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2002 Martin Dunitz Ltd

International Journal of Psychiatry in Clinical Practice 2002 Volume 6 Pages 225 ± 258

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Speaker Abstracts Wednesday 27 November Plenary lecture S01. Genetic predictors of response to antidepressant Alan F. Schatzberg, Greer Murphy USA Pharmacogenetics offers an important tool for understanding which patients are most likely to respond to a specific medication or to experience intense side effects. We applied pharmacogenetics in an eight-week study comparing paroxetine with mirtazapine under double-blind conditions in approximately 250 elderly patients with major depression. In this study patients treated with mirtazapine demonstrated significantly greater responses (as defined by change on Hamilton Depression Rating Scale scores) at weeks 1, 2, 4, and 6 but not at 8 weeks. In addition, a significantly higher dropout rate due to adverse events was observed with paroxetine. We explored the possible pharmacogenetic contributions of APOE-4, P450 2D6, and the 102T/C polymorphism for the 5HT2a receptor. APOE-4 has been demonstrated to be a risk factor for developing Alzheimer’s disease or for greater cognitive morbidity secondary to head trauma or surgery. We hypothesized that patients with one APOE-4 allele would respond more poorly or slowly to antidepressant treatment. Overall, APOE-4 patients did not respond more poorly or slowly to treatment. However, a significant interaction of specific treatment with allele status was observed such that APOE-4 treated with mirtazapine responded more rapidly than did non APOE-4 patients. In contrast, APOE-4 paroxetine treated patients responded more slowly than did non APOE-4 subjects. A possible explanation may be mirtazapine’s potent effects on prefrontal norepinephrine-containing neurons, a system that is particularly affected in APOE-knockout mice. Antidepressant side-effects can be problematic for some patients. Over the years, considerable attention has been paid to the possible role of P450 2D6 enzymes in the liver as explaining undue side effects on specific medications, which are either substrates or inhibitors of D26 or both. Paroxetine is both a substrate and inhibitor of 2D6. Mirtazapine is primarily a substrate. We explored allelic variation for 2D6 in the sample using an Affymetrix ``gene chip.’’ In this analysis, ultra-rapid and extensive metabolizers were compared with slow and intermediate metabolizers. Although slow and intermediate metabolizers demonstrated higher drug blood levels, they did not demonstrate significantly greater dropout rates due to side-effects on either drug than did ultra-rapid and extensive metabolizers. The 5HT2A receptor is found both centrally and peripherally. Allelic variation for the 102T/C allele has

been reported to be associated with treatment response to clozapine in schizophrenia and to suicidal ideation in depression. In this study, patients with a C/C allele status demonstrated extremely high dropout rates due to adverse events on paroxetine (47%) in contrast to T/T or T/C subjects (18%.) Adverse events seen were typical for SSRIs ± gastrointestinal disturbance, agitation, insomnia, etc. In contrast, 102T/C allele status did not predict mirtazapine adverse events dropouts. These data can be explained by paroxetine being a potent blocker of serotonin reuptake with little or no effect on the 5HT2a receptor. In contrast, mirtazapine is a potent 5HT2a receptor antagonist. Thus, variations in pharmacodynamics rather than pharmacokinetics appear to explain intolerance to paroxetine. S02. Symposium: Difficult to treat depressions: exploring new breakthroughs Sponsored by Eli Lilly and Company Chairman: Alan Schatzberg S0201. Understanding the complexities of difficult-totreat depressions: defining the burden of illness Alan F. Schatzberg, Kenneth T. Norris, Jr. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA The burden of mental illness in general, and depression in particular, has long been underestimated. One in eight persons in Europe will, at some point, suffer from major depression. Depression is a highly treatable disorder; however, most adequate antidepressant trials only show a 70% response rate. Difficult-to-treat depressions may account for the remaining 30% of partial responders or nonresponders. Difficult-to-treat depressions, such as treatment-resistant depression, bipolar depression, and major depression with psychotic features, are characterized by relatively high levels of severity, chronicity, comorbidity, and disability. The burden of illness in these disorders is great due to persistent impairment, high risk of suicide, comorbid substance abuse, and higher medication costs associated with polypharmacy. Further, the economic and social impact is dramatic, as these patients may utilise 40 ± 50% of treatment resources for depression. S0202. Treatment-resistant depression: breaking new ground Sidney Kennedy University of Toronto, Department of Psychiatry, University Health Network, Toronto, Ontario, Canada Success in the treatment of depression has been redefined in recent years. Previously, treatment response (generally a

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50% reduction in symptoms) was considered adequate. Success is now defined by remission. Treatment to an endpoint of symptom remission leads to a lower risk of relapse and improved occupational and social functioning. However, patients suffering from treatment-resistant depression still do not experience a significant remission of symptoms. New strategies are developing to facilitate efficacy, and include optimisation, switching, and combination or augmentation of current pharmacologic treatments. In addition, recent data suggest that therapies demonstrating an ability to affect a broader range of neurotransmitters display promise in the treatment of treatment-resistant depression. S0203. Bipolar depression: novel treatment solutions Mauricio Tohen Lilly Research Laboratories, Indianapolis, Indiana, USA, McLean Hospital, Harvard Medical School, Boston, Massachusetts, USA Presently, there is not an available drug with an approved indication for the treatment of bipolar depression. Therefore, the current therapeutic approach is polypharmacotherapy, which usually consists of combinations of antidepressants with mood stabilisers, antipsychotics, and anticonvulsants. However, antidepressant treatments do not help every patient, and antidepressant therapy, particularly with TCAs, has the associated risks of inducing mania and rapid cycling. Unfortunately, there have been a lack of standard, clinically accepted treatment algorithms for patients who fail to respond to adequate antidepressant treatment. Olanzapine and olanzapine/fluoxetine combination (OFC) have demonstrated efficacy in patients with bipolar depression, and were significantly more effective than placebo starting at week one, with no evidence of induction of mania. The combination of olanzapine/ fluoxetine was also significantly more effective than olanzapine monotherapy, with no difference in side effect profile. Thursday 28 November S03. New developments in depression Chairmen: A.C. Altamura, R. Emsley S0301. Rapid response antidepressants: Is there any? A.C. Altamura1 , S.R. Bareggi2 , E. Mundo1 1 Department of Psychiatry and Department of Clinical Sciences ``Luigi Sacco’’, University of Milan; 2Department of Pharmacology, University of Milan The onset of action of antidepressants requires 3 to 4 weeks of treatment. This latency is problematic as it prolongs the impairment associated with depression, increases the likelihood that the patients will be non

compliant, and increases the risks of suicide behavior in depressed patients. On the other hand, some lines of clinical evidence show that a more rapid antidepressant effect can be obtained. The short latency of the effect of sleep deprivation and electro-convulsive therapy (ECT) and the rapid influence on the antidepressant response of tryptophan depletion or restoration are examples of this evidence. Both pharmacodynamic and pharmacokinetic factors have been involved in the explanation of the latency of the clinical response to antidepressants. The role of presynaptic somatodendritic receptors in influencing the onset of the antidepressant response has been recently pointed out. The effect of the combined administration of selective blockers of the somatodendritic 5HT1A receptors (i.e. pindolol) is to shorten the response to selective serotonin reuptake inhibitors (SSRIs) in Major Depressive Disorder (MDD). The rationale of administering pindolol together with SSRIs, as an adjuvant treatment for MD, is rooted in both the mechanism of action of SSRIs and in the complex regulation mechanisms of 5HT neurotransmission.1,2 The administration of SSRIs induces, within hours, blockade of the serotonin transporter and, as a consequence, increased availability of serotonin (5HT) in the synaptic cleft. The increased availability of 5HT stimulates the pre-synaptic autoreceptors (5HT1A), which, as a compensatory mechanism to maintain homeostasis, reduce the firing of the 5HT neurons, decreasing 5HT transmission. This is one of the explanatory hypotheses of the 3-4 week latency of the clinical response to antidepressant compounds, the time needed for the appropriate down-regulation of the 5HT1A autoreceptors. However, it is becoming increasingly clear that, beyond the pre-synaptic mechanisms regulating the onset of action of antidepressants, differences exists between the different antidepressant compounds both within and between different pharmacological classes. Within the SSRIs citalopram has shown a shorter latency of antidepressant response and the new dual-action antidepressants, i.e. venlafaxine and mirtazapine, appear to have a faster onset of action when administered to depressed patients. Pharmacokinetic factors may also influence the onset of action of antidepressant compounds. High plasma levels of tryciclic antidepressants (TCAs) in the first days of treatment appear to produce rapid, or even acute, therapeutic effects on depressive symptoms. This effect may be explained with rapid adaptive changes of adrenergic receptors with high doses of different TCAs.3 Thus, the pulse loading strategy in administering antidepressants has been suggested as a good strategy to both improve and shorten the latency of antidepressant response, and plasma level determination may be a useful tool for early detection of potential responders and potentially refractory patients. Finally, genetic and biological inter-individual variability should be always taken into account in determining the correct strategy to deal with the delay of the onset of the antidepressant action.

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References 1. Artigas F, Perez V, Alvarez E (1994) Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 51: 248 ± 51. 2. Blier C, DeMontigny P (1998) Possible serotonergic mechanisms underlying the antidepressant and the anti-obsessive-compulsive disorder responses. Biol Psychiatry 44: 313 ± 23. 3. Altamura AC, Bareggi SR (1991) Do pharmacokinetic factors affect the rapidity of antidepressant actions? Biol Psychiatry, Proceedings of the 5th World Congress of Biological Psychiatry, 1: 328 ± 31.

S0302. Update on agomelatine Robin Emsley University of Stellenbosch, Cape Town Agomelatine (S-20098) is a new antidepressant with a unique pharmacological profile: it is an agonist of melatoninergic receptors as well as a selective antagonist 5HT2C receptors. Agomelatine has been shown to be active in well validated models of depression such as the learned helplessness test, the despair test and the chronic mild stress. It was shown that the involvement of the two pharmacological properties is necessary to provide an antidepressant effect in these models. In terms of mechanism of action, agomelatine appears completely different from SSRIs: no modification of 5HT extracellular levels in raphe and prefrontal cortex, no down-regulation of 5HT1A pre- and post-synaptic receptors. An increase in dopamine and noradrenaline release was observed specifically in frontal cortex after acute or chronic administration of agomelatine, the effect being related to the 5HT2C antagonist property. The effects of agomelatine on neurogenesis are currently being explored. A dose ranging study involving 711 patients clearly showed that the effective dose of agomelatine in the treatment of major depression was 25 mg/day. This dose was identified as the target dose. A wide development plan is currently ongoing. The available clinical results indicate that agomelatine appears to have a promising profile. Agomelatine was shown to be effective in the subpopulation of severely depressed patients and provided a high level of remission. Agomelatine appeared also effective in treating anxiety symptoms associated with depression. There was some evidence of rapid onset of action, and preliminary results showed maintenance of efficacy up to 6 months. The excellent acceptability of agomelatine has been confirmed across studies. As expected, no gastrointestinal and no anticholinergic effects were observed. No weight gain was shown even up to 6 months, and sexual acceptability explored by the ASEX appeared satisfactory. Furthermore, the improvement of sleep as evaluated by the Leeds questionnaire was not associated with sedation. Finally, preliminary results of a discontinuation study using paroxetine as validator should be presented.

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S0303. Update on escitalopram Hans Eriksson H. Lundbeck A/S, Copenhagen, Denmark Escitalopram is the therapeutically active S-enantiomer of the SSRI citalopram. It is the most selective and a highly potent SSRI. In a number of animal models for depression and anxiety, it has shown earlier onset of effect compared with citalopram. Escitalopram increases the levels of serotonin in the frontal cortex to a larger extent compared to the same amount of escitalopram when given as part of the racemate citalopram. The analysis of the three randomized, double-blind, placebo-controlled clinical registration studies in Major Depressive Disorder (MDD) that included both escitalopram and citalopram, demonstrated escitalopram to be significantly superior to placebo, from week 1 onward (mean change in Montgomery-AÊsberg Depression Rating Scale [MADRS] score from baseline, FAS-OC), in contrast to citalopram which was significantly superior to placebo from week 6 onward. At weeks 1 and 8, escitalopram was also significantly superior to citalopram. Analysis of the antidepressant efficacy of escitalopram and citalopram among those patients who were defined as severely depressed at baseline (MADRS score 530), demonstrated that the effect of escitalopram was rapid and sustained. In the LOCF analysis, escitalopram significantly reduced depressive symptoms compared with placebo from week 1 onwards. At weeks 1, 6 and 8, escitalopram was also significantly superior to citalopram in this severely depressed subpopulation. The efficacy of escitalopram relative to the nonselective antidepressant venlafaxine in the treatment of MDD was assessed in a randomised, double-blind study of venlafaxine XR and escitalopram. The primary efficacy variable (mean change in MADRS score from baseline) showed that escitalopram was at least as effective as venlafaxine. The response rate ((50% reduction in MADRS total score) for escitalopram versus venlafaxine XR was numerically superior at all time points after week 1. An exploratory time-to-response analysis showed a significant superiority of escitalopram relative to venlafaxine (p50.05). The robust antidepressant effect of escitalopram, combined with a favourable tolerability profile, makes escitalopram a first-line antidepressant for general use. S0304. Update on duloxetine K. Demyttenaere University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium Duloxetine hydrochloride is a potent and balanced dual serotonin (5HT) and noradrenaline (NA) reuptake inhibitor. By blocking the reuptake transporters, it increases the levels of both of these neurotransmitters to 4300% of

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baseline, while having negligible affinity for specific neurotransmitter receptors, such as acetylcholine, histamine, etc. Duloxetine has been tested in six placebo- and/or active comparator-controlled clinical trials of major depressive disorder, and has demonstrated efficacy on several measures in five of these six studies. The recommended starting and effective dose is 60 mg once daily, but this may be titrated up to 120 mg/d in divided doses. Duloxetine has produced high remission rates in these studies, consistent with other data (tricyclics, milnacipram, venlafaxine, mirtazapine, combined fluoxetine and desipramine, reboxetine) showing that (additional) noradrenergic activity may result in greater efficacy. Duloxetine has also produced improvement in several secondary measures, including anxiety and painful physical symptoms, which are often part of the clinical picture in depressed patients. S04. Symposium: Everyday clinical use and possible new indications for a dual action antidepressant Sponsored by Asahi-Kasei Chairmen: Mike Briley, David Baldwin S0401. Essential considerations when choosing a modern antidepressant D. Baldwin Department of Psychiatry, University of Southampton, UK The man-years of disability produced by depression in industrialised nations is second only to that caused by ischaemic heart disease. One in ten patients seen by a primary care physician is suffering from depression (even though he/she may not always recognise it). Depression is clearly a major health problem, which can, however, be treated successfully by modern antidepressants in the overwhelming majority of cases. The problem for the primary care physician is not whether to treat but how to treat depression. The increasing number of antidepressants from different families with different mechanisms has become an embarrassment of riches. When choosing an antidepressant, efficacy, adverse effects, safety in overdose, potential drug interactions and withdrawal effects are among the principal criteria. Although all antidepressants may appear to be equipotent, in more severely depressed patients it is now demonstrated that dual action antidepressants acting on noradrenaline and serotonin have superior efficacy to compounds acting on a single neurotransmitter. In addition, certain types of symptoms may respond better to one antidepressant rather than to another. The importance of adverse effects goes beyond patient safety and comfort and has a major influence on efficacy. If, due to adverse effects, an antidepressant is prescribed at sub-optimal doses or the patient is not compliant, even the most effective antidepressant will perform badly. Certain antidepressants have a far greater potential for interactions

with other drugs with potentially toxic effects and should be avoided in patients taking several medications. Applying these criteria globally will not designate a single ``best antidepressant’’ but consideration of the importance of each criteria for an individual patient will help the clinician to find the antidepressant best adapted to each patient. S0402. Five years experience of using milnacipran in hospitalized depressed patients D. Papeta Naval Hospital, Brest, France interviewed by M. Briley, NeuroBiz Consulting & Communication, Castres, France The serotonin and noradrenaline reuptake inhibitor (SNRI), milnacipran, has been available in France for over five years. Although many of the published clinical trials were, at least partially, carried out in France, there has been little feedback in the medical literature concerning the everyday use of milnacipran in this country. In contrast to the tradition in some countries, the publication of case reports in French medical journals is not common. In order to get a feedback from day to day use of a compound it is therefore necessary to carry out use surveys which are expensive and time-consuming. In the absence of such surveys personal opinions forged over several years by extensive prescribers of a compound can give valuable insight, albeit with the risks of bias and of being nonrepresentative. Dr Didier Papeta has studied over 250 patients treated with milnacipran in the psychiatric department of the Naval Hospital in Brest in Brittany, France. His extensive ``hands-on’’ experience of the drug has given him some unique understanding of the type of patients that respond best, the symptoms which best indicate the first signs of remission, the preferred duration of treatment in order to avoid relapse and so on. Interestingly, many of his personal conclusions have been independently reinforced by comparative or open studies in Europe and in Japan. S0403. Japanese approaches to prescribing milnacipran A round table discussion chaired by D. Baldwin, Dept of Psychiatry, University of Southampton, UK with the participation of K. Yoshida, Dept. of Psychiatry, Akita University School of Medicine, Japan, A.Toyofuku, Dept. of Dentistry and Oral Surgery, Fukuoka University, Japan and T. Maruyama, Dept. of Neurology, Iida Municipal Hospital, Japan The serotonin and noradrenaline reuptake inhibitor (SNRI), milnacipran, is one of the three ``new’’ antidepressants available in Japan where it was launched over two years ago. The other two are the selective serotonin reuptake inhibitors (SSRI), fluvoxamine and

IFMAD Abstracts

paroxetine. Starved of innovative antidepressants for so long, Japanese clinicians have rapidly adopted the new drugs. The availability of milnacipran, with an excellent tolerability and an action on both noradrenergic and serotonergic neurotransmission, has led to extensive testing of this drug in a range of clinical situations and psychiatric and non-psychiatric indications other than major depression. Three Japanese clinicians ± a psychiatrist, a neurologist and a specialist in oral pain ± all with extensive personal experience of the use of milnacipran, will discuss their trials and everyday experience of this antidepressant. K. Yoshida will describe his experience of milnacipran as first-line therapy in depression in Japan. T. Maruyama has found milnacipran to be particularly useful in depression in patients suffering from Parkinson’s disease. A. Toyofuku will describe his experience of the use of milnacipran in chronic pain, especially glossalgia (pain of the tongue). Short presentations by the above speakers will be followed by a round table discussion which will attempt to draw wider conclusions on the use of milnacipran and other antidepressants that might be tested in an international context. A recent example of this approach is the demonstration of the activity of milnacipran in the treatment of neurogenic pain in Japan which has been followed by a phase II programme in fibromyalgia syndrome in the USA initiated by Cypress BioScience Inc. S0404. Evidence-based prescribing or prescribing-based evidence? S. Montgomery Imperial College School of Medicine, London, UK Modern antidepressants are required to undergo extensive clinical investigation before their commercialization is authorized. This body of evidence is the basis for the ``evidence-based recommendations’’ for their use. In spite of this, the clinical characteristics of a drug are still incompletely understood when it is launched. Formal clinical trials have the advantages of rigorous methodology such as double-blind randomized comparison with placebo or comparator drug. Because of this rigour, however, the populations studied and the conditions of use are often different from those encountered in everyday clinical practice. In addition the opportunity is limited in clinical trials for casual observation of the effects of the drug, or its use in patients with co-morbid disorders or outside of the strict indication for which the compound seeks a licence. Some of the chance observations that have changed the face of psychiatry would be unlikely under these conditions. For these reasons the observations, case studies, open trials and small comparative trials conducted on an antidepressant after its launch are important. The less rigorous methodology is compensated by their relevance to

