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Le trouble dépressif caractérisé est une pathologie psychiatrique fréquente représentant un enjeu majeur de Santé Publique. Malheureusement, il n’existe actuellement aucun biomarqueur prédictif de la réponse thérapeutique dans cette maladie. Cette étude pilote, prospective et multicentrique est baptisée EXCIPSY. Elle évalue l’intérêt de l’excitabilité corticale mesurée par Stimulation Magnétique Transcrânienne (TMS) comme biomarqueur prédictif de la réponse à un inhibiteur sélectif de la recapture de la sérotonine, le citalopram. Le schéma de cette étude est original et dynamique. Il prévoit que 22 patients âgés de 18 à 65 ans et présentant un épisode dépressif caractérisé soient inclus dans 3 centres (CH du Rouvray, EPS Ville-Evrard et Centre Esquirol à Caen). Le protocole comportera 5 à 6 visites réparties sur 60 jours et cherche à corréler la variation des paramètres de neuroexcitabilité, en particulier la période de silence cortical (CSP), avec la réponse au citalopram à différents temps (J3, J7, J14, J28, +/- J60). L’hypothèse principale de l’étude est que la variation de la CSP entre J1 et J28 sera supérieure chez les répondeurs au citalopram par rapport aux non répondeurs. Les résultats que nous présentons dans ce travail de thèse sont ceux de la procédure de mise en place de l’étude EXCIPSY qui a consisté en 2 séances de mesure TMS rapprochées chez 5 sujets sains. Ces résultats sont donc préliminaires mais permettent de conclure à 1) une cohérence intra-individuelle satisfaisante des mesures aux 2 temps (p > 0.05 au test des rangs signés de Wilcoxon pour chaque mesure), 2) la nécessité d’optimiser la fiabilité métrique de la procédure (corrélation de Spearman vérifiée uniquement pour 2 paramètres) et 3) la mise en évidence d’une excellente tolérance. L’ensemble de ces données est encourageant et ouvre donc la perspective d’exporter le dispositif en population clinique dès 2019. Au total, ces résultats prometteurs engagent à tester l’excitabilité corticale mesurée par TMS comme biomarqueur, simple, accessible et bien toléré pour évaluer la réponse au traitement antidépresseur dans le trouble dépressif caractérisé de l’adulte.

Toxicity of the serotonin-reuptake inhibitors (SRI) including citalopram, the most selective one, is considered as relatively low. However SRI may be responsible for serotonin syndrome, seizures, electrocardiographic abnormalities, respiratory failure, and even death. Implication of SRI in deliberate drug poisonings has not been assessed by recent data in France. Morbidity of SRI-related poisonings as well as the most common resulting presentations in the emergency department (ED) remains poorly described. Moreover, mechanisms of SRI-attributed death remain unclear. Objectives: We conducted these clinical and experimental studies: 1-to better understand the epidemiology of drug poisonings in one ED in Paris area and analyze SRI involvement; 2- to investigate a possible over-morbidity related to SRI in multidrug poisonings and describe the most common SRI-related complications; 3- to understand mechanisms of death induced by elevated doses of citalopram and its possible prevention. Methods: We conducted an observational study during 4 years in an ED matching patients who ingested at least one IRS with patients who did not. We also conducted an experimental study in the Sprague-Dawley rat to determine the median lethal dose (MLD) of citalopram and investigate citalopram-related neurological, respiratory, and systemic toxicity as well as mechanisms of citalopram-induced death. Platelet and plasma serotonin were measured to ensure the serotoninergic mechanism. Results: SRI were involved in 16% of the drug poisonings admitted to the ED, ranking at the second place after the benzodiazepines. Attribution of the observed signs and symptoms to the serotonin toxicity was rarely performed by the emergency physicians in charge, in only one out of five cases. Onset of serotonin syndrome and seizures were more frequent in SRI-exposed patients than in their matched controls. QT prolongation was observed in one patient while no direct respiratory toxicity was reported. Mechanical ventilation was more frequently used in SRI-exposed patients due to impaired consciousness, despite no resulting increased admission rate to the intensive care unit in comparison to the controls. Based on our rat study, citalopram-induced death always occurred after seizures which were dose-dependent, with a greater prevalence at the two highest doses of citalopram (80 and 120% of the MLD) than in the other groups (60% of control and the MLD). Citalopram-induced decrease in platelet serotonin and increase in plasma serotonin were dose-dependent. However, incidence of serotonin syndrome appears similar in all the groups. Citalopram did not induce hypoxemia, hypercapnia or hyperlactacidemia, but resulted in a slight prolongation in the inspiratory time and an "expiratory braking" that could be attributed to an adaptive phenomenon to hypoxemia. Pretreatment with diazepam and cyproheptadine prevented rats treated with lethal-doses of citalopram from seizures and death. Conclusions: SRI and citalopram in particular are mainly responsible for neurological toxicity, both in humans and rats. Serotonin syndrome and seizures should be grouped as markers of serotonin toxicity. Emergency physicians should become more aware of this specific toxicity. Using the simpler and probably more specific Hunter criteria may be useful in the ED. The exact indications of antidotes remain to be defined, but our experimental model seems to support their effectiveness to prevent IRS-related specific serotonin toxicity.; La toxicité des antidépresseurs inhibiteurs de recapture de la sérotonine (IRS) dont le citalopram est le représentant le plus sélectif, est réputée faible. Or les IRS ont été rendus responsables de syndromes sérotoninergiques, de convulsions, d’anomalies électrocardiographiques, voire de troubles respiratoires et de décès. L’implication de cette classe pharmacologique au cours des intoxications médicamenteuses volontaires (IMV) apparait peu documentée par des données récentes en France. Ainsi, la morbidité des IMV impliquant un IRS aux urgences (SAU) et les symptômes les plus fréquemment observés à la suite d’une exposition toxique aux IRS sont peu décrits. De même, les mécanismes toxiques impliqués dans les décès ne sont clairs. Objectifs : Nous avons mené ces travaux dans le but de : 1- mieux connaitre l’épidémiologie des IMV dans un SAU et y préciser l’implication des IRS ; 2- explorer une éventuelle sur-morbidité liée aux IRS dans les IMV polymédicamenteuses ; 3-comprendre les mécanismes de décès induits par de fortes doses de citalopram et les moyens de les prévenir. Méthodes: Nous avons conduit une étude observationnelle des IMV admises au SAU durant 4 ans, avec appariement des patients ayant ingéré un IRS versus des patients intoxiqués non exposés à un IRS. Nous avons également mené une étude expérimentale chez le rat Sprague-Dawley pour connaitre la dose létale médiane (MLD) du citalopram et explorer la toxicité neurologique, respiratoire et systémique impliquée dans le décès consécutif à l’administration de citalopram. Des dosages de sérotonine plasmatiques et plaquettaires ont été effectués afin de caractériser le rôle de la toxicité sérotoninergique. Résultats : Les IRS étaient impliqués dans 16% des IMV au SAU, soit en 2e position après les benzodiazépines. L’attribution des symptômes observés aux effets sérotoninergiques était rarement faite (dans environ un cas sur cinq) par les médecins urgentistes en charge des patients. La survenue d’un syndrome sérotoninergique et de convulsions était plus fréquente dans le groupe de patients intoxiqués par IRS que chez les témoins appariés. Un allongement du QT a été noté chez un patient et aucune toxicité respiratoire n’a été décelée. Le recours à la ventilation mécanique était plus important du fait de troubles de la conscience, sans augmentation pour autant du nombre d’admission en réanimation en comparaison aux témoins. L’étude expérimentale nous a permis de montrer que les décès induits par le citalopram étaient toujours précédés de convulsions, et que la prévalence des convulsions étaient dose-dépendante, significativement plus fréquente pour les fortes doses de citalopram (80 et 120% de la MLD) comparativement aux autres groupes (60% de la MLD et témoins). De même, le citalopram induisait une baisse dose-dépendante de la sérotonine plaquettaire et une élévation dose-dépendante de la sérotonine plasmatique. L’incidence du syndrome sérotoninergique était, par contre, comparable. Le citalopram n’induisait ni hypoxémie, ni hypercapnie, ni hyperlactatémie ; mais il était responsable d’un allongement du temps inspiratoire et d’un « braking expiratoire » mimant un phénomène adaptatif à l’hypoxémie. Par ailleurs, le prétraitement par diazépam ou cyproheptadine des rats intoxiqués avec une dose létale de citalopram prévenait les convulsions et le décès. Conclusions : La toxicité des IRS et du citalopram en particulier, semble essentiellement neurologique, tant chez l’homme que chez l’animal. Le syndrome sérotoninergique et les convulsions devraient être rassemblés en marqueurs de la toxicité sérotoninergique. Il est nécessaire de sensibiliser les médecins urgentistes à cette toxicité, en utilisant les critères de Hunter, plus simples et probablement plus spécifique. La place des antidotes restent à définir, mais, selon notre modèle expérimental, ils pourraient être efficaces pour réduire cette toxicité spécifique.

