[Crosscultural aspects of bipolar disorder: results of a comparative study between French and Tunisian patients]. / Les aspects culturels du trouble bipolaire : résultats d'une étude comparative entre des patients français et tunisiens.

BACKGROUND: Bipolar disorders are one of the most potentially severe psychiatric disorders, implying a high degree of morbidity and incapacity for patients. Indeed, the World Health Organization in 1996 ranked them as the sixth most disabling condition worldwide. Major advances have been achieved in their understanding and management. However, too many patients do not yet benefit from them. As a matter of fact, bipolar disorders are still underestimated and under-recognized, being too often misdiagnosed with major depression or schizophrenia; the DSM-IV acknowledges the trend of clinicians to overdiagnose schizophrenia (rather than bipolar disorder), especially in ethnic groups and young people. Indeed, cultural factors may impact the symptomatology and the course of the disease. In particular, it has been shown by many authors that schizophrenia-like features are more likely to be found in southern countries. Similarly, the same authors have reported more manic than depressive episodes during the course of bipolar disorder. OBJECTIVE: We aimed at comparing individuals with bipolar disorder living in two distinct geographic and cultural environments, namely France and Tunisia. METHOD: Our study included two samples of 40 patients each, natives from the country, who were admitted during 2007 to the hospitals of Razi (Tunis, Tunisia) and Le Vinatier (Lyon, France) and suffering from a bipolar disorder according to the DSM-IV criteria. The French sample was constituted by all the patients meeting the inclusion criteria and the Tunisian one was selected by matching the patients by gender and duration of the disorder. RESULTS: Our results were consistent with the existing literature, showing many similarities and some marked differences such as a greater rate of manic episodes in the onset and during the course of the illness as well. The main result was the type of the first episode: mania in three quarter cases in Tunisia and depressive in the same proportion in France. The same figures applied to the recurrences. Unipolar mania, in particular, was three times more common in Tunisia than in France. DISCUSSION: Beyond the methodological biases (in-patients recruitment, diagnosis habits, cultural tolerance), these differences are also probably linked to climatic factors, such as temperature and photoperiod. CONCLUSION: The early detection of bipolar disorder is of crucial importance to provide specific treatments to patients. In a world where psychiatrists are more and more exposed to meet patients from various backgrounds, it is necessary to be aware of culture-bound features. Besides, the primacy of mania, in southern countries, may be a key to deepen our understanding of bipolar disorder and consequently its management.

[Correlations between Beck's suicidal ideation scale, suicidal risk assessment scale RSD and Hamilton's depression rating scale]. / Corrélations entre l'échelle d'idéation suicidaire de Beck, l'échelle d'évaluation du risque suicidaire RSD et l'échelle Hamilton dépression.

