulation of cortisol production [1,2]. Previous intervention studies only focused on the acute effects of BZD on cortisol levels. Less is known about the endurance of cortisol suppression after BZD administration. One study reported that cortisol alterations only lasted for 2-3 hours despite persisting high oxazepam levels, which could indicate that cortisol suppression is only temporary [3]. Therefore, the present study investigated whether BZD use is associated with a persistently altered HPA axis (as assessed by salivary cortisol levels) in mainly long-term users. Design, Setting, Patients: The association between BZD use and cortisol levels was investigated in participants of the Netherlands Study of Depression and Anxiety (NESDA) with a lifetime diagnosis of anxiety or MDD (n= 1531). This group was subdivided into a 'daily BZD users' (n=96), 'infrequent BZD users' (n = 172) and 'non-users' (n = 1263) group. Further, possible associations between characteristics of BZD use (dose, duration, and addiction) and salivary cortisol levels were addressed. We corrected all analyses for sociodemographics (sex, age, education, and North-European ancestry), sampling factors (awakening time, work status, weekday, season, sleep duration), health indicators (smoking, physical activity), comorbidity and antidepressant use (NonelTCA/SSRIlOther antidepressants). Main outcome measure: Each subject provided seven saliva samples, from which three cortisol indicators were calculated: the l-hour cortisol awakening response (CAR), evening cortisol, and cortisol suppression after ingestion of 0.5 mg dexamethasone (DST). Summary of results: In multivariable adjusted models, no significant differences in CAR were found between the BZD user groups (daily users vs. non-users: p= 0.28; daily users vs. infrequent users: p= 0.16). Evening cortisol levels were significantly lower in daily BZD users as compared to non-users (p = 0.04, effect size (Cohen's d):O.2l). The adjusted DST did not differ significantly between groups (daily users vs. non-users: p=0.98; daily users vs. infrequent users: p=O.5l). Characteristics of use (dose, duration, and dependency) were not associated with salivary cortisol levels. Conclusions: Despite the finding of slightly lower basal cortisol levels in current BZD users, results indicate that BZD use is not convincingly associated with HPA axis perturbations. As most BZD users were long-term users (> 3 months of use), habituation of the HPA axis might have developed in reaction to chronic BZD exposure, leading to a much smaller effect of BZDs on salivary cortisol levels than the significant decreases in cortisol found in the majority of intervention studies on short-term. Alternatively, BZD exposure might not have long-term effects on the HPA-axis. Another possible explanation may be that BZD users had more severe psychopathology than non-users before the start of BZD treatment with accompanying elevated cortisol levels which were subsequently normalized by BZD treatment.

P.4.c Anxiety disorders and anxiolytics - Anxiolytics (clinical) References [1] Zahner, M.R., Li, D.P., Pan, H.L., 2007 Benzodiazepine inhibits hypothalamic presympathetic neurons by potentiation of GABAergic synaptic input. Neuropharmacology 52, 467--475. [2] Abelson, IL., Curtis, G.C., Cameron, O.G., 1996 Hypothalamicpituitary-adrenal axis activity in panic disorder: Effects of alprazolam on 24 h secretion of adrenocorticotropin and cortisol. Journal of Psychiatric Research 30, 79-93. [3] Gram, L.P., Christensen, P., 1986 Benzodiazepine Suppression of Cortisol Secretion - A Measure of Anxiolytic Activity. Pharmacopsychiatry 19, 19-22.