Such a prevalent disease as Major Depressive Disorder (MDD), associated with prominent impairment in physical and social functioning, implies as well an increased morbidity and mortality. Long-term treatments are required due to the frequent occurrence of relapses. Patient compliance is a core factor in both acute and continuation treatment, closely related to tolerability issues. We have partially reviewed the literature published on PubMed since 2004 which assess the relative antidepressant efficacy of escitalopram and comparator antidepressants in adult patients who met DSM-IV criteria for major depressive disorder (MDD). Clinically important differences exist between commonly prescribed antidepressants. These analyses are in favor of a superior efficacy and tolerability of long-term escitalopram treatment (10 to 20mg/day) compared with active controls, including selective serotonin re-uptake inhibitors (SSRIs) (paroxetine, citalopram, bupropion, fluoxetine, fluvoxamine, sertraline), serotonin/noradrenaline reuptake inhibitors (SNRIs) (venlafaxine, milnacipran and duloxetine) and noradrenergic and specific serotonergic antidepressants (NaSSAs) (mirtazapine). Cipriani et al. (2009) have performed a network meta-analysis of 12 new generation antidepressants. They have shown that clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favor of escitalopram and sertraline in acute treatment, defined as 8-week treatment. Kasper et al. (2009) conducted a post-hoc pooled analysis of data from two 6-month randomized controlled trials that revealed superior efficacy and tolerability of escitalopram when compared with paroxetine. The pooled analysis of four randomized, double-blind, active comparator, 6-month trials in MDD, by Wade et al. (2009), showed that short-term outcomes may predict long-term treatment compliance and outcomes. A higher probability of achieving remission was associated with responding after 8 weeks and with completing 6 months of treatment. Furthermore, Week 24 complete remission (MADRS≤5) was significantly (P0,01) higher for escitalopram (51.7%) than for the pooled comparators (45.6%). And after 6 months, fewer patients discontinued treatment with escitalopram (15.9%) than with the pooled comparators (23.9%) (P0.001). This fragmentary review of the literature shows that it is necessary to adopt a stringent definition of remission in depression, especially in clinical trials; a MADRS total score less or equal to 10 to define remission, a MADRS total score less or equal to 5 to define complete remission, and moreover no MADRS single item greater than 1 to define symptom-free remission. In all these meta-analyses, the superiority of escitalopram compared with other antidepressants was confirmed for both acute and long-term treatment of MDD, especially in harshly depressed patients.

Depression is one of the most common diseases. It is associated with a significant psychosocial disability and many studies have shown that it results in numerous sick-leaves, with substantial economic burden. However, most of the studies have been conducted in Northern Europe and the situation in France remains unknown.To describe the management of depressive patients and assess the impact of treatment on professional activity and sick-leave.An epidemiological observational longitudinal study (NEXTEP) performed by TNS Healthcare in private practice psychiatrists.Data of 2516 patients included by 771 psychiatrists were analyzed. Patients aged 20 to 60 years, with professional activity and presenting with major depression were eligible if they were prescribed an antidepressant drug for the first time by this psychiatrist on the day of consultation. Women represented 65% of the cohort. Mean MADRS score at baseline was 34±7.7/60 and 47% of patients had a severe depression; only 5% had mild depression. Professional activity was impaired in 95% of cases. A sick-leave certificate was granted to 35% of the patients at the end of the first visit (first sick-leave or renewal in 14% and 21% of cases, respectively), and 100% were prescribed a pharmacological treatment (antidepressant agent). After 2 months, MADRS scores had dramatically decreased (-21 points on average) and 50% of the patients were symptom free. Most patients (75%) perceived improvement in working capacity; only 13% of patients received a sick-leave certificate. Escitalopram was associated with a significantly greater improvement in depressive symptoms, along with a significantly lower number and duration of sick-leave certificates. In multivariate analysis, predictors of depression improvement were decreased in anxiety, improved in self-esteem, and escitalopram treatment.Frequency and duration of sick-leave appear lower than in other studies, notably those conducted in Scandinavian countries. However, employment laws are different, which may influence the physicians' attitudes.This study is the first that accurately describes the management of depressive patients and the impact of treatment on professional activity and sick-leave in France. It suggests that an appropriate management of depressive patients results in a rapid improvement of symptoms and work resumption in most cases.

Several recent studies have underlined the importance of anxiety in major depressive disorders. It has been shown that anxiety was responsible for worsening of depression and reduction of the efficacy of the antidepressant treatment. While it is well known that SSRI are efficient in treating depression or anxiety disorders, the authors tried to determine the influence of baseline anxiety on the response to SSRI treatment in patients with severe depression receiving either escitalopram or paroxetine. In a 24-week double-blind clinical trial, 459 patients with a primary diagnosis of severe major depressive disorder were randomised to receive escitalopram (20mg) or paroxetine (40mg). Post hoc analyses of efficacy in patients with a baseline HAM-A total score less or equal to 20 (n=171) or greater than 20 (n=280) were based on analysis of covariance. (ANCOVA) (ITT, LOCF). At week 24, the mean change from baseline in MADRS total score was -24.2 for escitalopram-treated patients (n=141) and -21.5 for paroxetine treated patients (n=139) (p0.05, between both groups) in high baseline anxiety patients (HAM-A20) and the mean change from baseline in HAM-A total score was -17.4 (escitalopram) and -15.1 (paroxetine) (p0.05, between both groups). As far as complete remitters (CGI-S=1) after 24-week treatment were concerned, their number was significantly higher with escitalopram in the case of marked baseline anxiety. No difference was shown in the low baseline anxiety group. Looking for the influence of baseline anxiety on SSRI treatment effects, the authors showed that antidepressant efficacy of 20mg escitalopram was better than 40mg paroxetine for patients highly depressed with comorbid anxiety symptoms and that, contrary to paroxetine, escitalopram maintained sustained antidepressant activity in patients featuring increased baseline anxiety levels.