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everyday prescribing and their openness to chance discoveries. They can provide information on responder characteristics and acceptance of side-effects. In addition such studies can investigate conditions and indications not originally foreseen. This body of data can be referred to as ``prescribing-based evidence’’. The obvious complementarity of these two bodies of evidence will be illustrated by reference to the serotonin and noradrenaline reuptake inhibitor (SNRI), milnacipran, which has been the subject of intense post-marketing research, especially in Japan. The newly discovered efficacy of milnacipran in chronic pain both associated with depression and in conditions such as fibromyalgia is an example of the extended understanding that can be obtained by such studies. S05. Breakthroughs in anxiety and depression Chairmen: J. Zohar, J. Lofthus S0501. Are there inhibitor features which slow SSRI response? Connie SaÂnchez Neuropharmacological Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen, Denmark A combination of pre-clinical and clinical evidence suggest that enhancing serotonin (5-HT) neurotransmission underlie the therapeutic antidepressant action of selective serotonin reuptake inhibitors (SSRIs). The SSRIs bind to the 5-HT transporter protein and prevent re-uptake of serotonin into serotonergic neurones. Thus, the therapeutic action of the SSRIs centres upon raised extracellular 5-HT levels in various brain regions, for example, the frontal cortex. A prominent hypothesis related to the time lag between initiation of drug treatment and achievement of antidepressant activity is based on the pre-clinical observation that prolonged treatment with an SSRI produces a gradual increase of the 5-HT level in the brain. A number of mechanisms are involved in maintaining a stable 5-HT level; e.g. the so-called inhibitory feedback loops. These mechanisms will attenuate the increased 5-HT level produced by an SSRI. Therefore, it would appear that due to the inhibitory feedback, acute treatment with SSRIs is unable to raise the 5-HT levels in the brain to a level that is sufficient to induce a rapid antidepressant response. Prolonged SSRI treatment will attenuate the consequences of feedback inhibition and thereby gradually increase the serotonin activity. Several 5HT receptors are involved in regulation of serotonergic neurotransmission. For example 5-HT1A auto-receptors on the cell body of 5-HT neurones regulating neuronal firing and 5-HT1B auto-receptors in the nerve terminals. Other neurotransmitters also modulate 5-HT neurotransmission via synaptic connections associated with multiple receptors, including dopamine, noradrenaline, glutamate and GABA. These complex, interconnected regulatory feedback loops impact on the efficacy and onset to effect of SSRIs.

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The SSRI, citalopram, is a racemic mixture of an Senantiomer, escitalopram, and an R-enantiomer, R-citalopram. Escitalopram has recently been developed for treatment of depression and anxiety disorders. In vitro and in vivo pharmacological studies have demonstrated that escitalopram is a more potent SSRI than citalopram, and that R-citalopram is practically devoid of 5-HT uptake inhibitory potency. Interestingly the onset of antidepressant-like action seen with escitalopram in animal models of depression is more rapid than that seen with citalopram. Recently accomplished microdialysis studies of citalopram and its enantiomers on the 5-HT level in the frontal cortex of freely moving rats revealed that Rcitalopram appears to dampen the effect of escitalopram. Escitalopram (2.0 mg/kg, s.c.) increased the 5-HT concentration more than citalopram (4.0 mg/kg, s.c.), whereas Rcitalopram (2.0 mg/kg, s.c.) was devoid of effect. These findings further support the notion of an earlier onset to effect of escitalopram compared to citalopram. This finding represents tangible biological evidence for the notion that ecitalopram has an earlier onset of effect than citalopram. S0502. Advances in the treatment of PMDD Elias Eriksson Department of Pharmacology, GoÈteborg University, POB 431, SE-405 30 GoÈteborg, Sweden Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome, afflicting approximately 5% of all women of fertile age. The cardinal symptoms are irritability and anger, surfacing regularly between ovulation and menstruation, and disappearing completely within a few days after the onset of the bleeding; in addition, sadness, affect lability and mood swings are common complaints. In several recent trials, a number of serotonin reuptake inhibitors (SRIs) ± i.e. citalopram, clomipramine, fluoxetine, paroxetine, sertraline, and venlafaxine ± have been shown to reduce the symptoms of PMDD much more effectively than does placebo; in contrast, non-serotonergic antidepressants ± i.e. maprotiline, desipramine, buproprione ± appear to be ineffective (or at least less effective than strong SRIs). The onset of action of SRIs is much shorter when used for PMDD than when used for depression; patients with PMDD thus can restrict the medication to the two weeks between ovulation and menstruation (=intermittent treatment). In an ongoing study, the results of which will be presented at the meeting, the feasibility of an SRI as ``as needed’’ medication, to be taken when symptoms appear, is being explored. The possible efficacy of compounds displaying selective affinity for subtypes of serotonin receptors also will be discussed. The observation that SRIs effectively reduce the symptoms of PMDD is of considerable clinical importance since previously no effective treatment for this common condition ± apart from those disrupting ovarian cyclicity ± has been available. It is also of theoretical importance since

it lends support to the hypothesis that a major role for brain serotonergic neurotransmission is to modulate sex steroid-driven behaviour. The short onset of action of SRIs when used for PMDD finally is of pharmacological importance, since it indicates that these compounds ± in spite of the feedback influence on serotonergic neurons exerted by autoreceptors ± do indeed induce a prompt increase in synaptic concentrations of sertonin, in contrast to what has previously been suggested. S0503. Ten myths on PTSD Joseph Zohar Sheba Medical Center, Tel-Aviv University, Israel PTSD is a pathological response to trauma. Only 10 ± 20% of individuals who are exposed to traumatic events will develop a pathological fixation, namely PTSD. Although its prevalence in the general population will range from 3 ± 6%, most patients are not being diagnosed, mainly as comorbidity governing the clinical presentation. The cornerstones of PTSD include exposure to a traumatic event, re-experiencing of the traumatic event, avoidance and increased arousal, which leads to substantial decline in functioning. There are many myths attached to PTSD, including that PTSD is combat-related, while it can in fact be related to any type of event. Another myth is that PTSD is a normal response to exposure to an abnormal event, while in fact PTSD is a pathological response. There are also myths regarding the role of debriefing, of benzodiazepines and of denial. Other myths describe PTSD as a ``compensation neurosis’’ and not a ``real’’ disorder, while it has been found that the majority of people with PTSD do not apply for compensation, and that there is strong evidence for the biological basis of PTSD. PTSD is still waiting for better understanding and the turning of the myth mask, in order for us to be able to identify and eventually help those individuals who are tormented with their memories and doubts regarding their trauma. S0504. New treatments of Attention Deficit Hyperactivity Disorder Jan K. Buitelaar Dept of Child and Adolescent Psychiatry, UMC St Radboud, Huispost 333, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Attention Deficit Hyperactivity Disorder (ADHD) is a very common and impairing neuropsychiatric disorder with onset at preschool age. Although significant progress has been made investigating the neurobiology of this disorder, its precise etiology still remains unclear. Converging evidence from several areas of research underscores the involvement of fronto-striatal circuitry in ADHD. The

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strong response of subjects with ADHD to medications that affect the dopaminergic and/or noradrenergic neurotransmission point towards the involvement of these catecholaminergic systems that have important innervations in the striatal and frontal areas. The aim of this presentation is to review advances in the treatment of ADHD that include new data on (1) long-acting stimulant medication, (2) selective and non-TCA NA-reuptake inhibitors, and .(3) the relative efficacy of medication and behavior therapy in the treatment of ADHD. The introduction to the market of once-daily dosing forms of stimulant medication is an important step forward. Whole-day coverage of medication enables children with ADHD to function optimally after schooltime during extracurricular activities and during homework hours. In addition, problems with in school dosing, such as privacy issues and storage of controlled medication are avoided. Long-acting stimulant medication, such as Concerta (OROS methylphenidate), Metadate CD (extendedrelease methylphenidate), Adderall XR (extended-release amphetamine salts) and MethyPatch (transdermal methylphenidate) has been shown to as effective and safe as b.i.d.or t.i.d. administered short-acting stimulants. Although psychostimulants are the most frequently prescribed medications in ADHD, there are notable drawbacks of psychostimulant treatment. About 30% of the patients with ADHD fail to respond to stimulants or are unable to tolerate them. Additionally, stimulants are often difficult to use because of their status as controlled substances. Atomoxetine (formerly known as tomoxetine) is an investigational non-stimulant medication for the treatment of ADHD. Atomoxetine enhances NA function through highly selective blockade of the pre-synaptic NA transporter. Atomoxetine in a dose of 1.2 mg/kg/day and 1.8 mg/kg/day appeared to be superior to placebo, as was apparent from the main outcome measure, the ADHD DSM-IV rating scale. Symptom reduction appeared to be maximal at the 1.2 mg/kg dose, with no additional benefit for the higher dosage of 1.8 mg/kg. Atomoxetine was well tolerated, with discontinuations due to adverse effects occurring in less than 5% of the patients. Atomoxetine was also associated with improvements in overall social and family functioning. In the Multimodal Treatment Study of ADHD (MTA) the relative efficacy of four treatment modalities was examined in about 580 children with ADHD: medication management, behavior therapy, the combination of medication management and behavior therapy, and care as usual by the community paediatrician, general practitioner or psychotherapist. Overall, medication management proved to be superior to behavior therapy and community treatment, with small additional benefits for behavior therapy on top of medication treatment. Since community treatment included medication in about 80% of the cases, strictly protocolled medication treatment as delivered in the research setting, appeared to be much more effective than medication treatment that was part of usual care. This suggests that

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there is considerable room for improvement in medication management of ADHD in routine clinical practice. Friday 29 November S07. Advances in GAD Chairmen: D. J. Nutt, P. H. Robert S0701. Targets for developing new treatments in anxiety David J Nutt University of Bristol, Psychopharmacology Unit, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK Although there has been major progress in the treatment of anxiety disorders in the past decade there is still a long way to go despite the proven efficacy of the SSRIs. In addition to refinements of drugs targeting the 5HT system such as receptor blockers there are other compounds in development targeted at receptor systems that have only recently become implicated in anxiety.1 One group are the GABA-A receptor subtype agonists as these can have very focal actions in the brain and in animal tests at least show excellent separation of anxiolytic and sedative actions.2 An extra potential is offered by partial agonists at these receptors. The less selective partial agonist is pagoclone has some effect in panic disorder.3 Another approach is the stable small molecule peptide antagonists, for example of CRF to reduce stress actions in brain. 4 Alternatively the substance P (NK1) receptor antagonist MK 869 reduces anxiety in depression5 and other substance P antagonists have been tested specifically in anxiety disorders. Finally glutamate is an important target as it is the key excitatory transmitter in the brain with a potential role in anxiety especially PTSD6 which means that antagonists might be anxiolytic. It is also possible to reduce glutamate function by inhibiting pre-synaptic cell activity with a presynaptic auto receptor agonist. References 1. 2. 3. 4. 5. 6.

Nutt and Ballenger, Eds. Anxiety. Blackwell Science. (in press). Nutt DJ & Malizia AL (2001) Br J Psychiatry 179: 390 ± 6. Sandford JJ et al (2001) J Psychopharm 15: 205 ± 8. Zobel AW et al (2001) J Psychiatric Research 34: 171 ± 81. Kramer et al Science 281: 1640 ± 5. Nutt DJ (2000) J Clin Psychiatry 61: 24 ± 32.

S0702. The burden of generalized anxiety disorder and depression G.D. Burrows, T.R. Norman, J.S. Olver, C. McGrath Generalized anxiety disorder (GAD) is a chronic condition, characterized by excessive worry, which is pervasive, uncontrollable and often associated with physical symptoms such as muscle tension and fatigue. GAD occurs early in life, is associated with a decreased quality of life,

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increased social withdrawal and increased utilization of health care resources and is often comorbid with other psychiatric disorders. GAD has been proposed to play an important role in the development of depressive disorders. Results from clinical and family studies suggest that GAD may be a prodrome for major depressive disorder (MDD) since (1) 40% of patients with GAD have a comorbid major depressive disorder, (2) relatives of patients with comorbid anxiety/depression are twice as likely to have a MDD as those with depression alone and (3) longitudinal evidence suggests that GAD typically occurs at an earlier age than MDD and that the anxiety disorder precedes MDD in twothirds of individuals with both disorders. This presentation examines the relationship between GAD and MDD and provides an overview of the neurochemical changes underlying both disorders and potential treatments of these conditions.

on the alert to identify study subjects that relapse, and to provide them with the best available treatment. To minimize the number of subjects needed to show a difference in the relapse hazard ratio, the ECNP consensus group recommends a relapse observation period of 56 months. Updated EMEA draft guidelines will be circulated for consultation in 2003.

S0704. Relapse prevention in GAD C. Allgulander Karolinska Institutet, The Neurotec Department, Stockholm, Sweden

In vitro and in vivo pharmacological studies have demonstrated that escitalopram is a more potent SSRI than citalopram, and that R-citalopram is practically devoid of 5-HT uptake inhibitory activity. Furthermore, escitalopram is the most selective 5-HT uptake inhibitor available. 1,2 Escitalopram, but not R-citalopram, is active in the mouse forced swimming test, a model that is predictive for antidepressant effect.3 In the residentintruder animal model, acute treatment with antidepressants selectively suppresses assertive behaviour without disrupting other motivational categories of behaviour.4 Escitalopram is more potent than citalopram in reducing the assertive behaviour. The rat chronic mild stress (CMS) model of depression results in behavioural hedonic deficits, which can be measured as decreased consumption of a 1% sucrose solution. Daily injections with the tricyclic antidepressant imipramine (8.8 mg/kg, i.p.) normalize the sucrose intake to the level of non-stressed rats after four weeks of treatment. Escitalopram (3.9 and 7.8 mg/kg, s.c.) and citalopram (8.0 mg/kg, s.c.) reverse the CMS-induced decrease in sucrose intake to a similar extent to that of tricyclic antidepressants. Interestingly, escitalopram produces a complete reversal after only one week of treatment;5 citalopram produces a similar effect after two weeks. The signal of an earlier onset of effect of escitalopram is supported by findings in the resident-intruder paradigm.6 In line with this, studies in models predictive of anxiolytic effect indicate that escitalopram has superior efficacy compared to citalopram (e.g. Papp and SaÂnchez7 ). Recently completed microdialysis studies of citalopram and its enantiomers on 5-HT release in the frontal cortex of freely moving rats revealed that R-citalopram appears to attenuate the effect of escitalopram.8 Escitalopram (2.0 mg/kg, s.c.) increased the 5-HT concentration more than citalopram (4.0 mg/kg, s.c.); Rcitalopram (2.0 mg/kg, s.c.) alone had no effect on 5HT concentrations. A dose-response study revealed that

Patients with generalized anxiety disorder (GAD) usually improve within a couple of weeks or months on SSRI/SNRI medications, not only by reduced anxious apprehension, muscle tension and insomnia, but also by improved cognitive function. They report becoming more decisive, focused, and capable of managing risks, and then ask: For how long will I need this treatment? Little is known to give a valid response. There are three reported studies on relapse prevention in GAD: venlafaxine, paroxetine, and pregabalin. For the approval of a GAD indication, regulation requires that one establishes the risk of relapse following withdrawal of effective treatment in responders/remitters. There are two designs for this: to continue treatment in responders to active treatment or placebo for an extended period of time, or to randomize responders/remitters on active treatment for 8 weeks to either continued active treatment or to placebo (following a taper period to minimize discontinuation symptoms). The latter is the recognized scientific technique to assess the risk of relapse/ recurrence, thus satisfying the ethics of placebo (section 29 of the 5th revision of the Helsinki declaration). The relapse criterion is either a clinically meaningful deterioration on a symptom scale such as the HRSA or GADI, or that the treatment is regarded as ineffective by the clinician. Judging from clinical experience, most GAD subjects relapse within 2-3 months from withdrawal of SSRI/SNRI treatment, and some within a year. Depending on the illness phase when the patient entered the study, reappearance of symptoms may be due to relapse (symptomatic exacerbation after a response) or to recurrence (a new episode of illness following recovery). Life events (trauma, bereavement, somatic disease) potentially confound the interpretation of causality. Investigators must be

S08. Symposium: New generation SSRI versus dual action antidepressants Sponsored by Lundbeck A/S Chairman: Siegfried Kasper S0801. Pharmacological correlations to the clinical profiles Connie SaÂnchez Denmark

IFMAD Abstracts

s.c. administered escitalopram produces a significantly larger maximum effect on 5-HT levels than does citalopram. Furthermore, local administration via the dialysis probe of escitalopram alone or in combination with R-citalopram confirms that the latter attenuates the effect of escitalopram in the frontal cortex. These findings represent tangible biological evidence for the notion that escitalopram has an earlier onset of effect and superior efficacy than citalopram. In conclusion, escitalopram is an extremely selective 5HT uptake inhibitor with earlier onset of effect and better efficacy than citalopram in animal models of depression and anxiety. References 1. Owens MJ, Knight DL, Nemeroff CB (2001) Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry 50: 345 ± 350. 2. SaÂnchez C, Larsen AK, Gupta. Escitalopram, the most selective serotonin reuptake inhibitor ± in vitro data. Poster presented at SCNP, 2002. 3. Hogg S, SaÂnchez C. The antidepressant effects of citalopram are mediated by the S-(+)- and not the R-(7)-enantiomer. Poster presented at ECNP 1999. 4. Mitchell PJ, Hogg S. (2001) Behavioural effects of escitalopram predict potent antidepressant activity. Poster presented at P, 2001. 5. Montgomery SA, Loft H, SaÂnchez C, et al. (2001) Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol & Toxicol 88: 282 286. 6. Mitchell P, Hogg S. Escitalopram’s behavioural effects predict rapid antidepressant activity. Poster presented at APA. May 2001. 7. Papp M and SaÂnchez C. Escitalopram potently reverses conditioned footshock-induced suppression of exploratory activity in rats ± an animal model of generalised anxiety. Poster presented at ECNP, October 2002. 8. Mùrk A, SaÂnchez C, Kreilgaard M, et al. In vitro and in vivo effects of citalopram and its enantiomers on the serotonin uptake transporter. Poster presented at ECNP, October 2002.