INTRODUCTION: Most of the people who will attempt suicide, talk about it beforehand. Therefore, recognition of suicidal risk is not absolutely impossible. Beck's suicidal ideation scale and Ducher's suicidal risk assessment scale (RSD) are common tools to help practicians in this way. AIM OF THE STUDY: These scales and the Hamilton's depression scale were included in an international multicentric, phase IV, double-blind study, according to two parallel groups who had been administered a fixed dose of fluvoxamin or fluoxetin for six weeks. This allowed examination of the correlations between these scales and the relations, which could possibly exist between suicidal risk, depression and anxiety. RESULTS: (a) Relationships between the Beck's suicidal ideation scale, the suicidal risk assessment scale RSD and Hamilton's depression before treatment. Before treatment, the analysis was conducted with 108 male and female depressive outpatients, aged 18 or over. Results revealed a significant positive correlation (with a Pearson's correlation coefficient r equal to 0.69 and risk p<0.0001) between Beck's suicidal ideation scale and the suicidal risk assessment scale RSD. These scales correlate less consistently with Hamilton's depression (Beck/Hamilton's depression: r=0.34; p=0.0004-RSD/Hamilton's depression: r=0.35; p=0.0002). We observed that the clinical anxiety scale by Snaith is also strongly correlated to these two suicidal risk assessment scales (Beck/CAS: r=0.48; p<0.0001-RSD/CAS: r=0.35; p=0.0005). Besides, the item "suicide" of Hamilton's depression scale accounts for more than a third of the variability of Beck's suicidal ideation scale and the suicidal risk assessment scale RSD. According to these results, the suicidal risk evaluated by these two scales seems to be significantly correlated with anxiety as much as with depression. On the other hand, the Clinical Global Impression is fairly significantly correlated with Beck's suicidal ideation scale (r=0.22; p=0.02), unlike the suicidal risk assessment scale RSD (r=0.42; p<0.0001) and Hamilton's depression scale (r=0.58; p<0.0001); (b) Relationships between Beck's suicidal ideation scale, the suicidal risk assessment scale RSD and Hamilton's depression under treatment. The follow-up under treatment (fluvoxamin or fluoxetin) during six weeks revealed the significantly better sensitivity of the RSD in comparison with Beck's suicidal ideation scale and Hamilton's depression scale, showing the significantly faster improvement in the RSD (p<0.0001). There was no significant difference between the evolution of Beck's suicidal ideation scale and Hamilton's depression scale. So, under treatment with fluvoxamin or fluoxetin, the improvement in suicidal risk appears to be as rapid as the improvement in depression. If we look at the treatment prescribed, only the suicidal risk assessment scale RSD revealed a significant difference between the two molecules, with more rapid improvement with fluvoxamin (p=0.015) from D14. CONCLUSION: In conclusion, the results of this study hypothesize that the suicidal risk, as assessed by Beck's suicidal ideation scale and the suicidal risk assessment scale RSD, appears to be consistently correlated with both the level of anxiety and depression. The study also suggests that all antidepressants may not be equally effective on suicidal risk.

[Clinical potentialities and perspectives for the use of aripiprazole in other disorders than its classical indications. A critical analysis of the recent literature]. / Potentialités cliniques et perspectives d'utilisation de l'aripiprazole hors de ses champs classiques d'indication. Analyse critique des données de la littérature récente.

Aripiprazole is indicated for the treatment of schizophrenia in Europe and the United States, and for bipolar disorders in the latter. Nevertheless, a review of recent literature has shown that aripiprazole has been studied in many other disorders, notably resistant depression, anxiety, obsessive-compulsive disorder, borderline personality, Tourette syndrome, addiction, psychotic symptoms in children and adolescents, and neurological and psychiatric disorders in the elderly (late onset delusional disorders, Alzheimer, Parkinson, and delirium). The study of aripiprazole in these numerous indications is motivated by its excellent tolerance and original pharmacological effect (partial agonistic effect on the D2 and 5-HT1A receptors, and antagonistic effect on the 5-HT2A receptors). This paper reviews the recent literature, with particular attention paid to the level of proof provided by these various studies.

[Present data and treatment schedule of aripiprazole in the treatment of schizophrenia]. / Données actuelles et modalités d'utilisation de l'aripiprazole dans le traitement de la schizophrénie.

Among the second generation antipsychotics, aripiprazole presents a new pharmacological profile, basically differentiated by a partial agonist effect on the D2 and D3 dopaminergic receptors. Five short-term efficacy studies, conducted on 1648 patients presenting with schizophrenia or acute relapse of schizoaffective disorders, demonstrated the greater efficacy of aripiprazole than the placebo and comparable efficacy to that of haloperidol and risperidone. The short-term tolerance profile was characterised by a lesser incidence of the extrapyramidal side effects and drowsiness than with haloperidol. Two thousand six hundred and eighty five patients were followed-up over a period of 26 to 52 weeks in five clinical trials versus a placebo and haloperidol, olanzapine, quetiapine and risperiodone: demonstrated efficacy in maintaining the response to treatment and on the delay before relapse was comparable to the other antipsychotics. The classical side effects of antipsychotics decreased in the long-term. Versus olanzapine, a glucid and lipid profile, clearly in favour of aripiprazole, was completed by a lesser incidence of hyperprolactinaemia. Aripiprazole is effective on all the dimensions of schizophrenia: the positive and negative and depressive and anxious symptomatology. It appears to be of interest, notably on the cognitive dimension, which should motivate more in-depth exploration of its place in the treatment in the early stages of schizophrenia. Its therapeutic schedule and the methods of initiation are an essential criterion to the success of treatment, notably during the substitution of other antipsychotics. The clinical and pharmacological originality of aripiprazole would justify the terminology of a "third generation antipsychotic".