Zolpidem is an imidazopiridine with hypnotic properties. Compared to benzodiazepines, zolpidem has a mechanism of action that is thought to reduce the risk of dependence or abuse. However, in the past 10 years, several cases of zolpidem abuse, dependence and withdrawal reactions have been described in the litterature. Here, we describe a case of dependence and withdrawal seizure.

According to recent data in the literature, severe forms of depression represent almost half of all characterised episodes of depression; in view of this their treatment is a real public health challenge. According to the recommendations of various health authorities, treatment first relies on antidepressant medication. A recent meta-analysis of 12 new generation antidepressants has shown that these products are not all equivalent in the treatment of major depression, and that differences exist in terms not only of efficacy but also of acceptability. These differences in efficacy also appear true in the treatment of severe depression. Very recent publications, with a meta-analysis carried out on large cohorts of patients included in clinical trials, have shown the superior efficacy of escitalopram (which is the most active enantiomer of the racemic component, citalopram) in severe depression (defined by a total score on the MADRS scaleor =30). A pooled analysis by Kilts et al. assessed the response to treatment according to the baseline severity of the depression, under escitalopram and under six comparable products: citalopram, duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine. It showed that the rate of responders to the different treatments decreased when baseline severity increased, which agrees with the data in the literature, except for escitalopram, with which the rate of responders remained stable. The pooled analysis of Kennedy et al., that partly referred to the same studies, showed that for all the patients exhibiting severe depression, escitalopram was significantly superior to the other same six comparable products (mean estimated difference of 1.8 on the total MADRS score [p0.0001]; a rate of 64.4 responders vs 55.8% [odds ratio=1.60, p0.0001]; rate of remission of 47.7 vs 41.6% [odds ratio=1.39, p0.0007]). In parallel with the statistical significance of the results, the criterion of clinical pertinence of the differences revealed between the medicinal products is highly significant. Regarding antidepressants, the criteria of clinical pertinence most frequently applied are the difference in rate of responders, the number needed to treat (NNT) and, to a lesser extent, the difference between the rates of patients in remission and the difference in the effect of treatment. According to these criteria, Montgomery and Möller (2009) assessed the clinical pertinence of the results showing the superior efficacy of escitalopram on three products: citalopram, paroxetine and duloxetine. Hence, they established this clinical pertinence for all of the depressed patients, but also in the particular case of severe depression. All these new data confirm the interest of escitalopram in the treatment of characterised depression and notably in the severe forms, with a particularly favourable efficacy/acceptability ratio.

Severe forms of depression are a major therapeutic concern for psychiatrists. According to Health Authority recommendations, they require the systematic initiation of treatment with active drugs, and they respond less well to placebos than the less severe forms. Escitalopram, which is the most active enanthiomer of the racemic compound (citalopram), is tolerated well at the doses indicated in the marketing authorisation (10 to 20mg per day) and it is particularly effective in the severe forms of depression. Several studies have compared escitalopram to another specific serotonin recapture inhibitor (SSRI) in severe depression. In a 24-week study, 20mg per day of escitalopram, compared to 40mg per day paroxetin, demonstrated significantly greater efficacy (p0.05) on the primary criterion (modification of the total MADRS score between inclusion and the end of the study). In this same study, the difference in favour of escitalopram increased in parallel with the increase in initial severity. In a grouped analysis of three studies versus citalopram, the superior efficacy of escitalopram also increased in parallel with the initial severity. The antidepressants, combined serotonin recapture inhibitors and noradrenalin (SRINA), might, in theory, be more effective than the SRI because of their broader mode of action. Recent data on escitalopram have invalidated this fact. In a study comparing 20mg per day of escitalopram to 225mg per day of venlafaxine during eight weeks in severely depressed patients (MADRS30), escitalopram led to a significantly enhanced improvement (p0.05). A grouped analysis of two similarly designed studies showed that the difference in favour of escitalopram increased at the same time as the initial severity increased. An analysis of two studies comparing 10 to 20mg per day of escitalopram to 60mg per day of duloxetine in severely depressed patients, revealed the superior efficacy of escitalopram in the sub-sample of severely depressed patients (p0.01), with significant superiority on each of the 10 items of the MADRS taken singly. Despite the limits of regrouped analyses, all these results underline the fact that escitalopram is at least as effective as the comparators, and notably compared to the two SRINA studied, in the severe forms of depression.

Anxiety disorders are highly prevalent and disabling disorders, for which selective serotonin reuptake inhibitor (SSRI) antidepressants are an effective treatment. Escitalopram is the most selective SSRI available. Beyond its well-established efficacy in depression with or without anxiety, preclinical studies have demonstrated that escitalopram has a broad spectrum of anxiolytic activity.This review focuses on the therapeutic use and the tolerability issues of escitalopram in the treatment of adult patients with panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, and obsessive-compulsive disorder (OCD), on the basis of numerous recent short-term and long-term controlled studies in these disorders. In a 10-week randomised, double-blind trial in patients with panic disorder, escitalopram (flexible doses 5-10 mg/d) was significantly more effective than placebo in reducing the panic attack frequency, with a faster onset of action than citalopram. Fifty percent of escitalopram recipients and 38% of placebo recipients experienced no panic attacks, with a similar incidence of the most common adverse events for both groups. LITERATURE FINDINGS IN PD: In an open-label study in elderly (65 years) patients with panic disorder, improvement in panic attack frequency and secondary efficacy variables occurred more rapidly in escitalopram than citalopram recipients. LITERATURE FINDINGS IN GAD: In four double-blind, comparative, eight- to 12-week studies in patients with GAD, escitalopram was more effective than placebo and at least as effective as paroxetine in reducing the mean Hamilton Rating Scale for Anxiety total score. Escitalopram 10-20 mg/d demonstrated continued efficacy in a 24-week extension study of short double-blind trials and in a placebo-controlled, double-blind, 24/76-week relapse-prevention study. In this trial, escitalopram recipients showed a significantly longer time to relapse and reduced risk of relapse than placebo recipients, and the risk of relapse was 4.04 times higher in the placebo group than in the escitalopram group. Escitalopram was well tolerated and only 7% patients withdrew, due to adverse events in the escitalopram group, versus 8% in the placebo group. LITERATURE FINDINGS IN SOCIAL PHOBIA: In two randomised, double-blind, 12- and 24-week studies in patients with social anxiety disorder (social phobia), escitalopram 10-20 mg/d was generally more effective than placebo and at least as effective as paroxetine in reducing the mean Liebowitz Social Anxiety Scale total scores. In a 24-week double-blind, placebo-controlled relapse-prevention study, escitalopram recipients had a longer time to relapse and reduced risk of relapse compared with placebo recipients, and significantly fewer escitalopram than placebo recipients relapsed (22% versus 50%). In these studies, the treatment effects of escitalopram were independent of gender, symptom severity and chronicity, and comorbid depressive symptoms, and the drug was tolerated well. LITERATURE FINDINGS IN OCD: Finally, in patients with OCD, escitalopram 20mg/d for 12 weeks was more effective than placebo, and at least as effective as paroxetine 40 mg/day, with respect to a mean reduction from baseline in the Yale-Brown Obsessive Scale total score. In a 24-week, randomised, placebo-controlled relapse-prevention study, the proportion of patients who relapsed in the escitalopram group (23%) was 2.74 times lower than in the placebo group (52%). In both groups, the majority of adverse events reported were mild to moderate.On the whole, numerous clinical data indicate that escitalopram, 10-20 mg/d, is an effective and well-tolerated first-line treatment option for the management of panic disorder, GAD, social anxiety and OCD. Beyond short-term demonstrations of efficacy in these disorders, several controlled relapse-prevention studies showed the necessity and utility of maintaining the treatment six months or more after the remission has been obtained.