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(75 ± 150 mg/day). The initial doses were escitalopram 10 mg/day and venlafaxine XR 75 mg/day. The flexibledose design allowed physicians to increase the dose at 2 or 4 weeks if required for enhanced efficacy.3 Patients completing double-blind treatment entered a single-blind 1-week run-out period: patients remaining on the initial dose of study treatment received placebo for all 7 days; patients on the higher dose were down-tapered and received the initial dose for the first 4 days and placebo for the last 3 days of the run-out period.3 The primary efficacy variable, change in mean MADRS total score from baseline to Week 8, showed that escitalopram was at least as effective as venlafaxine XR. The robustness of this result was supported by secondary efficacy analyses of HAM-D total scores and CGI-I scores, and by the analyses of the response and remission rates. Survival analysis showed significant advantages for escitalopram compared to venlafaxine XR on both sustained response and sustained remission (p50.01). Sustained response was achieved 4.6 days faster (p=0.012) and sustained remission 6.6 days faster (p50.001) in escitalopram-treated patients than in venlafaxine-treated patients.3 More patients treated with venlafaxine XR withdrew due to adverse events (11%) than patients treated with escitalopram (8%). The incidence of nausea, increased sweating and constipation was significantly higher for venlafaxine than for escitalopram. The study clearly demonstrates that escitalopram is at least as efficacious in the treatment of MDD as venlafaxine XR, with escitalopram-treated patients reaching sustained response and sustained remission significantly faster than venlafaxine-treated patients. Furthermore, escitalopram offers a better tolerability profile compared to venlafaxine XR. References

S0802. Is dual action necessary for effective treatment of depression? Stuart Montgomery UK The refinement of citalopram by resolving the single enantiomer escitalopram has produced a reuptake inhibitor with the greatest selectivity of all SSRIs. Gorman et al1 have shown that escitalopram offers improved efficacy and earlier symptom improvement in the treatment of depression with the same favourable tolerability as citalopram. Others have suggested superior efficacy with antidepressants acting on both the 5-HT and NA systems in the CNS.2 In a recent study, escitalopram was compared with the non-selective antidepressant venlafaxine XR. In this randomized, double-blind, 8-week, flexible-dose study of major depressive disorder (MDD), escitalopram (10 ± 20 mg/day) was compared with venlafaxine XR

1. Gorman JM, Korotzer A, Su G (2002a) Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: Pooled analysis of placebo-controlled trials. CNS Spectrums 7: 40 ± 44. 2. Thase ME, Entsuah AR, Rudolph RL. (2001) Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 178: 234 ± 241. 3. Montgomery SA, Huusom AKT, Bothmer J. Escitalopram is at least as effective as venlafaxine XR in the treatment of depression and is better tolerated. Poster presented at the 15th Congress of the European College of Neuropsychopharmacology (ECNP), Barcelona, Spain, October 5 ± 9, 2002. 7 (8): 291 Suppl.

S0803. Optimising pharmacotherapy in depressed patients Barbara Hochstrasser Switzerland Escitalopram has been clinically evaluated in the treatment of major depressive disorder (MDD), clearly demonstrating efficacy at 10 mg/day both in specialist and primary care settings.1,2 Escitalopram was effective in a wide range of

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patients, including severely depressed patients, and was well tolerated. In a pooled efficacy analysis, comprising three placebo-controlled studies, escitalopram was compared with citalopram as the active reference drug. Escitalopram 10 ± 20 mg/day was more effective than citalopram 20 ± 40 mg/ day in reducing the severity of the symptoms of depression and resulted in more rapid improvement of symptoms.3 One of the studies used a four ± arm, fixed-dose design: escitalopram 10 mg/day, escitalopram 20 mg/day, citalopram 40 mg/day, and placebo. The other two studies used a flexible-dose design, with initial doses of escitalopram 10 mg/day, citalopram 20 mg/day or placebo. Doses could be increased to a maximum of escitalopram 20 mg/day, citalopram 40 mg/day or placebo based on clinical judgement. In the European study, increases in dose were permitted at Week 4 or Week 6, and in the US study, doses could be increased at Week 3. In both studies, patients could return to their initial dose at the investigator’s discretion. A total of 1321 patients were included in the ITT population (placebo n=398; escitalopram n=520; citalopram n=403).1 ± 4 Both escitalopram and citalopram significantly reduced the severity of the symptoms of depression and anxiety compared with placebo. Efficacy measures included change from baseline in MADRS total score, the CGI-I scale and the MADRS inner tension item. In addition, the percentage of responders (50% decrease from baseline in MADRS total score) was significantly higher in the escitalopram and citalopram groups than in the placebo group (59%, 53% and 41%, respectively; p50.01).3 Escitalopram resulted in more rapid improvement of the severity of the symptoms compared to both citalopram and placebo. As early as Week 1, escitalopram was significantly better than citalopram and placebo assessed on the MADRS (p50.05) and CGI-I (p50.001) scores.3 The superior efficacy of escitalopram relative to citalopram was also observed at Week 6 in the LOCF analysis (p50.05) and Week 8 in the OC analysis (p50.05).3 This pooled analysis demonstrates that escitalopram is more effective than citalopram and provides more rapid improvement in symptoms in patients with MDD. Furthermore, escitalopram has a favourable tolerability profile and is at least as well tolerated as citalopram.1 ± 3 References 1. Burke WJ, Gergel I, Bose A (2002) Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 63: 331 ± 336. 2. Wade AG, Lemming O, Hedegaard K (2002) Escitalopram 10 mg/day is effective and well-tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 17:95 ± 102. 3. Gorman JM, Korotzer A, Su G (2002) Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: Pooled analysis of placebo-controlled trials. CNS Spectrums 7:40 ± 44. 4. Reines E, Lepola UM, Loft H. Escitalopram at flexible doses is efficacious and well tolerated in the treatment of depression in primary care. Presented at the ECNP, October 2002.

S0804. New aspects in treatment of anxiety disorders Borwin Bandelow Germany SSRIs are the first-line treatment in anxiety disorders. Escitalopram is the most selective SSRI available. The clinical efficacy and tolerability of escitalopram in the treatment of patients with major depressive disorder (MDD) have been established in several placebo-controlled studies. Additionally, several randomized, double-blind, placebo-controlled, parallel-group multi-centre studies have evaluated the efficacy and tolerability of escitalopram in social anxiety disorder (SAD), generalized anxiety disorder (GAD) and panic disorder (PD). Patients diagnosed with generalized SAD (DSM-IV criteria) were assigned to 12 weeks of treatment with either escitalopram 10 ± 20 mg/day or placebo. The primary efficacy measure (mean change in the Liebowitz Social Anxiety Scale (LSAS) total score from baseline to endpoint), demonstrated a statistically significantly superior effect for escitalopram compared with placebo. In the GAD study, patients fulfilling DSM-IV criteria for GAD were assigned to 8 weeks of treatment with either escitalopram 10 ± 20 mg/day or placebo. Escitalopram 1020 mg/day produced a statistically significant improvement in the symptoms of GAD and quality of life as measured by HAMA, HAD, CGI, and QOL. In the PD study, escitalopram was compared to placebo in patients diagnosed with PD with or without agoraphobia in a 10-week trial. Escitalopram was superior to placebo on the following measures: Panic and Agoraphobia Scale (P&A),1 panic attack frequency and anticipatory anxiety items from the Sheehan Panic Attack and Anxiety Scale (PAAS), Clinical Global Impression severity (CGI-S), Patient Global Evaluation (PGE), Quality of Life Scale (QOL) and other measures. Escitalopram was as well tolerated as placebo. In summary, escitalopram 10 ± 20 mg was efficacious and well tolerated in patients suffering from social anxiety disorder, generalized anxiety disorder or panic disorder. These results demonstrate the efficacy of escitalopram in the treatment of patients with these persistent and disabling anxiety disorders. References 1. Bandelow B (1995) Assessing the efficacy of treatments for panic disorder and agoraphobia. II. The Panic and Agoraphobia Scale. Int Clin Psychopharmacol 10:73 ± 82.

S09. The outing of social anxiety disorder Chairmen: J. P. Lepine, D. Baldwin S0901. The biology of anxiety disorders Johannes Tauscher Department of General Psychiatry,University of Vienna,Austria Anxiety disorders belong to the most common psychiatric disorders with a lifetime prevalence of 25% (Kessler 1994).

IFMAD Abstracts

Anxiety disorders are divided in subgroups, namely panic disorder (PD), agoraphobia, generalized anxiety disorder (GAD), and social phobia. While the separation of GAD and panic disorders/agoraphobia is not difficult if a patient has frequent spontaneous panic attacks and particularly if there are agoraphobic symptoms, there is a close overlap between GAD and social phobia (Rickels 2001). This overlap is confirmed by the neurobiological finding that (1) a serotonergic pathway originating from the dorsal raphe nucleus ascending to the amygdala and frontal cortex is involved in anticipatory anxiety and avoidance as seen in GAD and social phobia, while (2) a second pathway to the periaqueductal gray matter is believed to be involved in the mediation of panic (Deakin 1991, Nutt 2001). A number of neurotransmitters such as GABA/benzodiazepine and the catecholeamines serotonin and norepinephrine have been implicated in the neurobiology of anxiety disorders. The known effectiveness of benzodiazepines in reducing anxiety made the GABA/benzodiazepine system a focus of research in GAD (Roy-Byrne 1990, Kroboth 1998, Tiihonen 1997). Taken together, this research provided evidence that in anxiety disorders, patients have reduced central benzodiazepine receptor function. The norepinephrine-sympathetic nervous system has been implicated in the response to stress, and several researchers have investigated possible abnormalities in catecholeamine function in anxiety disorders. These studies indicated that resting norepinephrine levels may be normal in anxiety patients; however, there may be reduced adrenergic receptor sensitivity in these patients, possibly as a response to chronic over-activity of central norepinephrine (Mathew 1982, Khan 1986, Kelly 1998, Abelson 1991). There is evidence that the neurotransmitter serotonin (5-HT) plays a crucial role in anxiety. Its concentration in the cerebrospinal fluid is reduced in patients with GAD (Brewerton 1995). Recently, research has focused on the 5HT1A receptor which seems to play a key role in modulating anxiety. `Knock-out’ mice lacking the gene that regulates the expression of 5-HT1A receptors displayed decreased exploratory activity, and increased fear of aversive environments in the open field and the elevated plus maze test, as well as decreased immobility in the forced swim test, which all serve as indicators for anxiety (Parks 1998, Ramboz 1998). Furthermore, partial 5-HT1a receptor agonists (e.g. buspirone, gepirone) exert at least modest antianxiety effects (Laakmann 1998, Sramek 1997, Pecknold 1997, Rickels 1997). Using [carbonyl-11 C]WAY100635 and positron emission tomography (PET), 5-HT1A receptors can be investigated in humans in vivo (Farde 1998). Our group recently presented a PET study in 19 healthy volunteers exploring the relationship between 5HT1A binding and a personality facet that assesses anxiety (Tauscher 2001). In this pilot study, an inverse relationship between cortical 5-HT1A receptor binding potential and trait anxiety could be demonstrated. Subjects with lower 5-HT1A

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receptor density were more likely to display higher levels of anxiety, which is in line with results from animal studies showing increased anxiety in mice lacking 5-HT1A receptors. S0902. Neurobiology of social phobia Dan J. Stein Unit on Anxiety Disorders, University of Stellenbosch, Cape Town and University of Florida, Gainesville, USA There is growing awareness that an amygdala based fear circuit plays a crucial role in mediating fear conditioning as well as anxiety symptoms. The efficacy of selective serotonin reuptake inhibitors (SSRIs) in certain anxiety disorders has been argued to reflect their ability to modulate this circuit, and there is now also evidence that particular kinds of psychotherapy can have a similar impact. Whether additional neurocircuits play a differentiating role in specific anxiety disorders such as social anxiety disorder (SAD) is an ongoing subject of investigation, and a review of recent research suggests that In SAD dopaminergically mediated striatal circuits may also be important. Future work will undoubtedly clarify how genetic and environmental factors interact to fashion the neurocircuitry that mediates social anxiety symptoms. S0904. Recent advances in the treatment of social anxiety disorder D. Baldwin Dept. of Mental Health, University of Southampton, UK Social phobia is no longer `the neglected anxiety disorder’. In recent years, considerable advances have been made in understanding the epidemiology and pathophysiology of this previously elusive illness. Many treatment studies have been published, and patients with social anxiety disorder can now be offered a range of `evidence-based’ treatments. The results of double-blind placebo-controlled studies with monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRIs) indicate that both classes can be efficacious in the short-term treatment of patients with social anxiety disorder. The effects of longterm treatment have been studied less extensively, although some SSRIs have proven efficacy in the prevention of relapse. But the existing drugs are not ideal, and rather little is known about the effectiveness and acceptability of treatment in standard clinical practice1 . This presentation will include new data, relating to the treatment of patients with social phobia with the most selective SSRI, escitalopram; the serotonin-noradrenaline reuptake inhibitor, venlafaxine; and the novel anxiolytic drug pregabalin. Where possible, an attempt will be made to examine the relative efficacy and tolerability of different treatment approaches.

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References 1. Baldwin DS, Birtwistle J (2000). Selective serotonin reuptake inhibitors in anxiety disorders: room for improvement. In: Briley M, Nutt DJ (eds) Anxiolytics. Birkhauser, Basel, pp. 55 ± 75.

S10. Symposium: The changing paradigm in depression and the role of substance P (NK1 receptor) antagonists (SPAs) Sponsored by Merck Sharp & Dohme Chairman: Hans-JuÈrgen MoÈller S1001. Molecular Targeting of Substance P Related Genes in Depression Julien Mendlewicz 1, Pierre Oswald1 , Daniel Souery1, Christine Van Broeckhoven2 1 Department of Psychiatry, University Clinics of Brussels, Erasme Hospital, Free University of Brussels, Brussels, Belgium, 2Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UIA), Antwerp, Belgium Substance P (NK1 ) receptor antagonists have been shown to be active in pharmacological models of depression and anxiety and in reducing depressive symptoms in affectively ill patients. These findings permit the exploration of novel molecular genetic markers of depression and new mechanisms of antidepressants. We have identified Single Nucleotide Polymorphisms (SNP) within four NK1 related genes: NK1 receptor gene (TACR1), Peptidylglycine Alpha-Amidating Monooxygenase (key enzyme in NK1 bioactivation) gene (PAM), NK1 precursor gene (TAC1) and Angiotensin Converting Enzyme (implicated in the degradation of NK1 ) gene (ACE). A case-control association study was conducted in a population of 92 unipolar affective disorder (UPAD) patients matched with normal controls for age, sex and ethnogeographical origin. No association was found in the overall sample of UPAD-control pairs regarding allele and genotype frequencies for TACR1, TAC1 and PAM genes. An association was found in the first SNP of ACE gene regarding G-allele frequency (OR=2.35, P50.0001) and genotype frequency (P=0.001). Furthermore, haplotype analysis within ACE gene using ARLEQUIN revealed a global P value of 0.0003, indicating an excess of a specific haplotype in UPAD population. This robust association between UPAD and ACE SNP polymorphism suggests that ACE could be one of the risk factors in UPAD. This study, if confirmed, points to the importance of NK1 for the understanding of the molecular basis of UPAD. S1002. Neuroimaging and NK-1 Receptors in Depression Richard Hargreaves Department of Pharmacology and Imaging Research, Merck Research Laboratories West Point, PA, USA Substance P (SP) and neurokinin 1 (NK1 ) receptor pathways have been implicated in the pathophysiology of

emesis and depression. Autoradiographic studies in monkey and human brains have shown a high expression of NK1 receptors in regions important for the regulation of affective behaviors and the neurochemical response to stress. Recent clinical studies have demonstrated that treatment with the SP (NK1 receptor) antagonist (SPA) aprepitant (also known as MK-0869) significantly improves depression symptoms and reduces the incidence of chemotherapy-induced nausea and vomiting. An important objective of all neuroscience drug discovery and development programs is to establish the correlation between dose, receptor occupancy, and the observed clinical effect (the dose-response relationship). These goals can be achieved using radioactive receptorspecific tracers and dynamic noninvasive brain imaging modalities, such as positron emission tomography (PET). In the SPA program, a tracer [18 F]SPA-RQ was chosen for PET studies based on several criteria, including high affinity for the NK1 receptor, low nonspecific binding and good blood-brain barrier penetration. Pre-clinical biodistribution and PET imaging studies established the usefulness of this probe for clinical in vivo NK1 receptor occupancy studies. PET occupancy studies in humans predicted that very high levels of central NK1 receptor occupancy (490%) are required to achieve and optimize therapeutically significant antidepressant and antiemetic effects. PET imaging studies have since focused on quantification of NK1 receptor expression in depressed patients in order to examine the potential involvement of SP and the NK1 receptor system in the pathophysiology of this disorder. S1003. Determining the antidepressant mechanism of action of Substance P Antagonists (SPAs) Graham Burrows University of Melbourne and Mental Health Clinical Service at Austin & Repatriation Medical Centre, Heidelberg, Australia Substance P (NK1 receptor) antagonists (SPAs) represent a significant medical advance and a novel mechanism of action for treating depression. Substance P, a peptide neurotransmitter, is released in response to stressful stimuli. NK1 receptors, highly expressed in brain regions important for the regulation of affective behaviors and the neurochemical response to stress, are the predominant tachykinin receptor in the human CNS. Upon binding to the NK1 receptor, the substance P/NK1 receptor complex is internalized by the cell and degraded. NK1 receptors are then recycled and placed back into the cell membrane. SPAs appear to supplement their direct actions in the hypothalamus and amygdala with regulation of 5-HT and NE neuronal function in a way that is unique when compared with that of currently available antidepressants. Chronic administration of a selective SPA to guinea-pigs has demonstrated an increased dorsal raphe neuronal

IFMAD Abstracts

firing and burst firing rates in addition to modest increases in dorsal raphe 5-HT levels and potentiation of certain behavioral effects of 5-HTP. Evidence further supporting the novel mechanism for achieving antidepressant activity, including the anxiolytic profile, of SPAs will be discussed. S1004. Clinical significance of Substance P antagonists (SPAs) Siegfried Kasper Department of Psychiatry, University of Vienna, Wien, Austria Substance P is a neuromodulator from the tachykinin family of peptides, first isolated from brain and intestine, and characterized pharmacologically in 1931. Recently, it has been shown that it is the preferred endogenous agonist acting at neurokinin (NK1) receptors. Substance P is widespread throughout the brain and extensively co-localized with neuroamines. PET imaging studies indicate eing widespread distribution of NK1 receptors in areas of the brain that have been associated with depression. MK-869 has demonstrated a unique pharmacology compared with other antidepressants since it blocks NK1 receptors and therefore acts as a Substance P antagonist (SPA). Phase II and Phase III studies demonstreated antidepressant efficacy and superior tolerability over the selective serotonin reuptake inhibitor (SSRI) paroxetine. Specifically, there was no indication of nausea, sexual dysfunction or headache with MK-869. The available data from the clinical development program for MK-869 indicates that this compound addresses a number of unmet needs as yet not covered by the available compounds in everyday practice. Saturday 30 November S11. The rise in bipolar depression Chairmen: T. Suppes, P. Baumann S1101. Lamotrigine in the treatment of bipolar depression Gary Evoniuk GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA. Background: Bipolar disorder is a chronic and severe disease and is associated with high morbidity and mortality. Recent data from the World Health Organisation suggest that the disorder is responsible annually for 1.7 million years of lost healthy life due to premature death or disability, making it the sixth most common cause of disability worldwide, second only to unipolar depression among mental illnesses. In particular, bipolar depression is associated with an

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increased risk of suicide, poorer psychosocial functioning, and a greater amount of symptomatically ill time when compared with mania and hypomania. However, until recently, most drug trials have concentrated on the treatment of mania. Lamotrigine, an established anticonvulsant drug, has now demonstrated efficacy in a number of randomized controlled clinical trials conducted in bipolar depression. Methods: Discussion of data will be limited to randomized, controlled clinical trials. These data will include four acute trials in the treatment of depression and the first-ever trial to be conducted solely in rapid cycling bipolar patients. More recent evidence from two large lithium- and placebo-controlled maintenance trials (GW Studies 605/606) will also be discussed in detail. In the latter studies, a total of 1315 currently or recently symptomatic bipolar I patients (DSM-IV) were enrolled in a preliminary phase, of whom 638 were stabilized and randomized to 18 months of double-blind monotherapy with lamotrigine (n=280; 50 ± 400 mg/day fixed and flexible doses), lithium (n=167; 0.8 ± 1.1 mEq) or placebo (n=191). The primary outcome measure was the time from randomization until intervention for an emerging mood episode or withdrawal from the study that was unrelated to bipolar illness. Key secondary endpoints included time to intervention for an emerging depressive episode or for an emerging manic, hypomanic or mixed episode. Results: Acute study results indicate statistically and clinically significant antidepressant effects for lamotrigine in bipolar I patients. Efficacy appears to be most robust on core depressive symptoms including depressed mood, guilt feelings and work and interest, either as monotherapy or add-on to SSRI treatment. In rapid cycling patients, the efficacy of lamotrigine was most robust against depressive symptoms, especially in bipolar II patients. In the two maintenance studies, both lamotrigine and lithium elicited statistically and clinically significant delays in the time to treatment intervention, survival in study and time to any bipolar event. In separate analyses of manic/hypomanic/ mixed and depressive events, lamotrigine significantly delayed time to intervention for depressive events while lithium delayed time to intervention for manic/hypomanic/ mixed events. Lamotrigine therapy has been well tolerated in this patient population, with a low risk of mania exacerbation or weight gain. Simple rash has been observed in 8.3% of patients (vs. 6.4% of placebo patients) with an incidence of serious rash (50.1%) comparable to other anticonvulsants such as carbamazepine. Conclusion: Lamotrigine appears to be an important new treatment option for bipolar disorder patients, particular in the management and prevention of depressive episodes. This efficacy profile is complementary to other mood stabilizers such as lithium, which appear to be most effective in the treatment and prevention of mania. As such, lamotrigine may represent the prototype of a new class of mood stabilizers that target bipolar disorder from the depressive pole of the illness.