[Impact of a new cognitive remediation strategy on interpersonal problem solving skills and social autonomy in schizophrenia]. / Impact de la remédiation cognitive dans la schizophrénie sur les stratégies de résolution de problèmes et l'autonomie sociale: utilisation du logiciel REHACOM.

INTRODUCTION: Despite recent developments, the impact of pharmacotherapy on social autonomy and interpersonal problem solving skills in patients with schizophrenia remains limited, with consequences in terms of socio-professional functioning. Indeed, independently of the positive, negative and/or disorganization symptoms, functional deficits in patients with schizophrenia rely mainly on various cognitive impairments. OBJECTIVES: To determine the impact of a new Cognitive Remediation Strategy on interpersonal problem solving skills, social autonomy and symptoms in patients with schizophrenia. METHODS: Thirty patients with schizophrenia were enrolled in a program consisting of 14 training sessions of 4 cognitive functions (attention/concentration, topological memory, logical reasoning, executive functions) using the REHACOM software. Measurements of attention (Continuous Performance Test, CPT), memory (Rivermead Behavioural Memory Test, RBMT) and executive functions (Wisconsin Card Sorting Test, WCST) as well as interpersonal problem solving skills (Assessment of Interpersonal Problem-Solving Skills, AIPSS) and social autonomy (Social Autonomy Scale, EAS) and finally schizophrenia symptoms (Positive And Negative Syndrom Scale, PANSS) were undertaken at the beginning and the end of the 14 remediation meetings. RESULTS: Cognitive functions, interpersonal problems solving skills, social autonomy and symptoms were significantly improved by the Cognitive Remediation Strategy. CONCLUSION: Our results confirm the therapeutic impact of a Cognitive Remediation Strategy among 30 schizophrenic patients stabilised on clinical, therapeutic and functional levels. The question of the long-term maintenance of such improvements still requires further investigation.

[A new patient focused scale for measuring quality of life in schizophrenic patients: the Schizophrenia Quality of Life Scale (SOL)]. / Création et validation d'un autoquestionnaire mesurant la qualité de vie de patients souffrant de schizophrénie: l'échelle schizophrenia quality of life (SOL).

UNLABELLED: RATIONALE/OBJECTIVE: Quality of Life (QOL) has been recognized as an important measure of the outcome of patients by clinicians and policy makers in Mental Health. The emerging consensus in the health field that personal values and the patient's preferences are important in monitoring the quality of medical care outcomes makes it even more important to assess the patient's perspectives. Unfortunately, there is little consensus about what constitutes QOL or how to measure it, particularly in psychotic patients. The objective of this study is to report the stages of development and validation of a QOL questionnaire based on issues pertinent to patients with schizophrenia. METHOD: During a first phase, identical pattern were identified among interviews (conducted by psychologists) of schizophrenic patients (DSM IV, n = 100), mental health staff (n = 20) and families (n = 20). The data gathered in the first phase were discussed and organized, by 25 experts, into a structure that made up the skeleton of the scale (133 items, 17 factors). Based on a prospective epidemiological study conducted with 337 French psychiatrists, a validation analysis of structural and psychometric proprieties was performed. Finally reliability of the scale was assessed by a second test/retest (D0, D7) study (n = 100). RESULTS: A total of 686 schizophrenic, schizophreniform or schizoaffective patients (DSM IV) were included. Internal consistency analysis identified 14 factors (74 items), all with a Cronbach's alpha of at least 0.75: professional life (0.95), affective and sexual life (0.92), illness knowledge (0.90), relationship (0.92), life satisfaction, (0.87), coping with drugs (0.79), drugs impact on the body (0.87), daily life (0.83), family relationship (0.81), future (0.88), security feeling (0.84), leisure (0.87), money management (0.76) and autonomy (0.75). Construct validity was confirmed (Pearson test) using established clinical (Brief Psychiatry Rating Scale and Clinical Global Improvement), social (Psychological Aptitude Rating Scale) and generic quality of life (Functional Status questionnaire) measures, correlation coefficient was significant for all factors but 2 in the BPRS (illness knowledge and coping with drugs) and 3 in the CGI (illness knowledge, coping with drugs and life satisfaction). Lastly, test/retest indicated high reliability for each factor (p < 0.001), the lower correlation coefficient (r) was 0.526. CONCLUSIONS: The Schizophrenia Quality Of Life-scale (SOL), based on a patient's point of view approach, is an efficient, multidimensional instrument designed for the measurement of the consequences of schizophrenia on individuals' lives.