Escitalopram has shown some different pharmacologic properties compared to its racemic molecule, citalopram. When comparing with venlafaxine, similar efficacy of this drug was observed, notably when considering the frequency of responders [50% of decrease on the Montgomery and Asberg Depression rating Scale (MADRS)] and the frequency of remitters (MADRS12), even when the doses of both drugs were increased up to 20 mg per day for escitalopram and 225 mg per day for venlafaxine. In addition, a recent study conducted by Jonas et al. (2006) [Jonas J, Bose A, Alexopoulos G, et al. Double blind comparison of escitalopram and duloxetine in the acute treatment of Major Depressive Disorder 45th Annual Meeting of the American College of Neuropsychopharmacology December 2006] suggested a better efficacy of escitalopram in comparison to duloxetine. When considering severe major depressive episodes, the efficacy of escitalopram compared to noradrenalin and serotonin reuptake inhibitors (NaSRI) could be superior, with a more important rate of remitters in the escitalopram group. Regarding the tolerance of both types of drugs, the percentage of patients who withdrew the drug for side-effects would be higher in patients on venlafaxine. This increase in frequency of side-effects has been observed in different studies conducted with venlafaxine and duloxetine. All these data highlight the advantages of escitalopram in the treatment of major depressive episodes and escitalopram has, therefore, obtained marketing approval in France with some specific mentions in favour of this drug.

We report a case of serotonin syndrome caused by interaction between nasal fentanyl, oxycodone and escitalopram. Due to chronic painful episodes with paroxistic level of pain, a 66-year-old patient, treated for prostate adenocarcinoma and bone metastases received an association of major opiate analgesics (oxycodone 120 mg/day for 6 months, and fentanyl nasal spray four puff of 200 microg/puff). After the addition, for mood disorders, of a small dose of escitalopram (5 mg/day), he developed severe serotoninergic features including diaphoresis, night sweating, tremor, diarrhea, visual disorders with mydriasis and weight loss of 8.8 lbs (4 kg). Discontinuation of escitalopram resulted in complete resolution of his symptoms within 48 h except for persistent blurred vision.The clinical manifestations of this case meet Sternbach's criteria of serotonin syndrome. Its possible etiologic factors include adverse drug reaction and pharmacodynamic interaction between selective serotonin reuptake inhibitor (SSRI) antidepressant and opioid analgesics. The Naranjo probability scale suggested a probable causality of escitalopram, oxycodone and fentanyl treatment on the serotonin syndrome. Serotonin syndrome occurrence is estimated around 0.04% in the literature with incidence rates between 14 to 16% in voluntary overdose with serotoninergic agents. It is an infrequent syndrome with, most of the time, a mild to moderate clinical expression. Nevertheless, lethal evolution might occur resulting from either monotherapy with serotoninergic agents (eg: SSRI antidepressants) or the combination of several medications that will increase serotoninergic transmission and therefore intra cerebral serotonin levels. Its physiopathology is related to a hyperstimulation of 5-HT(1A) receptors. Its clinical manifestations involve mental status impairment and cognitive disorders, neuromuscular disorders and neurovegetative impairment. The prescription of SSRI antidepressants among patients depressed, and in pain, exhibiting somatic diseases, and who require regimens of major opiate or related analgesics, is not without risk.Clinicians and especially psychiatrists should be aware of possible interaction and the risk of serotonin syndrome when a patient receives a combination of different opioid analgesics and serotonin reuptake inhibitor antidepressants. Improved information and collaboration with somatic and pain specialists and the general practitioners could help reduce the occurrence of this syndrome which can have dreadful consequences. Patients must be informed of such complications, which means that patients should be asked for a history of such events and monitored for serotoninergic adverse events, in order to avoid delays in this diagnosis.

Due to the stimulation of central and peripheral 5-hydroxytryptamine receptors, the serotonin syndrome is a potentially lethal situation. The large variety of its clinical manifestations leads to a difficult diagnosis. We describe the case of a serotonin syndrome induced by the combined escitalopram and cyclosporine administration. An 84-year-old woman was hospitalized with a history of delirium associated with hyperthermia. The diagnosis of serotonin syndrome was suspected with the combination of the clinical features: the absence of infection, the selective serotonin reuptake inhibitor administration, and the absence of other metabolic and cerebral aetiology. After the discontinuation of escitalopram, the patient's condition improved rapidly. This report is a reminder of the clinical and pharmacological features of the serotonin syndrome from a recent literature review.

Although antidepressant medications are effective in about 50-70% of patients with major depressive disorder (MDD), they have a delayed onset of therapeutic effect. This latency is one of the current major limitations of these medications, in that it prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy, and increases medical costs associated with severe depression. It is becoming increasingly clear that differences may exist between antidepressants and some evidence suggests that some antidepressant agents may begin to work faster than others. Escitalopram, duloxetine, venlafaxine, and mirtazapine have shown statistically significant differences in some measures of antidepressant action within the first two weeks of treatment, both in placebo-controlled trials and in head-to-head comparisons with other antidepressants. Results of the current review should be regarded with certain important limitations in mind. First, differences in times to onset of antidepressant response have been shown in clinical efficacy studies not specifically designed to detect differences in onset of action (post-hoc analysis). Second, results observed in 'pure' clinical trial samples should not be directly generalized to the real clinical practice since it has been proven in clinical settings that less than one in seven depressed patients would be eligible to participate in antidepressant clinical trials. For instance, depressed patients who are suicidal or who score higher than 30 on the 17-item HAM-D are excluded from antidepressant clinical trials. Third, caution is warranted when applying these findings to clinical populations with more severe depressions with respect to the fact that among clinical populations, severity of depression coincides with comorbidity, including such psychiatric disorders as anxiety disorders, personality disorders and substance abuse. In addition, the magnitudes of the size-effects of antidepressants versus placebo are clearly higher in severely depressed patients. Fourth, specific items on depression rating scales may induce greater antidepressant/placebo differences. For instance, the 17-item HAM-D contains three questions pertaining to sleep. It questions the fact that earlier onset may appear not only via a specific antidepressant effect but also via a non-specific effect on anxiety, sleep, physical pain or other accessory symptoms. Thus, current data do not clearly support claims that one drug reduces the symptoms of depression faster than another, though the existing literature suggests that escitalopram displays some superiority in terms of rapidity of action. Given the potential benefits of early-acting antidepressant treatments, the possibility of superior speed of onset of escitalopram presented here merits further study in adequately designed, prospective clinical trials. A definitive demonstration of early onset of action awaits the results of appropriately designed and powered clinical studies, which may include (1) a prospective definition of early onset of action, (2) more focused assessments of core emotional symptoms and cognitive deficits of depression by using specific and sensitive tools, (3) a data-analytic approach capable of capturing the dynamic nature of symptomatic change (for example, survival analysis), and (4) strategies to minimize biases and heterogeneity of response.