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S1102. How important are switch rates in bipolar depression? Heinz Grunze LMU Munich Compared to mania, bipolar depression is characterized by a usually longer treatment duration as well as increased refractoriness to treatment. Increasingly the risks of antidepressant standard therapy are noticed, especially the switch into mania, as the possible induction of a Rapid Cycling course.1,2 On the other hand, it seems that at least some mood-stabilizers like lithium or some anticonvulsants may be effective for moderate depression, but possibly not sufficient enough in severe bipolar depression. With 15 ± 20% of bipolar patients dying as a result of suicide, antisuicidal effects are also important to consider besides pure antidepressive or switch prohibiting properties. Although lithium has been considered as having antisuicidal properties, recent studies suggest that antidepressants may be superior in preventing suicidal acts.3 In addition, increased suicidality after lithium discontinuation may constitute a problem with the known compliance problems of bipolar patients.4 This presentation will outline recent data of the Stanley Foundation Bipolar Network (SFBN, [5]) and of the LMU Munich documentation system6,7 that address the efficacy of antidepressants and mood stabilizers in treating bipolar depression, and balance the risk of switching and rapid cycling in short and long term treatment versus suicidality. Additionally, recent data of the SFBN will be presented favoring long-term treatment with modern antidepressants in severely ill bipolar patients.8,9 References 1. Altshuler LL, Post RM, Leverich GS et al (1995) Antidepressantinduced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 152: 1130 ± 8. 2. Ghaemi SN, Lenox MS, Baldessarini RJ (2001) Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry 62: 565 ± 9. 3. Angst F, Stassen HH, Clayton PJ et al (2002) Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord 68: 167 ± 81. 4. Baldessarini RJ, Tondo L, Hennen J (1999) Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry 60: 77 ± 84. 5. Post R, Altshuler L, Suppes T et al (2001) The treatment of bipolar depression. APA 2001 Syllabus & Proceedings Summary ???: 91 ± 3. 6. MoÈller HJ, Bottlender R, Grunze H et al (2001) Are antidepressants less effective in the acute treatment of bipolar I compared to unipolar depression? J Affect Disord 67: 141 ± 6. 7. Bottlender R, Rudolf D, Jager M et al (2002) Are bipolar I depressive patients less responsive to treatment with antidepressants than unipolar depressive patients? Results from a case control study. Eur Psychiatry 17: 200. 8. Altshuler L, Kiriakos L, Calcagno J et al (2001) The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry 62: 612 ± 6.

9. Altshuler L, Suppes T, Black D, Nolen W, Keck PE, Frye M et al Impact of antidepressant discontinuation after acute remission from bipolar depression on rates of depressive relapse on oneyear follow-up. Am J Psychiatry. In press.

S1103. Maintenance therapy in bipolar depression T. Suppes University of Texas Southwestern Medical Center, Dallas TX, USA Bipolar disorder is well-recognized by the periodic cycles of mania and depression. Many medications are effective to treat mania including drugs in a number of categoriesÐlithium, anticonvulsants, typical and atypical antipsychotics. Importantly, after two manic episodes, the need for ongoing treatment is generally agreed upon. In contrast, whether to treat depression in patients with bipolar disorder, when to treat, and if treatment should be continued long-term are all issues of debate. A clinically important question is what are best treatment practices for the long-term care of patients with bipolar disorder. For acute depression, like mania, there are a number of treatment options to minimize symptoms and relieve suffering. The need to develop data-driven guidelines is great when the potential for suicidal behavior and reduced quality of life is considered for these patients. There is a risk for antidepressants to cause a switch into the manic pole. The frequency and vulnerability for this occurrence is being studied, as well as the possibility that antidepressants may increase cycling. There is ongoing debate about the impact of any antidepressant treatment on the course of symptoms. The majority of guidelines suggest stopping antidepressant medication after alleviation of symptoms. Recent data from Altshuler and colleagues suggests this strategy may not always be the best treatment approach. Their clinical studies, which are naturalistic and retrospective, suggest a decrease in new depression, improved function, and fewer days ill over the next 12 months when antidepressants are continued in combination with antimanic agents after depressive symptoms remit. Additionally, data on options to traditional antidepressants are being studied to treat bipolar depression long term. Lamotrigine (LTG), an anticonvulsant, was significant in preventing a new episode of depression in bipolar patients recently manic or depressed (n=417). In two 18-month studies, the results of these monotherapy, double-blind, and placebo-controlled trials were also notable for the lack of switching noted in patients on long-term LTG. Depakote, another anti-convulsant, was found to provide more protection for new onset depression symptoms than placebo or Li in a one-year, double-blind, placebo study. The atypical antipsychotics are also being studied as potential agents to both prevent new onset depression and possibly provide a new treatment option for bipolar depression. In one recent short-term study, olanzapine

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and olanzapine plus fluoxetine were both more effective than placebo for patients with bipolar depression. Further studies with other atypical antipsychotics are underway. Recent maintenance studies and current guidelines for treatment of depression in bipolar disorder patients will be reviewed. S1104. Pluses and minuses of augmentation strategies Eduard Vieta Bipolar Disorders Program, Barcelona Stanley Foundation Research Center, Hospital Clinic, University of Barcelona, Barcelona, Spain The treatment of depression in bipolar disorder represents an understudied area in clinical psychiatry that needs further research, owing to the frequency of depressive episodes, the high rates of associated suicidality and comorbid psychiatric and substance-use disorders, and the negative impact on psychosocial functioning and quality of life. Two areas in particular deserve much further research: the efficacy of augmentation strategies for the treatment of breakthrough depressive episodes (depression emerging in patients taking mood-stabilisers), and the safety of such strategies, with special emphasis on the potential of a number of treatments to induce a switch to hypomania, mania or rapid cycling. Augmentation strategies include the addition of a second mood-stabiliser, antidepressants, some atypical antipsychotics, thyroid hormone, benzodiazepines, or non-pharmacological interventions such as electroconvulsive therapy, phototherapy, vagus nerve stimulation, or psychotherapy. The rationale, pros and cons of all these strategies will be discussed.

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the potential for dependency. A non-benzodiazepine anxiolytic like the tetracyclic opipramol seems a meaningful alternative. There is already much positive clinical data available which strongly support this assumption. However, hitherto clinical trials following the modern methodological criteria have been lacking. In recent years, two large clinical studies were performed in outpatients suffering from a somatoform disorder.1,2 Following a rigorous design with very well-defined outcome criteria, opipramol could demonstrate statistical superiority to placebo. The positive findings in patients with somatoform disorders were supported by another study in which opipramol was compared under double-blind conditions to both placebo and a benzodiazepine in patients suffering from general anxiety disorder. In this study, opipramol could demonstrate therapeutic efficacy in treating both psychic and somatic symptoms of anxiety. Altogether, opipramol seems to be a rational and evidence-based approach to treat somatic complaints in the context of somatoform disorders, general anxiety disorders and also mild mixed anxious depressive disorders. St. John’s Wort also seems to have a place in the treatment of this indication, as can be derived from the results of a recent study.3 References 1. Volz HP, MoÈller HJ, Reimann I, Stoll KD (2000) Opipramol for the treatment of somatoform disorders: results from a placebocontrolled trial. Eur Neuropsychopharmacol 10: 211 ± 7. 2. Volz HP, MoÈller HJ (2000) Placebokontrollierte 6-WochenStudie mit Opipramol bei somatoformen StoÈrungen. In: MoÈller HJ, MuÈller WE (eds) Opipramol, Sigmaligand und stimmungsaufhellendes Anxiolytikum. LinguaMed Verlags-GmbH, NeuIsenburg, pp. 109 ± 25. 3. Volz HP, Murck H, MoÈller HJ. St. John’s Wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial. Psychopharmacology (in press).

S12. New treatment approaches Chairmen: H. J. MoÈller, S. Montgomery S1201. Advances in somatization disorder Hans-JuÈrgen MoÈller Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany Somatic symptoms in clearly defined major depression generally respond satisfactorily to treatment with antidepressants. The somatic symptoms usually decrease together with the other depressive symptoms. However, the somatic symptoms of minor depressive disorders or socalled mild mixed anxious depressive disorders, which are very frequent in primary care settings, and also somatic symptoms in the context of somatoform disorders, often do not respond very well to antidepressant treatment. Therefore other therapeutic options have to be considered, such as benzodiazepines. Although treatment with benzodiazepines has a long tradition, their prescription is becoming increasingly restricted due to the growing awareness about

S1202. Hypericum in affective disorders Yves Lecrubier INSERM 302, HoÃpital de la SalpeÃtriere, Paris, France The treatment of mildly and moderately severe forms of major depression with extracts from St. John’s wort (Hypericum perforatum) is highly prescribed in Germany, and sales in the United States were $86 million in the year 2000. The efficacy of hypericum extract (HE) in alleviating mild to moderate depressive states was explored in comparisons with placebo and with effective standard antidepressants. Reviews and meta-analyses by Kim et al, Linde et al, and Volz suggested HE to be an effective anti-depressant. Despite the large body of published evidence supporting the efficacy of HE as an antidepressant, different authors (Kim et al 1999, Deltito et Beyer 1998) pointed out serious design problems in existing studies and have criticized the meagerness of the database. In addition when the global score of a scale

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such as the Hamilton Depression Rating Scale (Hamilton 1960, 1967) is used, one may question whether the observed score changes reflect a true antidepressant effect or a non-specific anxiolytic property. A way to explore this bias is to take into account the initial severity of the patient’s depression and its relationship to treatment efficacy. Laakmann and colleagues investigated mildly to moderately depressed patients with a pre-treatment total score on the Hamilton depression scale (17 item version) of 17 or higher, and suggested that antidepressant treatment with HE was more efficacious for the more severely depressed subgroup. We conducted a study in order to compare the efficacy of HE WS5570 to that of placebo in a large group of patients suffering from a mild to moderate major depressive episode according to DSM-IV. Particular attention was paid to the efficacy observed for the core symptoms of depression, as measured by the Bech melancholia scale (Bech et al 1975), and to the relationship between the initial severity of depression and response to treatment. This was a 6-week double blind, placebo-controlled, randomized phase III trial comparing the efficacy of WS 5570, 300 mg t.i.d, and placebo. Patients were randomly assigned, 186 to WS 5570 and 189 to placebo for six weeks. Follow-up visits were at 1, 2, 4 and 6 weeks. The primary outcome measure was the change from baseline in the total score on the 17-item Hamilton Depression Rating Scale. In addition, analyses of responders, remitters (patients with a total score of 6 or less on the Hamilton scale at treatment end) were carried out, and subscale/subgroup analyses were conducted. WS 5570 was significantly more effective than placebo on the total score of the Hamilton depression scale and significantly more patients had a treatment response or remission. It was more effective in patients with higher baseline Hamilton scores and at least as effective in patients with the melancholia subscale of the Hamilton scale. Contrary to data published recently in the United States, HE does appear to have antidepressant properties superior to placebo even in truly depressed patients. Interestingly, in this last study the drug was more effective in the more severe patients. S1203. Advances with nemifitide in depression S. Montgomery, J. Feigner UK Aim: This presentation summarizes a series of clinical phase 1 and 2 studies with nemifitide designed to evaluate its safety, pharmacokinetics and antidepressant activity. Method: Seven phase 1 safety-PK studies in over 260 healthy volunteers were completed at doses ranging from 9 ± 320 mg/subject. Several phase 2 safety/efficacy studies were conducted or are in progress. The current total

number of patients in the phase 2 studies is over 250. Nemifitide (or placebo) was administered SC once/day in one or two 5-day treatment cycles (up to 4 cycles for the treatment-resistant patients) with the dose ranging from 15 ± 240 mg. Enrollment requirements for the double-blind studies were HAMD-21 520, CGI 54. Response was defined as 550% change in HAMD-21 or MADRS from baseline. The highest observed plasma concentration (Cmax ) for each patient treated with nemifitide was used to calculate a minimum projected therapeutic concentration (MPTC). Results: A pharmacodynamic relationship was observed between Cm ax and response to treatment. In the two placebo-controlled studies there were significant differences in response between the group with Cm ax 5MPTC versus both the group with Cmax 5MPTC and the placebo group. To date, 27 patients have finished the extension study and the response rate was 73%. The study in patients with treatment-refractory depression is underway and data from the initial 21 patients indicate a response rate of about 47.6%. Nemifitide showed a good safety profile: side effects (injection site reaction, headache, dizziness, nausea, constipation) were mild and transient. Conclusion: Nemifitide demonstrated a promising clinical effect in the treatment of major and treatmentrefractory depression with robust response and early onset of action. Nemifitide was very well tolerated in all clinical trials. Further studies are ongoing. S1204. Do discontinuation symptoms lead the relapse? I. Hindmarch, J. Boyle HPRU Medical Research Centre, University of Surrey, Egerton Road, Guildford GU2 7XP, Surrey, UK Discontinuation reactions following cessation or tapering of antidepressant treatment have been reported since the 1950s with the reporting of symptoms such as sweating, dry mouth, dizziness and paraesthesias upon imipramine discontinuation. Since then, discontinuation reactions have been reported for other tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin/noradrenaline reuptake inhibitors (SNRIs) and noradrenaline and serotonin-selective antidepressants (NASSAs). Discontinuation symptoms may occur in up to 30% of patients therefore making it an important criterion in antidepressant selection. It has been proposed that the risk associated with an individual drug is related to its elimination half-life, pharmacokinetic profile, presence or absence of an active metabolite and selectivity and potency at the target site. Genetic factors and the cognitive sensitivity of individual patients may also influence discontinuation reactions. Although usually transient, discontinuation symptoms can be severe, leading to a loss in productivity and normal

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functioning. It is also apparent that although discontinuation symptoms have been widely reported, predominantly in the form of case reports, there is still a lack of awareness among some prescribing GPs. This can lead to unnecessary medical tests and treatment. The incidence of discontinuation symptoms varies widely across the different antidepressant drugs. In recent years a small number of controlled trials have investigated

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discontinuation reactions upon abrupt cessation of antidepressant treatment. The aim of this review is to provide a meta-analysis of these studies to give an objective measure of impairment following treatment cessation. In addition, individual case reports and adverse drug reaction reports will be reviewed to give a comprehensive overview of risk of discontinuation reaction for each antidepressant currently marketed.

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Poster Abstracts P01. High frequency repetitive transcranial magnetic stimulation (rTMS) in treatment refractory depression G. Abraham, J.S. Lawson, M. David, R. Milev Queen’s University, Kingston, Ontario K7L 4X3, Canada Aim: To investigate whether rTMS relieves depression in antidepressant refractory patients who are not currently taking antidepressants. Materials and Methods: Multiple antidepressant resistant depressed patients were withdrawn from their antidepressants and randomly assigned to receive true or sham rTMS. High frequency rTMS was administered to the left frontal cortext for a period of 10 working days. Depression, anxiety and memory were measured before TMS treatment, and at intervals thereafter. Results: Six patients thus far have completed their treatment, as part of a continuing study. Three received the sham, and three, the true treatment. None of the 3 who received the sham treatment showed any improvement (with mean HAMD and BDI scores of 23 and 39 at start and 23 and 33 respectively at end of study). Of the three patients who received true rTMS, one remitted (with the HAMD and BDI scores dropping to 11 and 14 from baseline scores of 22 and 33 respectively), while the mean scores for the group dropped from 27 and 36 to 21 and 27 on the HAMD and BDI respectively. As this responder had been disabled for 2 years before the TMS, she was given biweekly maintenance TMS. She remained well enough to return to her former full time job and stayed well for about a year. All patients tolerated TMS well and there was no evidence of worsening in the anxiety or memory scores. Conclusion: A 33% response rate in patients with multiple antidepressant resistance is a welcome and hopeful finding. Even more encouraging however, is the possibility that those who respond to TMS may be kept well and return to normal functioning with maintenance TMS. P02. The presenting symptoms of post traumatic stress disorder among children in Al-amiria shelter M.R. Al-Aboodi Al-Rasheed Military Hospital, Baghdad, Iraq Objective: Al-Amiria shelter is one of the common shelters in Baghdad, which had been the subject of bombardment in February 1991 during the Gulf War. The study aimed to explore the profile of post traumatic stress disorder (PTSD) symptoms and any other associated symptoms among Iraqi children. Method: Thirty children, aged from 7 ± 12 years, who were survivors of or witnesses to the bombardment, and who met the DSM-IV criteria for PTSD, were interviewed in

1993 and 1998. A semi-structured interview and symptom checklist for PTSD and stress related neurotic disorder were used. Results: All patients (100%) had experienced flashbacks and ruminations of ideas relating to the events. Avoidance of emotionally charged stimuli also occurred in all subjects (100%). The other main experiences reported were nightmares (72%), frequent failure in school (65%), startle reflex (60%), vague abdominal pain (40%), chronic depressive symptoms (27%) and nocturnal enuresis (10%). Conclusion: PTSD is a chronic and serious problem, which needs attention and proper management. The avoiding attitude among the children may underestimate the PTSD diagnosis. The associated symptoms of depression or anxiety may overlap the diagnosis of PTSD among children. P03. Difference in characteristics of soldiers with combat stress reaction applying to frontline versus home front treatment Daniella Amital, Joseph Zohar The Chaim Sheba Medical Center, Israel Background: Since the turn of the previous century treatment of combat stress reaction in the battlefield is constituted on three principles: proximity, immediacy and expectancy. The Israeli medical corps adopted this concept and posted mental health services integrated in medical units which are stationed close to frontlines, assuming that by these means the probability of developing later posttraumatic stress disorder (PTSD) will decrease. This therapeutic approach has been investigated for its effectiveness, under the assumption that applying for treatment in frontline situations is depend solely in the treatment availability in frontline, and not on the appliers themselves. In this study we studied this assumption, and compared the characteristics of veterans who received frontline treatment to those who received home front treatment, and later developed PTSD. Methods: We screened 5,871 records of veterans approaching the division of Rehabilitation of the Israeli Ministry of Defense (MOD) or the IDF clinic for treatment of combat reaction. In order to be able to compare the effect of the echelon treatment level we included only 1,461 PTSD subjects that experienced a combat stress disorder during war time. Two measures were used to evaluate the traumatic incident of each subject: a semi-objective evaluation of the intensity of the event and a parameter assessing the immediacy of the emotional reaction of the subject. Additionally, data concerning the psychometric and psychological and intellectual prerecruitment measures of the individuals were also analyzed.

