P.1.064 Pharmacological treatment of acute mania across Europe: Baseline findings from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) Study

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P1, Affection dieorders and anticlepreesaute

IP.1.0621 Reboxetine added to SSRI accelerates the improvement in depressed patients who failed to respond to SSRI alone I. Jaracz, M. Ch~opocka-Woxniak, I.K. Rybakowski. Unioersity

of Medical &~ence~, Department of A & # Psychiat~ Peened, Poland Inta'oduefion-" Combination strategies i,e, concomitant use of two different antidepressants has been proposed for management of treatment resistant depression. Usually, to the antidepressant that did not cause an adequate response, the second one with a different mechanism of action is administered to enhance effects. C~als-" The aim of these open study was to compare the efficacy of continuation treatment with selective serotonine reuptake inhibitor (SSRI) alone and combination therapy i.e. SSRI+reboxetine (RBX) in a group of patients with major depression who did not respond to d weeks treatment with SSXI. M~etll~lS: Out of 59 patients treated with SSXI 28 (47%) did not respond after 4 weeks of therapy. Non response was defined as less than 25% reduction on Hamilton Depression Rating Scale (Z--IDRS) and minimal or no improvement on Clinical @lobs1 Impression-Improvement Scale (CGI-I). Patients were assigned to recieve either the same SSXI (n=15) or combination treatment with SSXI and RBX (4-8 mg b.i.d.) for two weeks. R~esultn: At least 50% reduction of HDRS score, when compared to the onset of treatment was observed in d patients (26%) from SSRI group and 8 (61%)patients treated with SSRI+RPX. Mean HDRS score in SSXI+RBX group (9.5; SD-4-5,6) was significantly lower (p=0.01) when compared to SSRI group (16,1 SD-4-6.7). Combination of SSRI and RBX did not cause any significant side effects. Concision-- Addition of R]~X to SSXI seems to accelerate improvement in patients who did not respond to 4-weeks treatment with SSRI alone.

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Discriminative stimulus properties of the antidepressant, reboxetine, in rats: Mediation by ~l-adrenoceptors and substitution with the neurokinin (NK)I antagonist, GR20S,171

A. Dekeyne, L, Iob, M.J. Millan. 7nstitut de Recherches Seroier,

Paye~opharmacology Department, Croia~y ~ur Seine, Paris, France Inll~duelion: Discriminative stimulus (DS) properties of antidepressants are poorly documented, However, we recently demonstrafed that rats can recognize a D S elicited by the selective noradrenaline (NA) reuptake inhibitor, reboxetine (I, 2), Here, w e examined substitution patterns with drugs differentiallyinhibiting NA, dopamine (DA) or serotonin (5-HT) reuptake. We also explored the role of c~- and [3-adrenoceptor (ARs) subtypes in the DS properties of reboxetine, by use of sdeotive antagonists a these sites. Finally, since NK1 receptors have been implicated in depressive states and the modulation of monoaminergic transmission (3), we evaluated potential substitution with GR205,171, a highly-selective NK1 antagonist, l~etllod, Male Wistar rats (n=22) were trained (food-rewarded, fixed ratio 10 schedule) to recognize reboxetine (2,5 ms/ks, i,p,) from saline in operant conditioning chambers, After the discrimination criterionhas been reached, generalization/blockade testing was performed twice a week, Several doses (rng/kg) were

tested for each compound: the highest dose corresponded to that for which either '"full" generalization/blockade (defined as 80-100% "reboxetine" and "saline" lever selection, respectively) or a significant (P<0.05 in paired t-teat versus control session) decrease in response rates was obtained. Results: Reboxetine substituted for itsdf with an Effective DoseS0 of 0.8 mg/kg, s.c.. Substitution was also obtained with the NA renptake inhibitors, nisoxetine (4.9, i.p.), nomifensine (0.5, s.c.) and PW1555U88 (1.0, s.c.), with the mixed 5-HT/NA reuptake inhibitors, $33005 (0.3, i.p.), venlafaxine (d.8, i.p.) and duloxetine (26.8, i.p.), and with the tficyclio agents, imipramine (2.5, i.p.) and clomipramine (2.9, i.p.). In contrast, 5-HT reuptake inhibitors (citalopram, sertraline, paroxetine) and mixed 5-Z-IT reuptake inhibitors/5-Z-ZT2A antagonists (nefazodone and trazodone) did not (>2.5, i.p.) substitute for reboxetine. The "ats,pical" agents, mirtazapine (>10.0, s.c) and mianserin. (>2.5, s.c.), and the DA reuptake inhibitor, QPR12,935 (>10.0, i.p.) similarly failed to substitute for reboxetine. In antagonist studies, the reboxetine cue was dose-dependently blocked by the 0.63 and >2.5, i.p., respectively), nor by the [31-AR and [32-AR antagonists, betaxolol and ICIl18,551 (>2.5 and >10.0, i.p., respectively). Finally, C5R205,171 potently substituted for reboxetine (1.1, i.p.), while its less active isomer, GR226,206, was inactive (>10.0, i.p.). Conclusions: The DS properties of reboxetine are mimicked by antidepressants active at NA as compared to 5-HT (and DA) transporters, and they require functionally-intact c~l-ARs for their expression. An intriguing observation was substitution of the selective NK1 antagonist, QR205,171, possibly reflecting its induction of NA release in corticolimbic structures and, in any event, undemcoring interest in NT,21 receptors as a taeget for the treatment of depressive states.