Citalopram (Séropram) is an antidepressant of the selective serotonin (5-HT) reuptake inhibitor (SSRI) class, composed of equal amounts of S-enantiomer, escitalopram, and R-enantiomer, R-citalopram. Both clinical and preclinical studies have reported that escitalopram is a potent SSRI that possesses a faster onset of antidepressant activity in comparison with citalopram. Conversely, R-citalopram, although devoid of 5-HT reuptake inhibition property, was reported to counteract the effect of the S-enantiomer in several in vitro and in vivo experiments. For instance, microdialysis studies have shown that escitalopram increased the extracellular 5-HT levels in the frontal cortex and the ventral hippocampus, and this effect was prevented by concomitant injection of R-citalopram. The in vivo relevance of the antagonistic effect of R-citalopram on escitalopram efficacy was confirmed in dorsal raphe nucleus, a brain region known to be a target for SSRIs. In the later region, escitalopram was four times more potent than citalopram in suppressing the firing activity of 5-HT neurons and this effect of escitalopram was significantly prevented by R-citalopram. The antagonizing effect of R-citalopram on escitalopram efficacy was also observed in behavioural tests predictive of anxiolytic or antidepressant properties. In adult rats, R-citalopram reduced the anxiolytic-like effect of escitalopram obtained in the footshock-induced ultrasonic vocalization model, the conditioned fear model or the Vogel conflict and elevated plus maze tests. In validated chronic models with high predictive value for antidepressant activity, when escitalopram was administered for five weeks, either alone or with twice as much R-citalopram, the effect of the treatment regimens on reversal of hedonic deficit was significantly different. Importantly, chronic treatment with escitalopram reversed the decrease in cytogenesis in the rat dentate gyrus, induced by chronic mild stress. However, in naïve rats, while chronic treatment with R-citalopram did not modify the basal proliferation rate in the dentate gyrus, it blocked the increase induced by escitalopram when coadministered. This suggests that neuronal adaptive changes, which are essential for antidepressant response, are rapidly induced by escitalopram but prevented by R-citalopram coadministration. The attenuating effect of R-citalopram was suggested to underlie the delayed recovery of 5-HT neuronal activity following long-term treatment with citalopram versus escitalopram. This is confirmed since a treatment with R-citalopram antagonized the recovery of firing observed in escitalopram-treated rats. The exact mechanism by which R-citalopram exerts its action is not yet fully defined; however, an allosteric interaction between the enantiomers and the 5-HT transporter (SERT) has been proposed. In this context, in vitro studies have revealed the existence of at least two binding sites on SERT: (1) a primary high-affinity binding site or orthosteric site that mediates the inhibition of 5-HT reuptake and (2) an allosteric low-affinity binding site that modulates the binding of ligands at the primary site. In presence of escitalopram alone, both the primary and the allosteric sites are occupied. Thus, escitalopram exerts a stabilizing effect on this association to SERT, resulting in an effective inhibition of 5-HT reuptake activity. On the other hand, in the presence of the two enantiomers, R-citalopram binds to the allosteric site and decreases the escitalopram action on SERT. Such an innovative mechanism of action can constitute a basis for development of new allosteric antidepressants that demonstrate higher efficacy and earlier onset of therapeutic effect.

Citalopram, a selective serotonin reuptake inhibitor, is composed of 2 enantiomers, R-citalopram and S-citalopram, 2 different non-superimposable mirror image forms of the same molecule. Separating these 2 enantiomers has enabled studying their individual properties. Citalopram's pharmacologic activity is centered on the S enantiomer's high affinity for the serotonin transporter which is twice as high as citalopram's and 30 to 40 times higher than R-citalopram. This leads to an inhibition of serotonin reuptake two times higher for escitalopram compared with citalopram and confirms that citalopram's pharmacologic activity is due to the S-enantiomer. Contrary to what might be expected, the effect of escitalopram (DCI of S-citalopram) is not superimposable on an equivalent dose of citalopram but is superior. Several hypotheses could explain this superiority. First, conversions of the S-enantiomer into the R-enantiomer may occur, but there is no reason why this phenomenon would happen more when both enantiomers are present than when escitalopram is alone. Furthermore, pharmacokinetic studies have shown that S or R configurations are stable in vivo. Second, a particular action of R-citalopram may influence the S-enantiomer's kinetic from intestinal absorption to blood-brain barrier. But concentrations of both enantiomers in the frontal cortex are the same. Therefore, R-citalopram does not interfere with escitalopram's kinetic. Finally, interactions may appear at the synaptic level. Results of experimentation, after in situ injection to the cortex level, confirm that an interaction between the 2 enantiomers takes place at that level. A direct negative interaction of R-citalopram on one or several effectors that create the antidepressive effect seems justified. This negative interaction has been studied in depth. Animal models have shown that the R-enantiomer has no antidepressive potential and when associated with escitalopram prohedonic effects disappear. Escitalopram is more powerful than citalopram in reducing anxiety but the presence of R-citalopram reduces the positive effects of escitalopram. We then may conclude that R-citalopram antagonizes the antidepressive effects of escitalopram and that its presence limits the therapeutic effect and reduces the speed of action of citalopram. The antagonism of escitalopram by R-citalopram was not expected and one hypothesis is that a direct interaction between the 2 enantiomers may occur on a particular site of the serotonin transporter. Results have shown that R-citalopram has a significant affinity only for the allosteric site of the transporter, which regulates the affinity of the ligand for the active site at the origin of serotonin reuptake inhibition. Unlike citalopram, escitalopram's pharmacologic action is not blocked by R-citalopram explaining its greater therapeutic efficacy and more rapid mode of action.

Due to the stimulation of central and peripheral 5-hydroxytryptamine receptors, the serotonin syndrome is a potentially lethal situation. The large variety of its clinical manifestations leads to a difficult diagnosis. We describe the case of a serotonin syndrome induced by the combined escitalopram and cyclosporine administration. An 84-year-old woman was hospitalized with a history of delirium associated with hyperthermia. The diagnosis of serotonin syndrome was suspected with the combination of the clinical features: the absence of infection, the selective serotonin reuptake inhibitor administration, and the absence of other metabolic and cerebral aetiology. After the discontinuation of escitalopram, the patient's condition improved rapidly. This report is a reminder of the clinical and pharmacological features of the serotonin syndrome from a recent literature review.

Some behavioral side effects of selective serotonin reuptake inhibitor (SSRI) antidepressants have been known for a long time. Since the introduction of these drugs in the 1990s, publications have regularly reported behavioral side effects in children and adolescents, including excitation, motor restlessness, social disinhibition, and above all self-injurious ideation and behavior. Clinical trials provide only limited data. Although these data suggest that some self-injurious and suicidal behavior may indeed occur in children and adolescents receiving SSRIs, they are too disparate to specify the frequency of these acts. Clinical trials provide useful data about drug efficacy, but their methodology is inappropriate for determining the frequency of such side effects. SSRI and suicidality: the data are difficult to read. Although some epidemiologic data suggest that SSRIs may increase the risk of occurrence of self-injurious and suicidal behavior in children and adolescents, other epidemiologic data show that the rate of suicide mortality in children and adolescents has decreased since the introduction of SSRIs. No known mechanism explains how SSRIs might increase the risk of these behavioral side effects. It is clear, however, that these effects are not particular to children and adolescents but may also be observed among adults. SSRIs must be used rationally and carefully in children and adolescents. They should not be administered routinely in youth with obsessive-compulsive or depressive disorders. Their use should be reserved for severe disorders or when psychotherapy alone has been shown to be inadequate, and when they are used, efficacy and side effects must be monitored carefully and frequently.