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Results: The initial treatment of 235 subjects was at 1st echelon (16.1%), 424 at 2nd echelon (29.0%), while the majority of subjects (n=802, 54.9%) were treated at 3rd echelon. Young soldiers during their mandatory military service tended less often to seek 1st echelon medical facilities (8.6%) than 3rd echelon facilities (64.3%) compared to older reservists. Soldiers taking part in battle with their organic units showed a higher tendency to seek for help at 1st (16.2%) or 2nd (32.0%) echelons compared to subjects serving out of their organic units (1st 12.1%; 2nd 20.6%) (w2(2)=21.92, p50.0001). Officers and sergeants addressed more 3rd echelon treatment (officers 57.9%, sergeants 61.3%, soldiers 46.3%). Interestingly we could not detect a correlation between the intensity of event and the immediate emotional reaction (r=70.068, p50.05), indicating that events of higher intensity were not predictors of stronger emotional response. Discussion: Soldiers who apply to different treatment facilities are different in their characteristics. A high motivation degree that parallels with higher intellectualadaptational resources enabled subjects to cope initially with the traumatic event and to delay medical care to a later stage. A feeling of coherence considered to predict lower prevalence of PTSD, an important question that could not be answered by the current study. We can see only that greater coherence is associated with delaying in the initial treatment. Conclusions : The assumption of similarity between those who apply to different treatment facility is rejected. The current study show that different soldiers will apply to different echelons. These findings put into question the ability to investigate the effectiveness of the different treatments, considering the fact that they do not refer to the same people. P04. CYP2C19 dependent pharmacogenetics of (S)- and (R)-citalopram P. Baumann, R. Nil, A. Souche, M. Brawand-Amey, M. Jonzier-Perey, C.B. Eap University Department of Adult Psychiatry, CH-1008 PrillyLausanne, Switzerland, Lundbeck (Schweiz) AB, Switzerland The introduction of escitalopram ((S)-citalopram (S-CIT)) represents the first example of a ``chiral switch’’ in psychopharmacology1. (S-CIT) rather than R-CIT is the clinically active enantiomer. The N-demethylation of the racemic citalopram (CIT) occurs partly by CYP2C192,3, which in vitro N-demethylates S-CIT preferentially to R-CIT4. The role of CYP2C19 in the stereoselective N-demethylation of CIT in depressive patients treated with CIT was examined in a study where the clinical effectiveness of lithium was examined in CIT non-responders4 . 69 depressive patients were treated with CIT for at least 4 weeks4. At baseline (CYP2C19 phenotyping) and Day 14, pharmacogenetic and pharmacokinetic data were available from 63 patients. Six and 57 patients were poor (PM) or extensive (EM) metabolizers (CYP2C19), respectively.

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Trough plasma concentrations of CIT and its metabolites were measured after a 14-day treatment with CIT (40 mg/ day). Results presented in the Table, as well as the calculated N-demethylation ratios of (S)- and (R)-CIT (not shown), show that in PMs the metabolism of S-CIT is impaired. The ratio (S)-CIT/(R)-CIT allows the discrimination of EMs from PMs. These in vivo data confirm the stereoslectivity of CYP2C19 in the metabolism of racemic CIT. Means+s.d. (range) EM CYP2C19 (n=57) PM CYP2C19 (n=6)

S-CIT (mg/L)

R-CIT (mg/L)

(S)-CIT/ (R)-CIT

25+11 (4755) 74+28 (507126)

47+15 (14789) 73+24 (507117)

0.51+0.14 (0.2270.86) 1.00+0.05 (0.9471.08)

References 1. Baumann, P., Zullino, D.F., Eap, C.B. (2002) Eur. Neuropsychopharmacol. 12: 433 ± 444. 2. Rochat, B., Amey, M., Gillet, M., Meyer, U.A., Baumann, P. (1997) Pharmacogenetics 7:1 ± 10. 3. Sindrup, S.H., Brùsen, K., Hansen, M.G.J., et al. (1993) Ther Drug Monit 15:11 ± 17. 4. Baumann, P., Nil, R., Souche, A., et al. (1996) M. J. Clin. Psychopharmacol . 16:307 ± 314.

P05. Escitalopram is well tolerated and more efficacious than citalopram in long-term treatment of moderately depressed patients L. Colonna, E.H. Reines, H.F. Andersen University Hospital, Rouen Cedex, France Efficacy advantages for escitalopram versus citalopram in severely depressed patients have previously been established. However, moderately depressed patients constitute the majority of depressed patients seen in general practice. This paper examines the effect of treatment with fixed doses of escitalopram versus citalopram in this patient population. Patients with Major Depressive Disorder were randomized into a 24-week double-blind period, where they received 10mg/day escitalopram or 20mg/day citalopram. The mean change from baseline in MADRS total score showed that escitalopram (n=85) was numerically better at all time points compared to citalopram (n=85) and demonstrated a statistically significantly superior therapeutic effect at many visits, including Week 8 (p=0.02) and Week 24 (p=0.04). At Week 8, compared with citalopram, escitalopram showed a significantly higher response rate (550% reduction in MADRS total score) (75% with escitalopram versus 58% with citalopram, p=0.002) as well as a significantly better remission rate (MADRS total score 412) (75% with escitalopram versus 53% with citalopram, p50.001). Both escitalopram and citalopram were safe and well tolerated. Statistically significantly more patients in the citalopram group than in the escitalopram group withdrew

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from the study (31% with citalopram and 12% with escitalopram, p50.01). The overall adverse event profile for escitalopram was similar to that for citalopram. However, the higher withdrawal rate in the citalopram group was especially pronounced from Week 8 to Week 24 (19% with citalopram and 4% with escitalopram p=0.004), suggesting better long-term tolerability for escitalopram. This study demonstrates that 10 mg/day escitalopram shows significant clinical superiority to 20 mg/day citalopram in the treatment of moderately depressed patients. P06. Role of BDNF in the ventral tegmental area in the development of dopaminergic behavioural supersensitivity induced by chronic imipramine P.S. D’Aquila, F. Panin, P. Serra, A. Sini, A. Fresu, M. Collu, G. Serra Dipartimento di Scienze del Farmaco, UniversitaÁ di Sassari, Sassari, Italy Chronic treatment with antidepressant drugs results in the potentiation of dopaminergic neurotransmission, as revealed by an increase of the locomotor stimulant response to dopamine agonists. Given the role of dopamine in the control of reward-related behaviours, which are impaired in depression, it has been suggested that such potentiation might play an important role in the antidepressant therapeutic effect. Recent observations have shown that chronic administration of antidepressant drugs results in an increased synthesis of brain derived neurotrophic factor (BDNF) in different brain areas. Moreover, intra-cerebral infusion of BDNF results in an antidepressant effect in animal models of depression. The aim of this study was to determine whether BDNF in the ventral tegmental area (VTA) is involved in the development of dopaminergic behavioural supersensitivity induced by antidepressant treatment. Male Wistar rats were subjected to a three weeks treatment with either imipramine (2610 mg/kg/die) or vehicle. After the first week of treatment intracerebral cannulae were placed into the proximity of VTA of each subject (AP 75.3, DV 78.4, ML 0 from bregma). The cannulae were connected to a subcutaneous osmotic pump placed in the interscapular region delivering for two weeks either BDNF antisense oligonucleutide (TGGTAATTTTCCCCTTCT) or a non-sense oligonucleotide (TAGTGATCAGTCTTCTGC). Twenty-four hours after the end of treatment the subjects were placed into an apparatus for the measurement of motor activity and challenged with the dopamine D2-like receptor agonist quinpirole. Imipramine treatment potentiated the locomotor response to quinpirole, and this potentiation was prevented by BDNF antisense oligonucleotide infusion into the VTA. These results show that BDNF synthesis in the VTA is necessary for the development of dopaminergic behavioural supersensitivity induced by chronic treatment with imipramine.

P07. Duloxetine is effective in reducing anxiety symptoms associated with depression M.J. Detke1 , D.L. Dunner2 , C.H. Mallinckrodt1 , Y. Lu2 , D.G. Perahia3 1 Lilly Research Labs, Indianapolis, IN, USA, 2Univ. of Washington, Center for Anxiety and Depression, Seattle, WA, USA, 3 Eli Lilly and Company, Windlesham, UK This study investigated the effect of duloxetine on the symptoms of anxiety in depressed patients. This analysis summarizes anxiety outcomes from four multi-site, randomized, double-blind, placebo-controlled studies in which the primary objective was to assess the efficacy of duloxetine in treating major depressive disorder. Study 1 included duloxetine 120 mg/d (administered as 60 mg BID), fluoxetine 20 mg/d, and placebo. Study 2 included duloxetine 40 mg/d (administered as 20 mg BID), duloxetine 80 mg/d (administered as 40 mg BID), paroxetine 20 mg/d, and placebo. Studies 3 and 4 included duloxetine at 60 mg QD and placebo. All studies included the 17-item Hamilton Depression Rating Scale (HAMD17) as the primary efficacy measure. Therefore, anxiety was assessed in all studies using the HAMD anxiety/somatization subfactor and the anxietypsychic item (item 10). Studies 1 and 2 also included the Hamilton Anxiety Rating Scale (HAMA) and the HAMA total is analyzed. In all four studies, duloxetine had significantly greater mean change from baseline to endpoint on the HAMD17 total score compared with placebo. Mean changes on the HAMD anxiety/somatization subfactor were significantly greater for duloxetine compared with placebo in 3 studies, and were significantly greater for duloxetine than for fluoxetine and paroxetine in Studies 1 and 2, respectively. Mean changes on HAMD Item 10 were significantly greater for duloxetine compared with placebo in 3 studies, and were significantly greater for duloxetine than for fluoxetine in Study 1. In Study 2, mean change on the HAMA total score was significantly greater for both doses of duloxetine compared with placebo. Mean changes for the low dose duloxetine group (40 mg/d) were equal to or greater in magnitude than the corresponding mean changes for paroxetine on all three measures of anxiety, as well as on the HAMD17 total score. Duloxetine effectively reduced the symptoms of anxiety in patients with major depressive disorder in 4 randomized, controlled clinical trials. P08. Duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, exhibits excellent cardiovascular safety M.J. Detke1 , M.E. Thase2 , C. Wiltse1, B.A. Pangallo1 , E. Perrin3 1 Lilly Research Laboratories, Indianapolis, IN, USA, 2 Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA, 3Eli Lilly and Company, St. Cloud, France Many antidepressant medications are associated with adverse cardiovascular effects that restrict use, particularly in the elderly or patients with preexisting cardiac

IFMAD Abstracts

dysfunction. This study examined the effects of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on cardiovascular safety (heart rate, blood pressure (BP), and ECG intervals). Data from 7 double-blind placebo-controlled trials were pooled (duloxetine at 40 ± 120 mg/d, n=1032; placebo, n=723). Patients were treated for up to 12 weeks. Duloxetine had a mean increase in heart rate of 1.5 beats per minute (bpm) compared with a 0.5 bpm decrease for placebo. Mean changes in supine systolic and diastolic BP for duloxetine-treated patients were 1.2 mm Hg and 1.5 mm Hg, respectively. There were no significant differences between duloxetine and placebo treatment groups in the incidence of sustained elevations (at least 3 consecutive visits) in systolic (duloxetine, 0.5%; placebo, 0.2%), diastolic (duloxetine, 0.3%; placebo, 0.2%), or either BP (duloxetine, 0.7%; placebo, 0.4%). Differences in QTc, PR and QRS intervals between duloxetine and placebo were not significant. These data demonstrate that duloxetine has minimal effects on heart rate, blood pressure, and ECG intervals which do not appear to be clinically significant. These data indicate that duloxetine may have a favorable cardiovascular profile and warrant further study in patients with pre-existing heart disease. P09. Evaluation of duloxetine in the treatment of depression M.J. Detke1 , Y. Lu1 , P. Tran1 , C.H. Mallinckrodt1 , C. Wiltse1, D.G. Perahia2 Lilly Research Laboratories, Eli Lilly and Company, 1 Indianapolis, IN, USA, 2 Windlesham, UK Despite great advances in the treatment of depression and anxiety, many areas for improvement remain: slow onset of action, only two-thirds respond, and only one-third remit. Therapies with combined serotonin (5-HT) and norepinephrine (NE) activity may be more effective treatments for MDD than therapies that act on a single neurotransmitter (5HT). To evaluate this, the results from three clinical trials assessing duloxetine, a potent and balanced reuptake inhibitor of 5-HT and NE, are reviewed. The antidepressant efficacy of duloxetine was assessed in two 8-week, and one 9-week, randomized, double-blind, placebo-controlled studies in outpatients with MDD using HAMD17 total score (primary), MADRS, CGI, and PGI scales. Duloxetine was studied in doses ranging from 40 mg to 120 mg/day. In all studies, duloxetine (40 ± 120 mg/day) was superior to placebo in change on HAMD17 total score. In the first study, duloxetine 120 mg/day was numerically superior to fluoxetine on the primary and most secondary efficacy outcome measures. The estimated probability of remission was 56% for duloxetine, 30% for fluoxetine, and 32% for placebo. In the second study, duloxetine 80 mg/day, but not 40 mg/day, resulted in a significantly greater reduction in HAMD17 total score compared with Paxil. The estimated probability of remission for duloxetine (80 mg/day) was 57% compared with 34% for Paxil, and 25% for placebo. In the

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third study, duloxetine (60 mg QD) had an estimated probability of remission of 44%. These data suggest that dual reuptake inhibition of 5-HT and NE by duloxetine may offer greater therapeutic efficacy in the treatment of depression. P10. Alleviation of painful physical symptoms associated with depression ± association with higher remission rates? M.J. Detke1 , M. Fava2 , M. Wohlreich1 , C.H. Mallinckrodt1 , D.G. Perahia3 1 Eli Lilly and Company, Indianapolis, IN, USA, 2 Depression Clinical and Research Program, Massachusetts General Hospital, and Harvard Medical School, USA, 3Eli Lilly and Company, Windlesham, UK Depression is a recurrent, often chronic disease consisting of psychological and physical symptoms. While psychological symptoms have been clearly shown to respond to current antidepressants, physical symptoms may not be as responsive. Treating both psychological and physical symptoms of depression may lead to a higher percentage of patients reaching remission. Efficacy data were pooled from two identical but independent 9-week randomized, double-blind clinical trials of duloxetine 60 mg QD (n=244) and placebo (n=251). Efficacy measures included the 17item Hamilton Rating Scale for Depression (HAMD17) total score, HAMD17 Maier subfactor, Clinical Global Impression of Severity (CGI-S), Patient Global Impression of Improvement (PGI-I), and Visual Analog Scale for overall pain (VASOVER). Higher scores (increased severity) for overall pain were associated with lower estimated probabilities of remission both before and after accounting for the core emotional symptoms of depression (Maier subscale) (p40.0001). The Week 9 means for VASOVER were 13.0 for remitters (last observed value for HAMD1747) compared with 22.7 for non-remitters (p50.001), respectively, representing an approximately four-fold greater change in remitters. The depression remission rate for pain responders (improvement in VASOVER from baseline to last observation 550%) was twice the rate of remission of pain non-responders (36.2% vs. 17.8%, p50.0001). Lower pain scores (at endpoint?) were also associated with more favorable outcomes on the CGI-S and PGI-I. Early favorable responses in VASOVER were associated with favorable endpoint outcomes. These results suggest that patients treated with duloxetine 60 mg QD whose painful physical symptoms resolved demonstrated higher rates of remission. P11. Safety and tolerability of the antidepressant duloxetine M.J. Detke1 , P. Tran1 , C.H. Mallinckrodt1 , E. Perrin2 1 Eli Lilly and Company, Indianapolis, IN, USA, 2Eli Lilly and Company, St. Cloud, France The aim of this study is to examine the safety and tolerability of the antidepressant duloxetine, a potent and