Reference$ [l] Ddc~yne A, and Millan M,J, (2003) Behavioural Pharmacology 14:391-407, [2] DelceyneA, et al, (1999)Psydaopharmaoology 154:213-218, [3] Lejeune E et el, (2002) Brain Research 935:134-139,

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Pharmacological treatment of acute mania across Europe: Baseline findings from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) Study

F., Vieta 1, J,M, Hero 2, J, Van Os 3, M, Lorenzo 4, I, Goetz 4. ,

1Unioerx#y of Barcelona Hoxpital Clinic, Department of Psychiatry, Barcelona, Spain; 2Sent Joan De Deu-SSM, ~Researeh and Deoelopment Unit, Barcelona, 5~oain; SMaastricht Unioersity, ©eparzment of Psychiatry and Ne~opsychology, Maastric;#t, The NetMrland~; 4Eli Lilly & Compare, Statistics & Health Outcomes, Windle&~am, United Kingdom Objectives" To describe between-country differences in the pharmacological trea~'nent of acute mania in the context of bipolar disorder, Methods: EMBLEM is a 2-year, prospective, observational study on the outcomes of pharmacological treatment for mania conducted in 13 ZEuropean countries, Adult patients with a diagnosis of bipolar disorder and acute mania are enrolled within the standard course of care as in- or ou~atients if they have initiated/changed oral medication (excluding benzodiazepines) for

PI. Affeetioe disorders and ant~cle.pre~saut~ treatment of acute mania. All treatment decisions are at the discretion of the treating psychiatrist. Patients are enrolled in 2 principal cohorts: (1) initiated/changed to olanzapine, and (2) initiated/changed to non-olanzapine trea~nent. 600 psychiatrists are recruiting 4000 patients bebveen 12/2002 and 06/2004 using the same study methods assessing demographics, psychiatric history, clinical status (CGI-t)P, YMRS, tJ,_A_M-D, Life Chart Method), functional status (relationships, dependants, housing conditions, work, social contacts, Slice of Life items) and pharmacological treatment patterns including tolerability, compliance, and conoomitant medication. Results, Data collection is ongoing, with the last patient to be enrolled in June 2004. At the time of writing, 3,000 patients have been enrolled. We performed a preliminary analheis on 1845 patients who were consecutively entered into the database. The range of patient distribution by country in this preliminary data varies between Germany (29%) and Portugal (<1%). 64% of the sample population were ou~atients. The overall mean age of patients was 44.5 years (sd 13.2). 26% of patients had attempted suicide in the past and 41% of the patient~ were dissatisfied (32%) or very dissatisfied (9%) with their life in the previous 12 months. A total of 41% of the patients presented with significant impairment of their working ability with 24% unable to work and 17% being severely impaired due to their illness. The mean Clinical Global Impression - Overall Bipolar Illness score (CGIBP) on a scale from 1-7 was 4.6 (sd 1.1). A third of the patients (32%) were treated with Monotherapy whereas the m~ority (68%) followed a treatment regimen of multiple medications, the most common combination being one atypical antipsyohotic combined with one mood stabiliser (33%). Conclusions-" We will present baseline data for the entire study population as well as country specific analysis. As the biggest naturalistic study so far conducted in bipolar disorder, EMBLEM will provide invaluable information on background and health outcomes of patients with mania who are receiving pharmacological treatment during routine clinical practice as well as important differences in patterns of care in Europe.