Intravenous (iv) administration of an antidepressant is a common practice in some European countries, particularly in France, Spain, and Italy in the initial treatment phase of hospitalised, severe depressed patients. After a beneficial response is observed, patients are switched to an oral formulation. The approved treatment period of the iv form of citalopram is limited to 8-10 days. The high bioavailability of citalopram permits the use of identical iv and oral doses. Citalopram is a racemate, consisting of a 1:1 mixture of the S- and R-enantiomers. The therapeutically active component is the S-enantiomer (escitalopram). Pharmacokinetic single dose administration studies in healthy subjects have demonstrated that daily oral administration of 20 mg of escitalopram or 40 mg citalopram results in similar plasma concentrations of the S-enantiomer of citalopram. This open-label multicentre French prospective study investigated the tolerability and efficacy of oral escitalopram 10 and 20 mg/day, administered for a 6-week period as continuation treatment of citalopram (20 mg or 40 mg daily) intravenous (iv), in patients with Major Depressive Disorder. A total of 171 patients were enrolled, of whom 147 (85%) completed the study. The mean MADRS score at inclusion (last citalopram dose) was 31.6 +/- 9.9. The total MADRS score decreased after 3 days of oral treatment with escitalopram. Escitalopram demonstrated a continuous effect in treating depressive symptoms throughout the study. The decrease in MADRS mean total score from baseline was statistically significant to each visit (day 3, 15; p0.0001). At final visit (J42), the decrease was - 18.9 +/- 11.7 (p0.0001) and the MADRS mean total score was 12.7 +/- 9.3. There were no differences seen in the patient response comparing gender, age, and the single or recurrent episodes. The changes of Clinical Global Impression scores (CGI-S, CGI-I, PGE-Patient Global Evaluation) were also indicative of an improvement of the patients' depression. The CGI-I and PGE scores were significantly correlated indicating good agreement between investigator and patient in rating the degree of improvement. At the end of the study, 67% of patients were classified as responders (decrease of MADRS score from baselineor = 50%), and the majority of them were considered remitters (final MADRS scoreor = 12). Overall, the switch from intravenous citalopram to oral escitalopram was well tolerated in the study population. In all, 57 patients (33%) reported at least one adverse event (AE) during the study (21 patients in the 10 mg group and 36 patients in the 20 mg group); of these, 7 patients (4%) withdrew from the study. The most frequently reported AEs were suggestive of residual symptoms of depression (anxiety, 9%; insomnia, 5% of patients). In conclusion, in this study oral escitalopram (10 mg or 20 mg) was well tolerated as continuation treatment after switching from intravenous citalopram (20 mg or 40 mg). From the efficacy and safety data of this study, it can be concluded that the switch from citalopram iv to oral escitalopram (10 and 20 mg/day) is effective in decreasing depressive symptoms, and could be safely proposed in patients with major depressive disorder.

Several drugs are now marketed or being developed as single enantiomers in place of a previous racemic mixture as esomeprazole, levofloxacin, levocetirizin and escitalopram. Among all separative analytic techniques, High Performance Liquid Chromatography is the user method for its high power of resolution. The study of the four enantiomer drugs marketed after their racemic mixture doesn't prove a better benefit-risk ratio. So, we think that the market of enantiomer drug is an industrial strategy to protect their drug from generic competition and keep the monopoly in market.; Ces dernières années, plusieurs médicaments, déjà disponibles sous la forme racémique, ont été commercialisés séparément sous la forme d'un de leurs deux énantiomères, tels que l'ésoméprazole (Inexium®), la lévofloxacine (Tavanic®), la lévocétirizine (Xyzall®) et l'escitalopram (Séroplex®). Parmi les techniques analytiques séparatives existantes, la Chromatographie Liquide Haute Performance est la méthode la plus utilisée pour sa fiabilité et son haut pouvoir de résolution. L'étude des quatre médicaments énantiomères commercialisés après que leurs mélanges racémiques l'aient été, apporte peu de preuves quant à une amélioration du rapport bénéfice-risque. Nous pouvons donc penser que la commercialisation d'un médicament énantiomère n'est qu'une stratégie utilisée par les laboratoires pharmaceutiques pour conserver leur monopole sur le marché et contrer l'arrivée des génériques.

Major depressive disorder in children and adolescents is associated with high risk of suicide and persistent functional impairment. While psychological treatments are used as a first line treatment in mild and moderately severe depression in this age group, the number of prescriptions for antidepressant medication (SSRI) has grown in recent years. Recently, FDA and MHRA advised that most of SSRI should not be used to treat MDD under the age of 18 years. They may increase the risk of suicidal thoughts and self harm. We reviewed the recent literature on efficacy and suicide risks of SSRI in depressed young people. Conflicting findings of SSRI efficacy have been reported in clinical studies. The discrepancies could be related to the heterogeneous samples and the absence of a standard definition of treatment effectiveness. In randomised placebo-controlled antidepressant clinical trials (RCT), the assessment of treatment effectiveness is commonly made with the CDRS-R (improvement of 20% or 30% or 40%) and CGI. SSRI demonstrated significantly, but modest, improvement compared with placebo in CGI score of 1 or 2: 10% more for sertraline, 16.8% more for paroxetine and between 16 to 24% more for fluoxetine. In adults, RCT studies have shown placebo response rates of 30% to 50%, drug response rates of 45% to 50% and drug-placebo differences of 18% to 25%. The highest placebo response rates, in young people, may be related to the highly selected group not representative of the general population of depressed patients and/or to the high youths' sensibility of psychotherapy. Patients participating in antidepressant clinical trials have a low BDI and CDI in Emslie's study for example (2002). In adults, previous reports suggest that SSRI use is associated with increased suicidal risk. But the analyse of 48 277 depressed patients participating in RCT for nine FDA approved antidepressants fail to support an overall difference in suicide risk between antidepressants (SSRI) and placebo treated subjects. An inverse relationship between regional change in use of antidepressants (increased) and suicide (decreased) is found in young -people in United States from 1990 and 2000. We can not draw a conclusion from few studies with few -participants. None suicide have been reported in pharmacological studies. And the link between "suicidality" and MDD can not be excluded. The instruments of assessment in depressed young patients are based on extensions of adult procedures. Whereas clinical picture of MDD in children, adolescents and adults have some differences. Depressed youngsters have more pronounced mood lability. Depressed adolescents have more anhedonia than depressed children. Future investigations into the efficacy and safety of treatments for children and adolescents depression should use specific instruments directly built on phenomenological and clinical picture of depressed children and adolescents. Comparison studies of pharmacotherapy, specific psychotherapies (not only CBT) and combined therapies are necessary to identify the adolescents who will benefit the most from specific or combined therapies. Further studies into the factors that influence treatment outcome including clinical picture (clinical dimensions, severity, duration, co morbidity), genetic factor, age, and i-llness course may help identify appropriate treatments for children and adolescents with MDD. Studies should include patients more severely ill, with associated psychiatric troubles, treatment resistance, history of relapses... In clinical studies, the link between "suicidality" and some clinical dimensions (which take part in clinical picture or not) must be analysed by assessing anhedonia, hopelessness feel, impulsive trait, borderline personality, familial inter-action, biological indices. New treatment should be expand and their efficacy and safety must be study: St John's worth, Bright light therapy, Trans-cranial Magnetic Stimulation.suicide and MDD have a strongest relation and it must be investigate syste-matically during the course of MDD. The suicide risk increases in the context of past history of suicide attempts, hopelessness, psychosis, impulsivity traits, substance abuse, familial dysfunction, life events, open access of arms. The use of SSRI in depressed children and adolescents is also the question of the quality and the support of the consultant and the mode of the prescription.