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IFMAD Abstracts

balanced dual reuptake inhibitor of serotonin and norepinephrine, across multiple clinical trials. Data from seven double-blind placebo-controlled trials were pooled for analyses (duloxetine at 40 ± 120 mg/,d n=1032; placebo, n=723). Patients were treated for up to 12 weeks. Discontinuation due to adverse events was 14.6% and 5.0% for the duloxetine and placebo groups, respectively. Treatment-emergent adverse events with an incidence for duloxetine of 55.0% and twice the rate of placebo were nausea, dry mouth, fatigue, dizziness, constipation, somnolence, decreased appetite, and sweating. Mean baseline to endpoint changes in supine systolic and diastolic blood pressure for duloxetine-treated patients were approximately 1.5 mm Hg, and did not increase markedly by dose. The incidence of treatment-emergent elevated blood pressures (diastolic590 or systolic5140, and change from baseline 510) at endpoint for duloxetine-treated patients (doses pooled) were 6.9% and 4.4% for systolic and diastolic BP, respectively. Corresponding rates in the placebo group were 3.3% and 2.3%. No significant differences existed between duloxetine and placebo treatment groups in the incidence of sustained BP elevations (at least 3 consecutive visits) in diastolic (duloxetine, 0.3%; placebo, 0.2%), systolic (duloxetine, 0.5%; placebo, 0.2%), or either (duloxetine, 0.7%; placebo, 0.4%). Duloxetine did not increase corrected QT interval and the incidence of abnormal increases in QTc (change from baseline 530 msec) were 4.2% and 5.3% for duloxetine- and placebo-treated patients, respectively. No significant differences existed between duloxetine and placebo in the incidence of treatment-emergent abnormal laboratory values at endpoint. The difference in mean change from baseline to endpoint in ASEX total score was not significantly different between duloxetine and placebo. Collectively these data indicate that duloxetine is safe and well tolerated. P12. Patients with borderline personality disorder with and without affective disorder S. Egli, L. Valach, M. Neuenschwander, H.-J.Haug Psychopathology, University of Zurich, Lenggstr. 31, 8029 Zurich, Switzerland It has been suggested that borderline personality disorder (BPD) and affective disorders (AD), such as depressive disorder, dysthymia and bipolar affective disorder, often cooccur and are difficult to distinguish (Gunderson, 2001). The aim of this contribution is to examine whether the BPD patients without AD differ from those BPD patients with AD in their socio- demographic and clinical characteristics. The hospital records since 1995 of all in-patients of the psychiatric clinics in the canton Zurich were computed. The records of those patients, who were diagnosed with BPD (on discharge) were included in the analysis (n=1556). One group contained patients with BPD and without affective disorder (n=749) and the other group

consisted of all BPD who were also diagnosed affective disorder (1st axis or first diagnosis (n=208)). These two groups of patients did not differ in gender (males 19.6% vs. 21.2%), in their marital status and in the frequency of self injurious behaviour (6.14% vs. 5.29%). However, we found differences in age (the BPD patients with an AD were older [mean 34.5 years, SD 10.0 vs. mean 32.3, SD 9.7]) and more of them lived at home prior to their hospitalisation (83.7% vs. 76.0%). For nearly twice the number of the patients with BPD and AD this target hospitalisation was their first one (11.1% vs. 6.8%). However, the BPD patients with AD stayed significantly longer in the in-patient treatment than the BPD without AD (mean rank=543.6 vs. mean rank=461.1). Also there were significantly more of the patients with BPD without AD staying less than a week than of the patients with BPD with AD (22.7% vs. 11.5%). These data indicate that the BPD patients with AD represent a group which partly differs in socio- demographic and clinical characteristics from the BPD patients without AD as they are recognized and treated differently. P13. Levetiracetam in the treatment of acute mania A. Forsthoff2, J. Langosch1, G. Schaub3 , J. Walden1, H. Grunze 2 Department of Psychiatry of the Universities 1 Freiburg and 2 Munich, and 3 Municipal Hospital of Zwickau, Germany Several old and new antiepileptic drugs have shown efficacy as mood stabilizers in the treatment of bipolar disorders. Levetiracetam is a novel antiepileptic drug with a broad spectrum of efficacy in epilepsy (Hovinga, 2001). A first single case report also indicated a antimanic effect of 2500 mg/day levetiracetam (Goldberg & Burdick, 2002). The aim of this investigation was to test the antimanic efficacy of levetiracetam in an open add-on trial to haloperidol applying an on-off-on design.10 bipolar I acutely manic inpatients were included. All patients were treated with 5 to 10 mg/day haloperidol, depending on tolerability, throughout the investigation. Levetiracetam (up to 4000 mg/day) was added until day 14, then discontinued and reintroduced at day 21. The psychopathological changes were assessed with the YMRS, the 21-item HAMD (HAMD-21) and the Clinical Global Impression scale, version for bipolar patients (CGI-BP). As a result, there was a mean decrease of the YMRS scores from 29.6 to 17.2 during the first ``on’’ phase, manic symptoms worsened during the ``off’’ period (YMRS score 20.9) and ameliorated again during the second ``on’’ phase with a decrease of the mean YMRS score to 14.7 at the end of the study. The mean dose of levetiracetam was 3125 mg/day. At day 14 only 20% of the patients were responders (deefined as a decrease of YMRS scores of 50%) compared with 70% responders at the end of the study at day 28. In conclusion, these results from this open on-off-on add-on study suggest

IFMAD Abstracts

that levetiracetam exhibited additional antimanic effects. As the onset of action appears not very fast, it may not be a first choice drug for the treatment of acute mania. However, it may be a suitable alternative for patients with mild manic syndromes and possibly for the prophylaxis of mania. It will be the task of future controlled trials to consolidate this impression. P14. Effects of training on non-selected personell regarding subjective coping strategies A. Jensen1 , R.J. Vñrnes2, L.M. Salhus3 1 Fredrikstad County Hospital, 2Nutec Crisis Management, 3 Human Factor Office, SAS Flight Academy, Norway The defense-concept has existed in ego psychology since Freud, and has been used extensively as an explanatory concept in clinical work. Defense is most likely to occur when no means of coping is available and the level of fear is high. The defensive distortion of the danger reduces efficiency in handling the dangerous situation. Defense is a filtering mechanism different from coping. It covers cognitive mechanisms that distort, deny or explain away threatening stimuli. This makes defense a strategy which may be rather dangerous to use, in particular when the stimulus really is signaling physical danger. The aim of the study was to see how coping occurred during a fear provoking situation and how defense interfered with personality factors. Offshore oil workers are trained to escape from platforms in a free fall lifeboat. The boat has 60 seats and accelerates from 0 ± 80 km/h within 2.4 seconds when falling. The participants are strapped by three safety belts. The aim is to establish confidence in the free fall concept. In the advanced course (level II) the aim is to train employees to be pilots of the boat in an emergency situation. The level III course take place one year after the level II course and is mandatory for the free-fall lifeboat pilots. There was no significant difference between defense mechanism, locus of control and trait among the groups in level II (n=23)and III (n=40). To investigate the students it was used measurements of defense, locus of control, trait-anxiety, state-anxiety, accept-index, cognitive test and cortisol. 1. The students at the level III course had a significant higher anxiety than the level II course and there were no difference in acceptance of the boat, cognitive performance test inside the boat and cortisol between the two groups. This indicates that there had been no training effect between the level II and level III course. 2. The correlation analysis showed that the level II course activated their defense mechanism during the fall and especially when they were strapped in they used regression as a ``coping’’ strategy. The more advanced students (level III) activated their defense strategies on arrival and when checking the boat. The fact that the more advanced students activated their defense mechan-

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ism earlier can indicate a training effect and a kind of ``work of worry’’ as described in other studies Our results suggests that additional training had no effect on performance, but created higher anxiety among those students you should expect to be more confident and thus have less fear. This study also shows that more experienced students activates different defense mechanisms at different stages during this fear provoking situation than inexperienced students. The need for a more deliberately aimed training to produce free-fall pilots is present, and we suggests a selection process that reflects psychological profiles. P15. Luteal phase treatment of fluoxetine in premenstrual dysphoric disorder (PMDD): Effect on sexual functioning S. Kornstein, C. Miner, E. Brown, J. Dillon VCU Mood Disorders Institute, Richmond, VA, USA Aim: The effect of luteal phase fluoxetine treatment on sexual functioning was evaluated in a multicenter, randomized, double-blind, placebo controlled trial of fluoxetine in 260 women with PMDD. Methods: Following a 2-cycle screening and a 1-cycle single-blind placebo period, 260 women received fluoxetine 10 or 20mg/day, or placebo (each dosed for 14 days prior to the next expected menses through the first full day of menses) for 3 cycles. Assessments included the Arizona Sexual Experience Scale (ASEX) (baseline and endpoint) and treatment-emergent adverse event reports (solicited at each visit). ASEX data were analyzed by analysis of variance using last-observation changes from baseline to endpoint. Results: Data from 222 women were analyzed. Mean changes in ASEX total scores were not significantly different among the 3 groups (placebo 0.74, fluoxetine 10mg 0.81, fluoxetine 20 mg 1.21; overall p=0.863). No women discontinued the trial due to sexual adverse events. `Libido decreased’ was reported by more women receiving fluoxetine than placebo (fluoxetine 10mg 6%, fluoxetine 20mg 9%, placebo 0%; overall p=0.007). Conclusion: Luteal phase dosing of fluoxetine effectively treats PMDD, and produces similar changes in sexual functioning, assessed by a scale utilized specifically to measure sexual functioning, to that of placebo. P16. Enhancing mental health awareness in children (6 ± 12 years) B.A. Lauria-Horner, S.P. Kutcher, S.J. Brooks Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada Aims: This study aimed to enhance the awareness, understanding and knowledge of mental health/illness issues in elementary school children (grades 1 ± 7; 6 ± 12 years of age; total n=169) in a linguistically and geographically

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isolated francophone community located in a rural and fairly remote region of a predominantly anglophone Canadian province. Methods: A novel, school-based curriculum on mental health/illness was developed for implementation by the children’s normal grade teachers. It contained four modules: Normal emotional development; Depression; Anxiety disorders; and Attention-deficit/hyperactivity disorder (ADHD). Each module contained key information to be imparted to students and a variety of classroom activities to elicit thinking and discussion about the issues and to reinforce the new information (e.g. matching pictures to statements, role-plays, discussions of what to do in `problem scenarios’). The curriculum was delivered in French (the school’s normal language of instruction) 4 ± 5 hours per week for 4 months. Children and teacher’s knowledge and attitudes concerning mental health/illness were surveyed before curriculum implementation (baseline) and post-implementation, by means of focused group discussions conducted with teachers and children from all 7 grades and self-report questionnaires completed by all students in grades 4 to 7 and teachers from grades 1 to 7. Results: Baseline data from the children revealed very little accurate knowledge about mental health/illness and fairly prevalent negative/unhelpful attitudes regarding mental illness. Post-implementation data indicated statistically significant gains in knowledge about depression, anxiety and ADHD (including what a child should do on noticing warning signs in him/herself) and suggested significant improvements in attitude towards people with these disorders. Conclusions: Elementary school children are capable of comprehending mental health and aspects of depression, anxiety and ADHD. They are also receptive to information that appears to improve their attitudes towards people with these disorders, and to instruction on the appropriate actions to take on noticing the warning signs for these disorders. P17. Gad in the elderly ± is there evidence of safe and effective drug treatments? M.G. Livingston, H.M. Livingston Department of Psychiatry, Southern General Hospital, Glasgow G51 4TF, UK Elderly people have a high incidence of mental disorders and are frequently prescribed psychotropic drugs (Preville, Hebert and Boyer et al, 2001). Despite this, relatively few controlled studies specifically address the issue of the response of this population to drug treatments (Livingston and Livingston, 1999). There are several reasons for such a lack. Older patients may be unsuited for trials due to concurrent illness and/or the prescription of other medication. Researchers and sponsoring pharmaceutical companies are often concerned about their inclusion, as they may be especially prone to develop side effects. Furthermore, some elderly people may be unable to give informed consent to

participation in a study. As many as 10 ± 20% of elderly people expeirence clinically significant anxiety (Banazak, 1997). The treatment of choice is often a psychotropic agent such as benzodiazepines, antidepressants and antipsychotics. The use of these drugs for anxiety in older patients is based on extrapolation from trials of the treatment of anxiety disorders in younger people. We reviewed the available literature to determine which treatments for generalised anxiety disorder are safe and effective for use in patients over the age of 65. We found very few randomised controlled trials in elderly patients with anxiety and there is therefore an urgent need for carefully performed trials in this area. References 1. Preville M, Hebert R, Boyer R et al (2001). Correlates of psychotropic drug use in the elderly compared to adults aged 18 ± 64: results from the Quebec Health survey. Ageing Mental Health; 5(3): 216 ± 224. 2. Livingston MG and Livingston HM (1999). New antidepressants for old people? (Editorial) British Medical Journal; 7199: 1640 ± 1641. 3. Banazak DA (1997) Anxiety disorders in elderly patients. J Am Board Fam Pract 10: 280 ± 289.

P18. Involvement of dopamine d4 receptors in naloxoneinduced morphine withdrawal syndromes with morphine in mice T. Mamiya, T. Matsumura, M. Ukai Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan In this study, we examined whether dopamine D4 receptor is involved in morphine dependence in mice. Mice pretreated with morphine (10 mg/kg, s.c.) twice a day for five days showed withdrawal syndromes such as jumping, rearing and forepaw tremor following the administration of naloxone (5 mg/kg, i.p.) on the sixth day. Such mice exhibited a significant elevation of cAMP levels in the thalamus compared to the control mice. Co-administration of L-745,870 (1 mg/kg, i.p.), a selective dopamine D4 receptor antagonist with morphine on the 6th day significantly attenuated the severity of withdrawal syndromes and the increase in cAMP levels after the administration of naloxone. These results suggest that (i) the elevation of cAMP levels is involved in the expression of withdrawal syndromes with morphine, and (ii) dopamine D4 receptor antagonists inhibit the expression of withdrawal syndromes with morphine accompanied with biochemical changes in mice. Furthermore, dopamine D4 receptor antagonists may be useful drugs for attenuating the expression of morphine dependence. Acknowledgments : This study was supported in part by Grants-in-Aid for Scientific Research, Scientific Frontier Research Project and High-Tech Research Center Project from Ministry of Education, Culture, Sports, Science and Technology, Japan.

IFMAD Abstracts

P19. Depression ± multidimensional psychotherapy approach A. Martischnig, N. Habsa, B. Steinbrenner, M. SchoÈnauer-Cejpek, M. Steinbauer Department of Psychiatry, University of Graz, Austria Background: The incidence of depression has increased greatly in recent years. The concept of Integrated Painting Therapy is a multidimensional patient-orientated approach, which includes psychopharmacological, psychotherapeutical and psychosocial strategies. Biological, physiological and socio-cultural influences are discussed as etiological factors. The aim of this study was to assess the clinical effectiveness of this psychotherapeutic concept applied to inpatients suffering from major depression, at the Department of Psychiatry. Methods: The subjects of this study were 25 female inpatients of the Department of Psychiatry at University of Graz, who meet the DSM-IV criteria for major depression. Patients were evaluated at the beginning and at the end of the hospital stay. All subjects underwent interviews with the Beck Depression Inventory, the Symptom Check List, the State-Trait-Anxiety Inventory and Body-Image Inventory. Results: At the beginning of the study the mean score of the Beck Depression Inventory was 29.8 (SD=13.2) and significantly decreased to 10.1 (SD=10.2) at the end of the stay. Furthermore, subscales of the symptom checklist presented a similar result for example, the mean score of somatisation decreased from 17.6 (SD=8.8) to 6.5 (SD=5.9) and the mean score of compulsion decreased from 19.7 (SD=5.9) to 7.8 (SD=6.9). In addition, the mean score of anxiety decreased significantly from 59.4 (SD=12.2) at the beginning of the study to 40.1 (SD=15.9) at the end. Interestingly, patients exhibited more vitality at the end of hospital stay (Body-Image Inventory). Conclusion: Our data indicate that the concept of Integrated Painting Therapy represents a very suitable and effective tool in the treatment of depression. P20. Milnacipran is effective in treating depression associated with Parkinson’s disease T. Maruyama Department of Medicine (Neurology), Iida Municipal Hospital, Iida City, Japan The purpose of this study was to clarify the clinical effect of milnacipran for treating anhedonia and apathy, symptoms of depression associated with Parkinson’s disease (PD). Eight patients (3 male, 5 female; mean age: 61.6+9.1 years) diagnosed with PD and determined to have depressive disorders without psychosis according to the Hamilton Rating Scale of Depression (HAMD-17; score 413) were included in this study. All the patients suffered from depression (mean initial HAM-D 17 score: 20.6+5.6) to the extent that it damaged their quality of life (QOL), although their motor symptoms were well

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controlled. The mean disease duration and mean motor score of the Unified Parkinson Disease Rating Scale (UPDRS) were 6.5+2.6 years and 10.7+4.4, respectively. The patients were taking various types of antiparkinsonian drugs, such as levodopa/DCI, dopaminergic agonists (bromocriptine, pergolide, cabergoline) and amantadine, except selegiline (MAO-B inhibitor). The patients did not take psychotic drugs for at least 14 days before entry into the trial and were not given any other psychotropic drugs except occasional hypnotics throughout the 12-week milnacipran treatment. Milnacipran was administered twice daily (after breakfast and before bedtime) starting at 30 mg/day in the second week and thereafter adjusted as necessary up to 60 mg/ day. Parkinsonian and depressive symptoms were evaluated using the HAM-D 17, the Hamilton Rating Scale of Anxiety (HAM-A), the Snaith ± Hamilton Pleasure Scale (SHPS), and the Marin’s Apathy Scale (MAP) before treatment and at weeks 2, 4, 8, and 12 of the study. All adverse events including worsened parkinsonism were monitored throughout the trial. One patient dropped out of the clinical trial after experiencing palpitations and agitation. None of the patients had worsened parkinsonian motor dysfunction (UPDRS). Milnacipran therapy was significantly effective in 6 patients (75%) for total score of HAM-D 17 and inclined to be effective in one patient. Apparent antidepressant effects were seen in many patients beginning in week 4. Noticeably, the specific symptoms of parkinsonian depression anhedonia and apathy, improved significantly from baseline to final evaluation. These results demonstrated the usefulness and safety of milnacipran in the treatment of depressive patients with PD. Firstly, milnacipran had an effect on the specific depressive symptoms of anhedonia and apathy in PD. Secondly, milnacipran had few adverse drug-drug interactions, although patients received multiple antiparkinsonian drugs. Milnacipran is considered a first-choice medication for the treatment of parkinsonian depression. P21. Six month compliance with fluoxetine or paroxetine treatment in depressed outpatients K. Demyttenaere, P. Mesters, W. Dewe, B. Boulanger, K. De Bruyckere, M. Sangeleer, A. De Nayer, L. De Weirdt, F. Janssen, C. Reynaert, D. Steemans, E. Verhaeghen University Hospital Gasthuisberg, Department of Psychiatry, Herestraat 49, 3000 Leuven, Belgium Introduction : An adequate duration of antidepressant treatment for a depressive episode, i.e. 6 months, is often not reached. Moreover, previous research demonstrated that the adherence (the regularity of intake of an antidepressant) of patients varies widely during acute treatment, compromising the efficacy of the treatment. Materials and Methods: Compliance with fluoxetine 20 mg (N=42) or with paroxetine 20 mg (N=43) was