IPA.c.0091 Dose-dependent effects of a clinically effective and non-effective dose of lorazepam on 7.5% C02-induced anxiety IE. Bailey 1 ., A Diaper1 , AS. Rich 1 , G.R. Dawson/, D.I Nutt 1 . 1 University ofBristol, Psychopharmacology Unit, Bristol, United Kingdom; 2P 1Vital Ltd, Department ofPsychiatry, Oxford, United Kingdom Previous research from our group has shown that drugs acting on the GABAA receptor may be effective in attenuating 7.5% C02-induced anxiety symptoms more than other anxiolytics [1,2]. Both the psychological subjective and physiological objective symptoms of anxiety induced by a 20-minute inhalation of 7.5% C02, when compared with air inhalation, can be attenuated by anxiolytics such as lorazepam and paroxetine [3]. The current study has been designed to investigate if these effects are general to benzodiazepine receptor agonists, or dose-related, by comparing the effects of a 0.5 mg dose of lorazepam (thought to be nonclinically effective) with a 2 mg dose of lorazepam (clinically effective) on the symptoms induced by 7.5% C02 inhalation. Eighteen healthy male participants (mean age 20.6, sd 1.29) provided informed consent and were judged to be fit by a physical and psychiatric screening. All participants attended for three visits each a week apart to take one of 0.5 mg lorazepam, 2 mg lorazepam and placebo each week in a randomised double-blind within-subjects design. Drugs were given 60 minutes prior to the first inhalation of 20 minutes of medical air, which was followed by 20 minutes inhalation of 7.5% C02. The order of gas presentation was single-blind and gas was delivered via an oro-nasal face Hans Rudolf face mask. Subjective ratings using Visual Analogue Scales (VAS) and questionnaires (panic symptom inventory, generalised anxiety disorder inventory and Spielberger State Anxiety)were recorded before and after each inhalation and for peak effects. Blood pressure (BP), heart rate (HR), respiration rate and expired C02 were recorded during each inhalation. The study was performed to ICH GCP standards in our clinical research unit. Both doses of lorazepam were well tolerated. As with previous studies, 7.5% C02 inhalation significantly raised blood pressure, heart rate, and respiration rate, and increased subjective reports of anxiety symptoms, compared with the air inhalation. During C02 inhalation, lorazepam dose-dependent trends were sobserved, where mean scores for VAS stressed, tense, worried, and feeling like leaving the room were lower after 2 mg lorazepam than 0.5 mg, and this was lower than placebo. VAS scores for fear were significantly lower after the 2 mg dose than 0.5 mg, which were significantly lower than placebo (x2(2, n = 17) = 7.13, P < 0.05). After the C02 inhalation, VAS scores of alertness were significantly reduced after 2 mg lorazepam compared to 0.5 mg and placebo (x2(2,n=17)=7.82, p<0.05). There was a dosedependent trend towards a smaller increase in BP during C02

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inhalation after 2 mg lorazepam compared to 0.5 mg, and this was smaller than the increase after placebo. There was a significant dose-dependent increase in HR (F(2,17)=8.31, p
1P.4.C.0101 Effects of diazepam on the processing of aversive faces: a fMRI study C.M. Del-Ben 1 ., C.A Queiroz 1 , T.A Sanchez/. WC. AlvesNeto 1 , Y.G. Guapo 1 , D.B. Arauj 0 2, EG. Graeftl. 1Faculty of Medicine ofRibeiriio Preto University ofSao Paulo, Neuroscience and Behavior - Division of Psychiatry, Ribeiriio Preto, Brazil; 2 Faculty ofPhilosophy and Sciences ofRibeiriio Preto University ofSao Paulo, Physics and Mathematics, Ribeiriio Preto, Brazil Background and Aims: Although benzodiazepines are typical anxiolytic drugs, few studies have been carried out so far investigating their effect on aversive stimuli processing. This study aimed at measuring the effect of diazepam on the haemodynarnic response to emotional faces, using bold oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Methods: Twelve healthy male volunteers, aged between 19 and 31 years (mean = 24.83, SD=3.16), were evaluated in two occasions in randomized, balanced order, double-blind, placebo controlled crossover design. An oral dose of diazepam (10mg) or placebo was given 1 h before the neuroimaging acquisition. In a blocked design task, subjects were presented with pictures of neutral (A) and aversive (B) (angry or fearful) faces from the Pictures of Facial Affect Series (Ekman and Friesen 1976). The blocks lasted 30 s in an ABABABABA design for each emotion. Whole-brain images were acquired over 4.5 min for each emotion, in a randomized order. Subjects were asked just to identify the sex of the faces. After the scanner, participants were submitted to a behavioural task consisted of 40 faces of both sexes, showing six basic emotions (anger, disgust, fear, sadness, surprise and happiness). Volunteers were asked to choose the response that best described the emotion in the picture. Subjective anxiety was evaluated during the procedures, using a visual analogue scale. Images were acquired in a 1.5 T scanner (Siemens Magneton Vision). Imaging data were analysed using statistical maps obtained in Brain Voyager 4.96 (Brain Innovation, Maastricht, The Netherlands), using a general linear model with fixed effects model. Amygdala, insula, orbitofrontal cortex and anterior cingulate gyrus were chosen as a priori hypothesis areas. The statistical threshold was set to P < 0.05 corrected for multiple comparisons, for clusters with at least 50 mm3. Behavioural and