Escitalopram is a highly selective serotonin reuptake inhibitor (SSRI). It is the therapeutically active S-enantiomer of citalopram. It has been shown, compared with placebo, to be an effective and well-tolerated treatment for major depressive disorders (MDD) in both primary and specialist care settings. A recent meta-analysis has found that escitalopram-treated patients showed significant higher response rates and increased mean change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total scores at weeks 1 and 8 compared with citalopram-treated patients. Each of these active drugs shares similar safety profiles. Although the efficacy of newer antidepressants has been well established for the treatment of mild-to-moderate depression, there are very few studies concerning severe depression.To determine if escitalopram is more effective than citalopram in patients with severe depression.Data were pooled from three different clinical trials, each similar in design and inclusion/exclusion criteria, primary endpoints and assessment schedules. This analysis was exhaustive because it included all trials in which the maximum dose for escitalopram (20 mg) could be administered. According to the cut-off point taken to define severe depression based on the MADRS total score ( 30), 506 patients were considered as severely depressed patients and so included in this analysis. Among them, 169 received escitalopram, 171 received citalopram and 166 received the placebo. The primary efficacy parameter was the mean change from baseline to end of treatment in MADRS total score between escitalopram and citalopram groups, based on last-observation-carried-forward method. The change from baseline to endpoint of the Hamilton rating scale for Depression (HAM-D) and the Clinical Global Impression of Improvement and Severity (CGI-I and CGI-S) were also analysed as secondary criteria. Clinical response was defined by at least a 50% reduction in baseline MADRS total score or by at least a 60% reduction in baseline HAM-D score or by a score of 1 (very much improved) on the CGI scale, and remission by a MADRS total score pound 12.Results showed that the mean change from baseline in the MADRS total score was significantly higher in the escitalopram group compared with the citalopram group (- 17.3 vs - 13.8 respectively, p=0.003). This significant difference was observed as early as week 1 (p=0.01). Response rates were significantly higher for escitalopram than for citalopram (56% vs 41% respectively, p=0.007). A borderline significant difference was found for remission rate in the observed-cases analysis (43% vs 33% respectively, p=0.07). Analyses of the HAM-D, CGI-I and CGI-S scores revealed consistent results.This study shows that the new SSRI escitalopram has better efficacy in the treatment of severe depression than citalopram, its racemic parent. Mean differences between treatments groups were in favour of escitalopram for all scales. The benefits of escitalopram compared with citalopram, as demonstrated by both magnitude of effect and time of onset, are superior to the benefits of citalopram, an antidepressant drug with proven efficacy. This evidence clearly supports the use of escitalopram as a legitimate first-line treatment for MDD.

A first improvement in the treatment of depression was achieved in 1970-80 with the development of selective serotonin reuptake inhibitors (SSRI) because these drugs, which are as potent antidepressants as the tricyclics, are devoid of most of the secondary effects of the latter drugs (orthostatic hypotension, weight gain, dry mouth, etc, mainly caused by their capacity to block alpha1-adrenergic, H1 histaminergic and muscarinic receptors). However, SSRI did not solve all the problems inherent to the treatment of depression because (i) approximately 30% of depressed patients do not respond to these drugs, and (ii) their antidepressant effect becomes really significant only after 3-4 weeks of treatment, like that observed with tricyclics. A further improvement in the development of antidepressant drugs has recently been made with the synthesis of the S enantiomer of citalopram, called Escitalopram. Indeed, this active enantiomer is the most selective among all SSRI available to date, including citalopram. In addition, the potency of Escitalopram to inhibit serotonin reuptake (K(i)=2,1 nM) and to induce antidepressant-like effects in relevant animal paradigms (forced swimming test; chronic mild stress; stress-induced ultrasonic vocalization) is markedly increased as compared with citalopram and other SSRI. In particular, in the forced swimming test, which is especially relevant for assessing the potential antidepressant properties of drugs, Escitalopram was shown to be at least 15 fold more potent than any other SSRI to delay helplessness-induced immobility of rats. Even more interestingly, under chronic treatment conditions, Escitalopram was found to be significantly more rapid than any other antidepressant (tricyclics such as imipramine, SSRI such as fluoxetine) to restore sucrose intake in rats subjected to chronic mild stress, suggesting a reduced delay in its antidepressant action. This was indeed fully confirmed in humans as only 1-2 weeks of treatment with Escitalopram was enough to significantly reduce MADRS score in depressed subjects, compared to 3-4 weeks with any other antidepressant drug. These unique properties led to further investigations of the pharmacological profile of Escitalopram. It thus appeared that, at equipotent doses, the S enantiomer was significantly more efficient than citalopram (racemate) to increase the extracellular levels of serotonin within the frontal cortex of freely moving rats bearing a locally implanted microdialysis probe. Further experiments showed that R-citalopram counteracted the capacity of Escitalopram to enhance extracellular 5-HT levels, thereby explaining why the racemate had only a limited action in this regard. In addition, behavioural studies (stress-induced ultrasonic vocalization test) also showed that R-citalopram exerts effects opposite to those (antidepressant--and anxiolytic--like effects) of Escitalopram. The reason for these differences between the two enantiomers might concern the secondary molecular targets at which citalopram acts, but with affinities at least two orders of magnitude less than for the serotonin transporter. Indeed, R-citalopram has a 7-10-fold higher affinity for H1 histaminergic (K(i)=180 nM) and alpha1-adrenergic (K(i)=560 nM) receptors than Escitalopram (respective K(is)or = 2 000 nM), and this difference might contribute not only to the better selectivity of the latter enantiomer for its therapeutically relevant target (i.e. the serotonin transporter) but also to its improved capacity to enhance central 5-HT neurotransmission. On the other hand, the global affinity of Escitalopram (K(i)=200-430 nM) for both subtypes of sigma receptors (sigma1 and sigma2) is higher than that of R-citalopram (and of the racemate citalopram; K(i)=200-1 500 nM), and this might also strengthen the antidepressant and anxiolytic effects of the S enantiomer because behavioural studies showed that selective sigma1 and sigma2 agonists are endowed with both antidepressant--and anxiolytic-like properties in relevant animal models. However, to date, the exact nature (agonist or antagonist) of the action of Escitalopram at sigma receptors is not known yet, and this question has to be addressed in future investigations. Altogether, these data open novel perspectives for both a better treatment of depressive disorders and a better knowledge of the neurobiological mechanisms underlying antidepressant therapy, and, possibly, depression itself.

The occurrence of a pathological gambling behavior in a 61-year-old patient with idiopathic Parkinson's disease treated with dopaminergic drugs is reported. This is the first case reported with bromocriptine. The main characteristics and the mechanism of this recently described and a unexpected, adverse drug reaction are discussed.