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IFMAD Abstracts

investigated in a double-blind, randomised, multicentric study. After a one-week placebo lead-in, patients with the DSM-IV diagnosis of major depressive disorder were followed for 6 months or till drop-out status. Adherence was assessed electronically with the Medication Event Monitoring System (MEMS). The 17-item HAMD was used to assess the efficacy of the antidepressant treatment. Results: Efficacy was comparable in both treatment arms: response rates after 7 and 23 weeks of active treatment were 54% and 74% for fluoxetine, 43% and 76% for paroxetine. 66% of the patients reached 6 months of treatment: there was no significant difference in rates of dropouts between fluoxetine and paroxetine users (17/42 and 12/43, fluoxetine and paroxetine, respectively). Completers were significantly older than drop-outs (P=0.004), were significantly more depressed (HAMD) at baseline (P=0.02) and showed a trend towards a lower quality of life (WHO-QOL) at baseline (P=0.06). The baseline impairment (Sheehan Disability Scale) however was comparable in completers and drop-outs. Adherence (% of days with a correct intake) decreased with time in fluoxetine as well as in paroxetine users but was significantly higher in completers than in drop-outs (P=0.003). Overall adherence was high in the acute phase (95.3%) as well as in the continuation phase (87.9%). An interesting finding is that in drop-outs but not in completers, patients with a higher underconsumption (at least 2 consecutive days without any pill intake) improved less on the HAMD. Discussion: Compliance and adherence were comparable in fluoxetine and paroxetine users. Adherence was higher in older patients and in patients with higher baseline severity. A lower adherence was predictive of becoming a drop-out and of improving less on the HAMD. P22. Escitalopram is at least as effective as venlafaxine xr in the treatment of depression and better tolerated S.A. Montgomery, A.K.T. Huusom, J. Bothmer Imperial College School of Medicine, London, UK The efficacy of escitalopram relative to venlafaxine (an SNRI) in the treatment of major depressive disorder (MDD) was assessed in a randomized, double-blind, non-inferiority study of standard dosages of venlafaxine XR and escitalopram. Patients in primary care with a MADRS total score 518 at baseline were included. Patients were randomized to 8 weeks of double-blind treatment with either escitalopram (n=148) or venlafaxine XR (n=145). Patients started with 10 mg/day escitalopram or 75 mg/day venlafaxine XR; if needed, the dose could be doubled after 2 or 4 weeks of treatment. Patients completing treatment entered a single-blind washout period to evaluate discontinuation symptoms. The primary efficacy variable showed that escitalopram was at least as effective as venlafaxine. Patients in both

treatment groups had mean baseline MADRS total scores of approximately 29, which decreased to less than 9 at Week 8. The response rate (550% reduction in MADRS total score) for escitalopram versus venlafaxine XR was numerically superior at all time points after Week 1. An exploratory time-to-response analysis showed a significant superiority of escitalopram relative to venlafaxine (p50.05). More patients treated with venlafaxine XR withdrew due to adverse events (11%) than did those treated with escitalopram (8%). Nausea was the most common adverse event, with a statistically significantly higher incidence for venlafaxine XR-treated patients (27% for venlafaxine XR and 17% for escitalopram, p=0.02). At the end of the washout period, significantly more venlafaxine XR-treated patients had a change in their discontinuation-emergent signs and symptoms score 54 (p50.01). In conclusion, escitalopram (starting at 10 mg/day) is a highly efficacious treatment for MDD, with numerical superiority on remission and response rates when compared with venlafaxine XR (starting at 75 mg/day), and with significant indications of better tolerability. P23. The clinical use of milnacipran for depression S. Morishita1, S. Arita2 1 Department of Psychiatry, Kawasaki Medical School, Kurashiki, Japan, 2 Department of Mathematics, Kansai Medical School, Hirakata, Japan Purpose: The purpose of this study was to examine the suitable dosage and appropriate trial duration of milnacipran for the treatment of depression and the predictors of the drug response. Methods: Thirty-two patients with depression were enrolled in an open trial over an eight-week period during which milnacipran was administered. We compared the dose-response and examined the initial significant clinical action and the predictors of response. Results: No difference was observed in response rate between the 50 mg and 100 mg daily dose. However, the cumulative improved percentage of the responding patients to a 100 mg daily dose was more than 80% after four weeks, while the same rate was not achieved even after six weeks in those receiving 50 mg. A Weibull regression analysis showed an age of thirty-nine years or younger and a first episode to be significant predictors of improvement. Conclusion: The present study demonstrated the optimal daily dose of milnacipran to be 100 mg as the initial dose. In addition, if a patient does not show an improvement by the end of four weeks, then the treatment regimen with milnacipran should be altered. Finally, both the patient age and frequency of episodes are considered to be predictors of the response to milnacipran treatment for depression.

IFMAD Abstracts

P24. Effects of milnacipran on anxiety and depression caused by workplace stress K. Nakayama Department of Psychiatry, Jikei University School of Medicine, Tokyo, Japan It has been suggested that changes in the workplace, changes of occupation or interactions with supervisors or colleagues can cause workplace stress. Such types of unavoidable persistent stress are factors not only for the occurrence of depression but also for recrudescence or a recurrence of depression. We are very concerned that many such patients may have chronic and prolonged depression. In this study, the author studied the usefulness and problems of milnacipran in patients who developed depression apparently due to workplace-related stress. We investigated 12 male patients diagnosed to have DSM-IV major depression apparently caused by workplacerelated stress. At the commencement of the study, all were rated as 18 points or over in the Hamilton Depression Score, and those who achieved a 20% reduction according to the score were assessed to have made an ``improvement’’, while those who achieved 10 ± 20% reduction in this score were assessed to have made a ``slight improvement’’ and those whose who achieved a less significant amelioration were assessed to have made ``no improvement’’. Of the 12 patients, five were assessed to have made an improvement, four a slight improvement and three no improvement. All the 12 patients had moderate depressive symptoms and mild inhibitory symptoms but had moderate to severe anxiety. The patients for whom milnacipran was effective had relatively mild depression and inhibitory symptoms but severe anxiety, and milnacipran was especially effective to alleviate their anxiety symptoms. Many of the patients for whom milnacipran was not effective had family-related or character-related problems. Mild urinary disturbance and diarrhea were observed as adverse reactions.The author had the impression that various types of workplace-related stress exacerbate anxiety symptoms in depressive patients. Milnacipran was especially effective for alleviating anxiety symptoms in patients suffering from depression. These findings indicate that the early use of milnacipran is effective for preventing chronic depression or a prolongation of depression in such patients. P25. Sleeping complaints in panic disorder patients T. Overbeek, F. Kruizinga, T. Baars, R. van Diest, K. Schruers, E. Griez Academic Anxiety Center, Psychiatric Hospital Vijverdal, Maastricht University, PO Box 88, 6200 AB Maastricht, The Netherlands Background: Panic disorder (PD) patients often report some kind of sleeping difficulties. Prevalence of subjective sleep quality was assessed in PD patients and compared to a group of matched healthy controls. Within the patient

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group we analyzed sleeping complaints and the role of comorbid depression, use of medication (specific serotonin reuptake inhibitors, SSRIs) and the occurrence of night panic attacks. Methods and Materials: Subjects were 70 PD patients and 70 healthy volunteers. The MINI 5.0.0. (Mini International Neuropsychiatric Interview) was used as screening instrument, and the SWEL (Sleep Wake Experience List) to assess the sleep difficulties. Results: PD patients experienced significantly more sleep difficulties than did healthy controls. The role of night panic attacks was important, but not the use of SSRIs nor, surprisingly, comorbid depressive disorder. Conclusion: Panic disorder patients do suffer more from sleeping complaints than normals. Sleep panic attacks partly explain these problems. P26. Symptom-profile of depression in OCD and panic disorder T. Overbeek, M. Kersemaekers, K. Schruers, E. Griez Academic Anxiety Center, Psychiatric Hospital Vijverdal, Maastricht University, PO Box 88, 6200 AB Maastricht, The Netherlands Background: The aim of this study was to compare the symptom-profile of comorbid depression in obsessivecompulsive disorder (OCD) with panic disorder (PD). Methods and Materials: Subjects were 30 OCD patients and 30 PD patients, all of them diagnosed with comorbid DSM axisI depressive disorder. The items of the Montgomery-AÊsberg Depression Rating Scale (MADRS) and the Zung Selfrating Depression Scale (SDS) were analyzed. Items were clustered in affective, somatic and cognitive symptoms. Results: Depressed OCD patients score significantly higher on the cognitive clustered items of the MADRS and SDS. OCD and PD patients do not differ on the affective and somatic item-clusters. Conclusion: Comorbid depression in OCD patients is characterized by more pronounced cognitive symptoms than depression in PD. There is no difference regarding somatic and affective symptoms. P27. Duloxetine in the long-term treatment of major depressive disorder J. Raskin1 , D.J. Goldstein2 , C. Mallinckrodt2, M.B. Ferguson 2, E. Perrin 3 Eli Lilly and Company, 1Scarborough, ON, Canada, 2 Indianapolis, IN, USA, 3St. Cloud, France Depression is a chronic recurring disorder and guidelines recommend long-term therapy. This clinical trial evaluated the long-term (1 year) safety and efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, in patients with major depressive disorder (MDD). This was an open-label, 52-week, multi-national clinical trial in outpatients (age

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IFMAD Abstracts

518) who received duloxetine at 80 mg (administered 40 mg twice daily) or 120 mg (administered 60 mg twice daily) for up to one year. Postbaseline data were available for a total of 1279 patients. Of these, 520 were exposed to duloxetine for at least 360 days, yielding approximately 808 patient-years of total exposure. Mean changes in Clinician Global Impression-Severity (CGI-Severity), Hamilton Depression Rating Scale (HAMD17) total score and subfactors, Beck Depression Inventory-II (BDI-II), Sheehan Disability Scale (SDS), and means for Patient Global ImpressionImprovement (PGI-Improvement) all showed highly significant (p50.001) improvements at all assessment times. The estimated probabilities of remission at weeks 6, 28 and 52 were 50.8%, 75.6% and 81.8%, respectively. Adverse events led to discontinuation in 218 (17.0%) patients. The most frequent specific events leading to discontinuation were nausea (1.5%), somnolence (1.4%), vomiting (0.9%), hypomania (0.8%), pregnancy (0.8), dizziness (0.6%), insomnia (0.6%), and hypertension (0.5%). Treatmentemergent adverse events that were reported by 410% of patients included nausea, insomnia, headache, somnolence, dry mouth, dizziness, constipation, sweating increased, anxiety, diarrhea, and fatigue. Mean changes in indices of cardiovascular function, body weight, and laboratory analytes were not clinically significant. Duloxetine is effective, safe, and well tolerated in the long-term treatment of MDD. P28. Escitalopram is efficacious and well tolerated in depressed patients in primary care E.H. Reines, H.Loft, U.Lepola H. Lundbeck A/S, International Clinical Research, Copenhagen, Denmark This primary care study compared the efficacy and safety of escitalopram and citalopram, the active reference, to placebo in patients with major depressive disorder. In all three groups, the mean MADRS total score at baseline was 29, indicative of moderate to severe depression. After a 1week, single-blind, placebo period, patients were randomized into an 8-week double-blind period where they received 10 mg/day escitalopram (n=155), 20 mg/day citalopram (n=160), or placebo (n=154), with the option of doubling the patient’s dosage after 4 or 6 weeks of treatment. The efficacy analysis of mean change in MADRS total score from baseline showed a statistically significantly superior therapeutic effect for escitalopram versus placebo with a treatment difference of 2.9 points (p=0.002) at Week 8 (LOCF). Further by-visit analysis of the change in MADRS total score at each week showed escitalopram to be statistically significantly superior to placebo from Week 1 onwards (OC). Additional efficacy analyses using the CGI-S and CGI-I scales showed a significant therapeutic effect (p40.05) for escitalopram versus placebo as early as Week 1 on each scale; this effect was sustained through to Week 8.

Escitalopram was very well tolerated with an adverse event profile that was at least as favourable as that for citalopram. The withdrawal rate from the study was 10% in the placebo group, 6% in the escitalopram group, and 5% in the citalopram group. The withdrawal rate (2.6%) due to adverse events in the escitalopram group was identical to that in the placebo group. This is one of two pivotal phase III studies conducted in primary care, both of which demonstrated escitalopram to be efficacious and well tolerated in treating patients with depression, thus establishing escitalopram as a first-line antidepressant in primary care. P29. Switching depressed patients from citalopram to escitalopram treatment is safe and effective E.H. Reines, L.E. Glesner, N. Despiegel H. Lundbeck A/S, International Clinical Research, Copenhagen, Denmark Escitalopram is a potent and highly selective SSRI, whose efficacy and safety in the treatment of major depressive disorder have recently been established. Depressed outpatients who completed treatment in an 8-week, doubleblind, placebo-controlled study with citalopram or escitalopram were given the option of continuing treatment with open-label escitalopram in an extension study. Patients received up to 52 weeks of escitalopram (10 to 20 mg/day) treatment. Continued improvement was seen, with further reductions in the MADRS and CGIS scores. The incidence of adverse events was further reduced during continued escitalopram treatment versus short-term treatment. No clinically significant mean changes in vital signs, ECGs, or laboratory values were observed in patients switching from citalopram to escitalopram treatment (n=52). Furthermore, no new clinically significant adverse events were observed in patients switching from citalopram to escitalopram treatment. Thus, if patients are switched from citalopram to escitalopram, there are no safety concerns, and depressive symptoms continue to improve. P30. In vitro and in vivo effects of citalopram and its enantiomers on the serotonin uptake transporter A. Mùrk1, M. Kreilgaard1, C. SaÁnchez2 , L.T. Brennum3 , O. Wiborg4 1 Dept. Neurochemistry & Discovery ADME, 2Dept. Neuropharmacology and 3 Dept. Molecular Pharmacology, H. Lundbeck A/S, Valby-Copenhagen, 4Institute for Basic Psychiatric Research, Psychiatric Hospital of Aarhus University, Denmark Escitalopram, the S-enantiomer of citalopram, mediates its serotonin (5-HT) reuptake inhibition and presumably the antidepressant and anxiolytic activity. This

IFMAD Abstracts

study aimed at investigating the effects of citalopram and its enantiomers on the brain 5-HT transporter (SERT). The selectivity of the compounds on monoamine transporters was tested in vitro. Furthermore, the modulatory effects of the compounds on extracellular levels of 5-HT were studied under in vivo conditions. The functional consequence of increased 5-HT levels was assessed measuring stimulation of the hypothalamus-pituitary-adrenal (HPA) axis. Finally, the in vitro effects of citalopram and its enatiomers on the human SERT were studied. The transporter selectivity was elucidated by studying uptake of 5-HT, dopamine and noradrenaline in rat brain synaptosomes. In vivo actions of citalopram on the SERT were determined by microdialysis on conscious rats by measuring extracellular 5-HT levels in the frontal cortex. The effect of citalopram on extracellular 5-HT was, furthermore, related to the extracellular level of citalopram in the brain. Animals were injected SC with the compounds. In some experiments, escitalopram was infused locally into the frontal cortex by reverse dialysis. Levels of 5HT and escitalopram in the brain dialysates were measured by HPLC-ECD and LC-MS-MS, respectively. The levels of escitalopram in the plasma were followed by continuous blood sampling. Stimulation of HPA axis was studied by measuring increases in plasma corticosterone using a RIA assay. Functional effects of the compounds in vitro were studied using the human SERT cloned into CHO cells. Escitalopram showed extremely high in vitro selectivity for 5-HT relative to dopamine and noradrenaline reuptake inhibition, indicating that escitalopram is the most selective 5-HT reuptake inhibitor (SSRI) among antidepressants developed for clinical use, including citalopram. The in vivo actions of escitalopram are discussed in relation to plasma and brain levels of escitalopram and relative to the in vitro potency. Furthermore, the results achieved for escitalopram are compared to those achieved for citalopram and the R-enantiomer, R-citalopram. It is concluded that escitalopram is an extremely selective 5HT uptake inhibitor both in vitro and in vivo. The potent effect of escitalopram on the human SERT, furthermore, suggests that the observations done in animal models also apply to the human brain. P31. Escitalopram potently reverses conditioned footshock-induced suppression of exploratory activity in rats ± an animal model of generalized anxiety C. SaÁnchez1, M. Papp2 1 Neuropharmacology, H. Lundbeck A/S, CopenhagenValby, Denmark, 2 Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland Selective serotonin reuptake inhibitors (SSRIs) are widely used for treatment of anxiety disorders. Escitalopram, the S-enantiomer of the SSRI citalopram, has recently been

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developed for treatment of depression and anxiety disorders. In vitro and in vivo studies in animals have demonstrated that escitalopram is the most selective serotonin reuptake inhibitor among antidepressants developed for clinical use, including citalopram. In the present study we have evaluated the anxiolytic potential of escitalopram in a rat model of generalized anxiety ± conditioned footshock-induced suppression of exploratory activity. The effect of escitalopram is compared with those of citalopram and the benzodiazepine diazepam. Wistar rats were habituated to the experimental room for two weeks. Four Opto-Varimex cages equipped with 15 infrared emitters and equivalent number of receivers on the opposite cage wall were used. The cage floor consisted of a metal grid connected to a footshock generator. The position of the rat was recorded 10 times per second. Locomotor activity was analysed by mean of the AutoTrack software and expressed as the accumulated distance travelled by the animal in a selected time interval. In an acquisition session (day 1) rats were allowed to freely explore the test cage for 9 min. During that time it received two inescapable footshocks (0.5 mA for 9 seconds) delivered in the second and fifth minutes of the session. Control animals that did not receive footshocks were placed individually in the apparatus for the same period of time. In the expression session (day 2) separate groups of the previously shocked rats and controls were injected IP with vehicle, escitalopram, citalopram or diazepam. After 30 min the rats were placed in the test cage and locomotion was recorded for 9 min omitting delivery of footshocks. All data were analysed by two-way analysis of variance followed by Newman-Keul’s post hoc test for comparison of means. Escitalopram dose-dependently reversed conditioned footshock-induced suppression of exploratory activity of rats. Similarly citalopram and diazepam attenuated the suppression of exploratory activity significantly. Escitalopram produced a higher maximum response than citalopram. Escitalopram, citalopram and diazepam did not affect exploratory activity of non-shocked controls. In conclusion, escitalopram is more effective than citalopram in this animal model of generalized anxiety. P32. Temperament and character determinants of a specific phobia S. Settineri, F. TatõÁ, L. Di Blasi, L. Gambacurta, L. Riggio Department of Neurosciences, Psychiatry and Anesthesiology, UniversitaÁ di Messina, Italy Objective: The aim of the study was to observe individual psychological aspects that may accompany fear of `the dentist’. Additionally, we examined more general psychological aspects that occur in the context of the dental care. In particular, we evaluated the role of temperament (expression of biological determinants) and the role of character (relational structure deriving from developmental experiences).

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IFMAD Abstracts

Method: 102 subjects were assessed by the Temperament and Character Inventory of C. Robert Cloninger, by the Self-liking and Self-competence scale of Swann & Tafarodi and through a questionnaire on dental problems and phobia of the dentist. Results: A factorial analysis was used to differentiate components of variables concerning personality, dental problems, `other representation’ individual problems and emotional modulation. Variance analysis illustrated that phobia is connected with character-specific variables concerning other-representation, with emotional determinants and with past dental experiences. Hypotheses on variables correlations were discussed. Conclusion: The study allowed us to highlight an interference on conditioned dental fear by means of symbolic and emotional elements. In addition we showed the importance of relational characteristics in defining dental-related problems of the patients. P33. Character of course of seasonal affective disorders G. Simutkin Mental Health Research Institute, Tomsk, Russia Objectives: To estimate specific weight of monopolar and bipolar course seasonal affective disorders (SAD). Materials and Methods: 133 patients (101 women [75.9%] , mean age 46.7+12.4 years and 32 men [24.1%], mean age 44.4+10.4 years) with recurrent depression (F33.1-F33.3) and bipolar affective disorder (F31.0-F31.6, F31.8) were examined. In this group, 41 patients (30.8%) showed signs of SAD according to DSM-IV criteria (33 women and 8 men). Results: Among the cases of SAD, the total share of bipolar affective disorder (type I and type II) was 51.2% (21 patients), and where a seasonal pattern was absent in the course of affective disorder 32.6% (30 patients). The reliable distinctions in the incidence rate at intergroup comparison (SAD vs. non-SAD) concerned only bipolar affective disorder (type I) ± P50.05 (Chi-squared test). Conclusions: dipole distribution of the whole complex of helio-geophysical factors within one year (winter ± summer, spring ± autumn) can be closely associated with pathogenesis of SAD and, probably, helps to the explain increase of specific weight of bipolar course in the case SAD. P34. Remifentanil vs. methohexital for electroconvulsive therapy P. Sullivan, E. Sinz, G. Hobbs, E. Glover, J. Cain, A. Kofke West Virginia University, Morgantown, WV, USA Aim: A retrospective comparison of the efficacy of 2 different anesthetic regimens for standard electroconvulsitve therapy (ECT) between November 1998 and June 2002.