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Effect of combined treatment with imipramine and metyrapone in patients wit~ drugresistant unipolar depression - clinical and pharmacokinetic studies

Z. Rog6z 1, G. Skuza 1, L W6jcikowski J , W.A. Daniel J , D. Dudek 2, A. Wrdbel 2, A. Zi~ba2 . 1Institute of Pl~armaeology,

Polis~ Academy of Sciences, Erakdw, Poland; 2Deyartment of Psychiatry, Collegium Medicum, 7aEiellonian Unioersi~, Krakdw, Poland It has been estimated that ca. 30% of patients diagnosed as suffering from unipolar depression do not respond to conventional therapy. The problem of antidepressant-resistant depression has been the subject of extensive study, yet with no apparent therapeutic success. In general, drug resistant depression has been treated with combinations of various antidepressant drugs (ADs). In the present study we approached this problem by treating the carefully selected group of drug-resistant patients with imipramine (IMI), an antidepressant drug widely used in the clinic together with metyrapone. It wa~ found earlier that metyrapone, a glucocorticoid synthesis inhibitor which blocks the 11-[3hydroxylation step of adrenocortical steroid synthesis showed

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antidepressant-like properties in the %reed swimming test. Furthermore, the antidepressant efficacy of metyrapone was demonstrated in depressed patients. However, clinical studies of antiglucocorticoid agents are usually performed on non-responders to conventional drugs. Possibly, such patient~ constitute a subgroup within the clinical spectrum of depression who may be particularly sensitive to antiglucocortioal therapy. It is well known that patients with endogenous depression often display enhanced activity of the hypothalamic--pituitary-adrenal (HPA) axis. Since the hyperactivity of the IiPA axis may be a significant factor in the pathogenesis of depression, and since the lack of normalization of the axis activity in the course of therapy with ADs often correlates with the absence of their therapeutic effect, it seemed purposeful to examine the effect of joint administration of ADs and metyrapone on drug-resistant depression. Patients were recruited on the basis of the history of their illness and therapy. An average duration of the illness was 13.24-1.0 year~, with the number of depressive episodes amounting to 6.0-t-0.9. At the beginning of the present experiment, 2 weeks after the washout period, the patients (1 man and 5 women, aged 4 5 60 years) were treated with IIVE (twice daily, 100 ms/day) for 3 and 6 week~; afterwards meth,rapone (500 mg/day, twice daily) wa~ introduced and administered for 6 weekm Then metyrapone wa~ withdrawn, and the patients were treated with IMI alone for another 2 weeks. At each (of the six) time points, the patients were rated with two depression rating scales in order to estimate their clinical improvement. The obtained results were a~ follows (according to the Hamilton Depression Rating Scale [ttAM]): a drop from 31.74-1.0 to 17.34-0.5, or (using Beck Depression Inventary [BECK]): a drop from 50.04-1.9 to 27.64-1.9 points. Additionally at the same time the plasma concentrations of IMI and iN metabolite desipramine were detected by the I-IPLC method. The plasma level of IMI was 70.84-3.7 ng/ml, of desipramine 128.,14-27.1 ng/ml, and a mean ADs concentration (IMI + desipramine) 199.24-28.4 ng/ml, and did not change during joint treatment with IMI and metyropone. The above results support the hypothesis that joint administration of IMI and metyrapone (a corticostemne synthesis inhibitor) may evoke a more effective antidepressant activity than does treatment with IMI alone. Moreover, pharmacokinetic interaction does not seem to have a substantial impact on the metyrapone-induced potentiation of the antidepressant effect of IMI in patients. These findings may be of particular importance in the pharmacotherapy of drug-resistant depression.

~ T h e interaction between selective sigma ligands and uncompetitive NMDA receptor antagonists in t~e forced swimming test in rats G, Skuza, Z, Rog6~, Inxt#ute of P~ar~acology, Departme~ of

P~armacology, Polis~ Academy of Sciences, Krakow, Poland The sigma receptors were first described as one of the opiate receptor subtypes. Now, it is well established that they are unique binding sites distinct from opiate and PCP receptors, which are implicated in higher brain Nnctions. Two different sigma receptor subtypes, sigmal and sigma2, have been distinguished on the basis of their different drug selectivity patterns and molecular weights. Since several antidepressants have high affinity for sigma receptors, the sigma binding sites (especially sigmal one) may be relevant to the mechanism of antidepressant action. Our previous studies indicated that the combined treatment with antidepressant drugs and uncornpetitive NMDA receptor