Selective serotonin reuptake inhibitors, the antidepressants most widely prescribed today, exert specific action against various anxiety disorders and have an excellent acceptability profile. In addition, anxiety problems are commonly seen in depression, in the form of either characterised anxiety disorders or associated anxious symptoms. Such symptoms of anxiety result in increased risk of suicide and appear to be associated with development of more severe and chronic depressive disorders. Because of the adverse effects associated with anxiolytics, in particular benzodiazepines, their indications have been restricted. Consequently, first-line drug therapy for anxiety symptoms associated with depression involves selection of an antidepressant having anxiolytic properties. Specific serotonin reuptake inhibitors are commonly favoured at present since they have a less pronounced sedative effect than the tricyclic antidepressants (e.g. amitriptyline, maprotiline). Escitalopram, the active enantiomer of citalopram, has demonstrated efficacy and rapidity of action upon depressive symptoms seen in major depressive episodes. Global analysis of three studies comparing citalopram and escitalopram with a placebo in depressive disorders allowed specific investigation of the activity of these molecules upon the anxiety component of depressive disorders. Anxiety was quantitatively evaluated using item 6 (inner tension) of the MADRS, and for two of the three studies, using the anxiety sub-score of the HAM-D as well as the HAM-A total score. The results for the two active molecules demonstrate significant superiority in comparison with the placebo. Furthermore, in the case of escitalopram, this improvement appeared significant as of the first week of treatment (p0.05); by the end of the second week of treatment, the degree of significance was even more pronounced (p0.001). The tolerability profile of these two active substances was very good. These studies thus demonstrate the efficacy of escitalopram against anxiety symptoms associated with depression, together with particularly interesting rapidity of action. Use of an antidepressant with proven activity against anxiety accompanying depression avoids the need for co-prescription of tranquillizers, which themselves are not devoid of adverse effects.

The inhibition of the serotonin and/or noradrenalin reuptake is often given as the mechanism of action of antidepressants. This may be true but it's certainly wrong! The diversity of chemical structure and pharmacological profiles of second generation antidepressants shows that the biochemical property that is the most often found is the inhibition of the uptake of 5-HT and/or NA. The difference of the kinetics between the inhibition of the monoamine reuptake and the antidepressant effect is only one of the reasons to believe that the real mechanism of their antidepressant action is elsewhere. The different hypotheses that have been proposed will be examined.

Citalopram, a new bicyclic antidepressant, is the most selective serotonin reuptake inhibitor. In a number of double-blind controlled studies, citalopram was compared to placebo and to known tricyclic antidepressants. These studies have shown their efficacy and good safety. The inefficacy of a psychotropic treatment in at least 20% of depressives has led a number of authors to propose original drug combinations and associations, like antidepressant/lithium (Li), antidepressant/sleep deprivation (agrypnia), antidepressant/ECT, or antidepressant/LT3. The aim of this investigation is to evaluate the clinical effectiveness and safety of a combined citalopram/lithium treatment in therapy-resistant patients, taking account of serotonergic functions, as tested by the fenfluramine/prolactin test, and of drug pharmacokinetics and pharmacogenetics of metabolism.A washout period of 3 days before initiating the treatment is included. After an open treatment phase of 28 days (D) with citalopram (20 mg D1-D3; 40 mg D4-D14; 40 or 60 mg D15-D28; concomitant medication allowed: chloral, chlorazepate), the nonresponding patients [less than 50% improvement in the total score on the 21 item-Hamilton Depression Rating Scale (HDRS)] are selected and treated with or without Li (randomized in double-blind conditions: citalopram/Li or citalopram/placebo) during the treatment (D29-D35). Thereafter, all patients included in the double-blind phase subsequently receive an open treatment with citalopram/Li for 7 days (D36-D42). The hypothesis of a relationship between serotoninergic functions in patients using the fenfluramine/prolactin test (D1) and the clinical response to citalopram (and Li) is assessed. Moreover, it is evaluated whether the pharmacogenetic status of the patients, as determined by the mephenytoin/dextromethorphan test (D0-D28), is related to the metabolism of fenfluramine and citalopram, and also to the clinical response.Patients with a diagnosis of major depressive disorders according to DSM III are submitted to a clinical assessment of D1, D7, D14, D28, D35, D42: HDRS, CGI (clinical global impression), VAS (visual analog scales for self-rating of depression), HDRS (Hamilton depression rating scale, 21 items), UKU (side effects scale), and to clinical laboratory examens, as well as ECG, control of weight, pulse, blood pressure at D1, D28, D35. Fenfluramine/prolactin test: A butterfly needle is inserted in a forearm vein at 7 h 45 and is kept patent with liquemine. Samples for plasma prolactin, and d- and l-fenfluramine determinations are drawn at 8 h 15 (base line). Patients are given 60 mg fenfluramine (as a racemate) at 8 h 30. Kinetic points are determined at 9 h 30, 10 h 30, 11 h 30, 12 h 30, 13 h 30. Plasma levels of d- and l-fenfluramine are determined by gas chromatography and prolactin by IRNA. Mephenytoin/dextromethorphan test: Patients empty their bladders before the test; they are then given 25 mg dextropethorphan and 100 mg mephenytoin (as a racemate) at 8 h 00. They collect all urines during the following 8 hours. The metabolic ratio is determined by gas chromatography (metabolic ratio dextromethorphan/dextrorphan greater than 0.3 = PM (poor metabolizer); mephenytoin/4-OH-mephenytoin greater than 5.6, or mephenytoin S/R greater than 0.8 = PM). Citalopram plasma levels: Plasma levels of citalopram, desmethylcitalopram and didesmethylcitalopram are determined by gas chromatography--mass spectrometry. RESULTS OF THE PILOT STUDY. The investigation has been preceded by a pilot study including 14 patients, using the abovementioned protocol, except that all nonresponders were medicated with citalopram/Li on D28 to D42. The mean total score (n = 14) on the 21 item Hamilton scale was significantly reduced after the treatment, ie from 26.93 +/- 5.80 on D1 to 8.57 +/- 6.90 on D35 (p less than 0.001). A similar patCitalopram, a new bicyclic antidepressant, is the most selective serotonin reu

In an open, clinical trial comprising a total of 49 depressed in-patients, a new selective 5-HT uptake inhibitor citalopram was administered by intravenous infusion in doses of 20-60 mg once daily for per 3 weeks. The therapeutic effect was assessed globally and by means of the CPRS subscale for depression (MADRS). About 40 per cent of the patients showed a complete response whereas about 25 per cent showed a partial response. Side effects which were rated globally and recorded according to a check-list were generally mild and infrequent. The side-effects most frequently observed were tremor, drowsiness, and dizziness which occurred in about 15 per cent of the patients.' Three patients were withdrawn prematurely because of nausea and one because of a skin rash. Cardiovascular recordings were normal except for one patient, who developed a hypertension which may have been related to the test drug. No pathological laboratory values were detected during the trial period. The authors conclude that intravenously administered citalopram is well suited for the treatment of depressed patients.

The antidepressant effect of citalopram, a specific inhibitor of the reuptake of serotonin, was explored in an open phase II study involving twenty-one patients hospitalized for depression. Fourteen patients responded, six did not and one was excluded from the study. These preliminary results suggest that citalopram is an effective, well tolerated antidepressant.