Methods: Patients with severe recurrent major depression who presented for ECT were treated with a standard anesthetic regimen of methohexital 1 ± 2 mg/kg and succinylcholine 1 mg/kg. (Reg 1). All treatments used a MECTA SR-2 brief pulse machine. Stimulus dose was determined by the dose-titration method. Thirty-one patients refractory to maximal ECT settings then received remifentanil 125 ± 4,000 mcg and succinylcholine 1 mg/kg. (Reg 2). Remifentanil dose was based on patient unresponsiveness prior to succinylcholine. Results: Electroencephalograph (EEG) and motor seizure duration (cuff method) and dynamic energy (J) for the final 3 treatments using Reg 1 were compared with the first 3 treatments using Reg 2 by matched-pair T-test. Mean EEG seizure duration using Reg 1 vs Reg 2 was 40+18 vs. 66+32 sec (p50.0001). Mean motor duration using Reg 1 vs. Reg 2 was 27+20 vs. 48+21 sec (p=0.0002). Mean dynamic energy for Reg 1 vs. Reg 2 was 89+25 vs. 43+33 J (p50.0001). Conclusions : Remifentanil anesthesia decreases the electrical requirement for induction of seizure in ECT therapy compared to methohexital while providing an enhanced motor and EEG seizure. Lower electrical stimulation is associated with decreased cognitive impairment. Longer seizure duration provides faster resolution of psychiatric symptoms. In patients who are refractory to ECT therapy with methohexital anesthesia, remifentanil provides superior anesthetic conditions for ECT. P35. Comparison of milnacipran and fluvoxamine in the clinical treatment of major depression A. Sumiyoshi Sumiyoshi Clinic, Sagamihara, Japan In the present study, the efficacy and safety of milnacipran in the treatment of mood disorders, particularly major depression, were compared to those of fluvoxamine. The subjects of this retrospective study were patients who received milnacipran or fluvoxamine at our hospital within three months of its introduction. Case logs were compiled to keep track of dosage and adverse reactions. DSM-IV was used to assess the psychological state of these patients. Among the patients with mood disorders, changes in disease severity were assessed in order to determine the degree of overall improvement four weeks after the start of administration. During the study period, milnacipran was administered to 66 patients. Seven patients who did not return for their second visit were excluded (10.6%), and thus 59 patients served as subjects. Of these, 46 patients were diagnosed as having mood disorders, and 35 patients had major depression. Fluvoxamine was administered to 107 patients, and 19 were excluded for not returning for their second visit (17.8%), and thus 88 patients served as subjects. Of these, 57 patients were diagnosed as having mood disorders, and 29 patients had major depression.

IFMAD Abstracts

While the ratio of significantly improved cases was higher for fluvoxamine, the ratio of moderately and significantly improved cases was higher for milnacipran, and the ratio of unchanged, exacerbated and withdrawn (patients who did not return for their second visit) cases was higher for fluvoxamine. Adverse reactions were seen in 25 of the 59 patients taking milnacipran (42.4%) and in 37 of the 88 patients taking fluvoxamine (42.0%). The incidence of nausea for milnacipran (n=6, 10.2%) was comparable to that for fluvoxamine, but the severity of nausea was milder for milnacipran, and none of these episodes were severe enough to discontinue drug administration. There were only a few other gastroenterological symptoms. However, the incidence of headache was high (n=7, 11.9%), and headache was severe enough to discontinue drug administration in some cases. In conclusion, the use of milnacipran as the first drug of choice for treating of depression in outpatient clinics is recommended. P36. Anxiety disorders during pregnancy and postnatal depression at 6 weeks postpartum A.L. Sutter, V. Giaconne-Marcesche, E. Glatigny, H. Verdoux, C.H. Perrens Service Universitaire, 121 Rue de la BeÂchade, 33 000 Bordeaux, France Background: A limited number of studies have evaluated the relation between anxiety disorders and postnatal depression (PND), and suggested that state-anxiety and anxiety disorders during pregnancy may be a risk factor for PND. The aim of the present study was to assess in a large sample of women the impact of anxiety disorders during pregnancy on the occurrence of a PND six weeks after delivery. Method: 497 mothers from the MATQUID prospective cohort study were recruited in the maternity ward of the University Hospital in Bordeaux, during the last trimester of pregnancy. The occurrence of anxiety disorders in the mother were evaluated during the eighth month of pregnancy (T1), with the Mini International Neuropsychiatric Interview and occurrence of PND, and at six weeks post-partum (T2) using the Edinburgh Postnatal Depression Scale (EPDS) (score412). Multivariate logistic regressions were used to adjust for confounding factors. Results: Results show that 120 (24.1%) women presented with at least an anxiety disorder at T1 (generalized anxiety/social phobia/obsessive compulsive disorder/ agoraphobia/panic disorder), and 29 (5.8%) women with a PND at T2. Women presenting with anxiety disorders at T1 had a 2.6-fold increased risk of presenting with a PND at T2 (OR=2.6; 95% CI 1.14-6.05; p=0.023), after adjustment for presence of major depression at T1, demographic factors, and marital adjustment. Conclusion: Anxiety disorder during pregnancy predict the occurrence of PND, independently from the existence

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of a prenatal maternal depression and other confounding factors. This finding may have implications for prevention of PND. P37. Efficacy of milnacipran in patients with chronic orthopeadic pain including degenerative spondylosis and osteoarthritis H. Tanikawa Department of Orthopedics, Azumi General Hospital, Nagano, Japan Chronic pain is thought to involve a dysfunction of the descending serotonergic and noradrenergic neurones. The aim of this study was to evaluate the efficacy and tolerability of the serotonin and noradrenaline reuptake inhibitor (SNRI), milnacipran, in patients with chronic orthopaedic pain. Initially 19 patients with a primary diagnoses of degenerative spondylosis, lumbar spinal canal stenosis or osteoarthritis of the knee were studied. Symptoms included lower back pain, ischialgia, intermittent claudication and arthralgia of the lower limb. Patients received milnacipran at 50 mg/day. Some patients received the drug alone while for others it was an add-on to previous NSAID therapy. Improvement was seen in ten patients with average pain scores being reduced from 10 (arbitary baseline value) to 3.3. In four of these patients, pain score was reduced to less than 2. Symptoms remained unchanged in two patients. Four patients withdrew as a result of side-effects and three were lost to follow-up. A second group of 15 patients suffering from pain in the trunk and/or extremities due to degenerative spondylosis were treated with milnacipran (flexible dosing). Patients were examined every two weeks for 2-8 weeks. Pain reduction was rated using a visual analogue scale (VAS). Patients also filled out a self-rating depression scales (SDS). Ten patients reported improvement of pain symptoms. In six of these the reduction of pain intensity was of 50% or more. No improvement was seen in three patients while two patients were lost to follow-up. All patients including those reporting no pain relief showed decreased depressive symptomatology as shown by the SDS scores. Conclusion: It is concluded that milnacipran maybe a useful in the treatment of orthopaedic pain. Further study is in progress. P38. Mood altering medication prescriptions among severely mentally iill: results from a survey R. Tempier, B. McGrath McGill University Health Centre, Montreal, Canada Severely mentally ill patients with diagnoses of schizophrenia or related disorders suffer from co-morbid mood disorders. Post psychotic depression or general anxiety

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IFMAD Abstracts

disorders are commonly found among them. In addition, the treatment of schizophrenia often requires adjuvant medication prescriptions. We wanted to know how many antidepressant and benzodiazepine prescriptions are written in a specialized clinic for schizophrenia outpatient treatment. We also wished to know if patients on atypical medications used more adjuvant medications. A data bank was set up for pharmaco-epidemiological purposes. All patients prescriptions (n=423) were entered in October 2001. Most patients (68%) had a diagnosis of schizophrenia, 14% being diagnosed with a schizoaffective disorder. About 70% were on atypical medications, 45% (n=190) of them took adjuvant medications while among those on conventionals only 38% took adjuvant prescriptions. In this population, 25% were prescribed benzodiazepine medications, 14% antidepressants and 6% mood stabilizers. We do not observe an overload of adjuvant prescriptions. Results will be discussed with comparison of other studies. P39. Efficacy of milnacipran for glossodynia patients A.Toyofuku Department of Dentistry and Oral Surgery, School of Medicine, Fukuoka University, Fukuoka, Japan Background: Glossodynia is a well-known chronic orolingual pain syndrome and that is characterized by a spontaneous burning sensation mainly affecting the tongue. It is considered to be of psychogenic origin and fulfils the criteria for ``persistent somatoform pain disorders’’ according to ICD-10. Depression is often an important component of the psychological profile of glossodynia patients. We have reported previously that tricyclic antidepressants (TCAs) are effective in treating glossodynia. However, side-effects such as dry mouth, drowsiness and constipation often prevent patients from achieving high enough doses. We administered milnacipran, a serotonin and noradrenaline reuptake inhibitor (SNRI) to glossodynia patients. The purpose of this study was to examine the efficacy and safety of milnacipran in glossodynia patients. Patients and Methods: The study involved nine patients with glossodynia who came to Department of Dentistry and Oral Surgery, Fukuoka University Hospital, Japan. They met the following criteria: 1) presence of pain or a burning sensation on the surface of the tongue, 2) absence of local or systemic diseases, 3) no history of significant psychiatric illness, 4) no administration of any drugs causing pain of the tongue. A six-week open study was conducted in these patients. Effect on pain was measured using visual analogue scales. Severity of depression was assessed using the Zung’s Self-Rating Scale for Depression. Results: Milnacipran was effective in six cases ± markedly effective in three and mildly effective in three cases. It was ineffective in the remaining three cases. The mean final

dose of milnacipran was 44.4 mg/day. No serious sideeffects were observed. Conclusion: At the end of the study 33.3% of the patients were in remission. Milnacipran was well tolerated. It is suggested that milnacipran may be an effective treatment for glossodynia. Further study is in progress. P40. Usefulness of milnacipran in the treatment of generalized anxiety disorder T. Tsukamoto , R. Kondo, K. Ichikawa St. Mary’s Tsukamoto Clinic, Yokohama, Japan Benzodiazepines (BDZ) have been used as first-line anxiolytics in the majority of cases of generalized anxiety disorder (GAD). Nevertheless, long-term therapy with BDZ involves the problem of dependency. BDZ drugs are still commonly used for treatment of patients with GAD in Japan, while the usefulness of paroxetine and venlafaxine have been demonstrated and marketing approval obtained for the drugs in Europe and the United States. The purpose of this study is to investigate the usefulness of milnacipran for GAD. The study sample comprised nine outpatients (1 male, 8 female; mean age 36.6 years) diagnosed as having GAD at this clinic according to the DSM-IV diagnostic criteria. The dosage of milnacipran was individualized according to symptoms and the study treatment lasted for eight weeks in each patient. Therapeutic responses were evaluated immediately prior to the start of study treatment and at each clinic visit thereafter, using the Hamilton Anxiety Scale (HAM-A), and the patients made self-assessments with the Visual Analog Scale (VAS) prior to the start of study treatment (baseline) and at each clinic visit thereafter. The mean baseline HAM-A score was 21.8. It decreased to 13.6 at one week of study medication and further declined to 1.6, indicative of remission, at week 8. There were essentially similar changes in VAS scores over time. The present results suggest that milnacipran not only exerts an anxiolytic effect with a prompt onset but may also lead to remission of GAD. Further, controlled studies in greater numbers of patients are needed. P41. Escitalopram provides continued improvement during long-term treatment of depressed patients in primary care A. Wade, N. Despiegel, E. Reines CPS Clinical Research Centre, Glasgow, UK Escitalopram is a highly selective and potent SSRI that has been proven effective and safe in the treatment of major depressive disorder (MDD) in several short-term phase III studies. Long-term clinical efficacy results have now been evaluated from a study with a total exposure time to escitalopram of 486 patient years.

IFMAD Abstracts

Escitalopram was administered at doses of 10 or 20 mg/ day (dose increase based on physician’s clinical judgement) in an open-label, 12-month extension study conducted in outpatients (n=588) who fulfilled the DSM-IV criteria for MDD. Patients entered the12-month study after completing one of two 8-week, double-blind, placebo-controlled, leadin studies. The primary efficacy parameter was the MADRS total score. At baseline (entry into the 12-month study), patients had a mean MADRS total score of 14.2, which decreased to 10.5 after 8 weeks and 5.8 after 52 weeks of treatment with escitalopram. The percentage of patients in remission (defined here as MADRS total score 412) increased from 46% at baseline to 65% by Week 8 and 86% by Week 52. There was a corresponding decrease in the number of moderately to severely ill patients (MADRS total score 522) from 22% at baseline to 8% by Week 8 and 2% by Week 52. A total of 437 patients completed the study, with an average exposure to escitalopram of 315 days. The robustness of these long-term efficacy results was confirmed by the results from the secondary efficacy parameter ± the CGI-Severity (CGI-S) scale. At baseline, 55% of patients had a CGI-S score of 3 or more (mildly ill, or worse), decreasing to 37% by Week 8, and 14% by Week 52. In conclusion, moderately to severely depressed patients in primary care treated with escitalopram (10 to 20 mg/ day) showed continued improvement throughout the study. P42. Persistence with initially prescribed antipsychotic medication and economic outcomes in the treatment of bipolar disorder R.E. White AstraZeneca, Wilmington DE, USA Objective: To compare persistence with initially prescribed antipsychotic therapy in the management of patients with bipolar disorder. Method: Longitudinal administrative claims data for the period 1 October 1997 to 31 March 1999 were obtained from approximately 180 US managed care organizations. From these data, 165 patients with a diagnosis of bipolar disorder (i.e. affective psychoses [ICD-9 code 296]) who were new to therapy and were receiving no other antipsychotic medication at the time of quetiapine prescription, were identified and tracked until June 2000. Patients prescribed haloperidol, clozapine, risperidone, and olanzapine were randomly selected and matched to quetiapine patients. Results: At 1 year, 34.6% of quetiapine patients were still on initially prescribed medication (i.e. quetiapine), compared to 22.5% of haloperidol patients (p=0.03), 26.5% of risperidone patients (p=0.12), 24.2% of olanzapine patients (p=0.04), and 25.2% of patients on a study atypical antipsychotic, other than quetiapine (p=0.03). As expected,

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significantly more haloperidol patients than quetiapine patients were prescribed an anticholinergic drug (34.2% vs. 9.7%; p50.01). Cost analysis indicates that for each additional day of persistence with the initially prescribed antipsychotic, managed care costs were reduced by US$5.69/patient. This would lead to cost savings of $722.63, $403.99 and $438.13 if quetiapine were used instead of haloperidol, risperidone, and olanzapine, respectively. Conclusions: Bipolar patients persist with initially prescribed quetiapine for longer than with initially prescribed haloperidol, clozapine, risperidone, or olanzapine. As persistence with antipsychotic medication is associated with reduced overall healthcare costs, quetiapine should be considered a useful option in the treatment of bipolar disorder. P43. Clinical efficacy of SNRI, milnacipran, on a depressive state in a department of neurology K. Yamane, A. Shirata, T. Takeda, M. Kobayashi Department of Neurology, Neurological Institute, OhtaAtami Hospital, Koriyama, Japan Depression and a depressive state are both frequently encountered in departments of internal medicine during routine clinical examinations, but treating these disorders appropriately using conventional tricyclic and tetracyclic antidepressants can only be managed effectively by psychiatrists. Recently, in Japan, antidepressants such as SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-noradrenaline reuptake inhibitors), which have a higher safety level than conventional agents, have now become available for clinical use, thereby facilitating the treatment of these disorders by internal medicine physicians. In the present study, we investigated the clinical efficacy and adverse effects of the SNRI, milnacipran, on patients treated in our department of neurology. Of 35 patients administered milnacipran, 32 cases received the drug for eight weeks and three withdrew from treatment because of adverse effects. Among these 35 cases, eight (22.9%) showed a remarkable improvement of their depressive state, 16 (45.7%) showed a moderate improvement, four (11.4%) showed a slight improvement and four (11.4%) showed no change. No worsening of the depressive state was observed in any patients, but three cases (8.6%) withdrew from the treatment because of adverse effects. These adverse effects appeared within one week after the administration of the drug and consisted of fatigue in one, headache in one and drowsiness in one patient, respectively, but all of these conditions disappeared after the termination of the milnacipran administration. In conclusion, the results of this study suggest that milnacipran is a useful and easy-to-use antidepressant for treating the depressive states accompanying neurological diseases.

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IFMAD Abstracts

P44. Milnacipran plasma levels and antidepressant response in Japanese major depressive patients: the second report K. Yoshida, H. Higuchi, H. Takahashi, M. Kamata, K. Ito, K. Sato, S. Naito, T. Shimizu Department of Psychiatry, Akita University School of Medicine, Akita, Japan Introduction : Milnacipran is a new specific serotonin and noradrenaline reuptake inhibitor (SNRI) that has been shown to be equally effective as tricyclic antidepressants (TCAs) in the treatment of depression (Kasper et al, 1996). Retz et al (1995) reported that there was no correlation between plasma levels of milnacipran and the clinical outcome (n=17). Our previous study (Higuchi et al, 2002) also did not demonstrate a correlation between plasma levels of milnacipran and the antidepressant response (n=31). Aims: The purpose of this study was to clarify the relationship between plasma levels of milnacipran and the antidepressant response in more subjects than in our previous study. Material and Methods: 52 patients meeting the DSM-IV diagnosis of major depressive disorder without psychotic features, whose score of Montgomery and AÊsberg (1979) depression rating scale (MADRS) was more than 20 points, were included in this study. Three cases were excluded

from the analysis of this study because of their poor compliance. The mean age of 49 patients was 51.7+12.3 years. The mean entry MADRS score was 28.5+5.5. All patients provided informed consent. Milnacipran was administered twice daily (after dinner and at bedtime at the same dose) for six weeks. The daily dose was 50 mg/ day for the first week, and up to 100 mg/day thereafter. No other psychotropic drugs were given except occasional brotizolam 0.25 or 0.5mg as a hypnotic. Depressive symptoms were evaluated by the MADRS before treatment and at one, two, four and six weeks after the beginning of this study. A clinical response was defined as a 50% or greater decrease in the baseline MADRS score. Four weeks after the administration of milnacipran, blood samples were collected approximately 12 hours after the bedtime dose and were analyzed using high-performance liquid chromatography (with fluorescent detector) method by Asahi Kasei Corporation (Tokyo Japan). Results: 34 patients (69.4%) were responders according to the definition mentioned above. Plasma milnacipran levels of 49 patients ranged between 38.9 and 156.8 ng/ml. The mean plasma milnacipran level of responders, 82.0+29.4 ng/ml, was similar to that of non-responders, 78.6+23.1 ng/ml. Conclusion: There was no significant relationship between plasma levels of milnacipran and the antidepressant response in Japanese major depressive patients.