Repetitive transcranial magnetic stimulation does not potentiate antidepressant treatment.

In a double blind controlled study, rTMS results in a similar antidepressant effect to sham in combination with paroxetine. Both groups had the same delay in scale's scores improvement. rTMS seems not to be efficient as an add-on treatment to pharmacological medication in non-resistant major depression.

[Concurrent validation of the suicidal risk assessment scale (R.S.D.) with the Beck's suicidal ideation scale]. / Validation concourante de l'échelle d'évaluation du risque suicidaire (R.S.D.) avec l'échelle d'idéation suicidaire de Beck.

The prevention of suicide is a top priority in mental health. The determination of high risk suicidal groups is not sufficient. The expressing suicidal ideas is not a protective factor, but in contrary a risk factor to take into account, or even to search and to quantify: 80% of the subjects who attempt to commit suicide or commit suicide express such ideas months before. Several evaluation instruments try to help the practitioners or the research workers in this reasoning. The suicidal risk assessment scale RSD can be cited in particular. It is composed of eleven sections. The 0 level corresponds to the absence of particular ideas of death or suicide. Levels 1 and 2, the presence of ideas of death. Levels 3-4-5, the presence of suicidal ideas. The difference compared to the majority of the other scales consecrated to the same subject, the passif desire of death, occupies a place totally particular in the RSD (level 6). From the level 7, the risk of acting out seems to become more important. It stops being a simple idea of suicide, but becomes a real will of dying, firstly retained by something or someone (level 7), the fear of causing suffering to dear ones or a religious belief., then determined (level 8). Finally, the patient has elaborated a concrete plan (level 9) or he has already started the preparation of acting out (level 10). It is just necessary to evaluate and to note the highest level of the scale. The inclusion of the suicidal risk assessment scale RSD and of the Suicidal Ideation Scale by Beck in an international multicenters, phase IV, double-blind study, according to two parallel groups, with a fixed dose of fluoxétine or fluvoxamine for six weeks, allowed to search correlations which could exist between the two scales. The ana-lysis before the beginning of the treatment was done on 108 outpatients depressive, male and female, aged 18 or over. It finds a satisfactory concurrent validity between the suicidal risk assessment scale RSD and the Suicidal Ideation Scale by Beck (r=0.69; p<0.0001) as well as between the RSD and the item "suicide" of the Depression scale by Hamilton (r=0.60; p<0.0001). On the other hand, it is less satisfactory between the suicidal risk assessment scale RSD and the Hamilton Depression scale overall score (r=0.35; p=0.0002). During the evolution under the treatment, the suicidal risk assessment scale RSD shows an improvement significantly faster than the Hamilton Depression scale or the Beck's Suicidal Ideation Scale (p<0.0001). This statement of fact arouses some questions about the suicidal risk of which the evolution in the case of a treated depressive episode could be quicker than first thought. All the more so as this difference is affected by the type of the treatment (p=0.015). Moreover, a score of 7 and more on the suicidal risk assessment scale RSD seems to represent a risk level judged particularly significant by the experimenters. In effect, the existence of such a suicidal risk was a criteria of exclusion and no patient with a level superior to 6 on suicidal risk assessment scale RSD was included. In conclusion, the utilisation of the suicidal risk assessment scale RSD could be interesting in the prevention of suicide.

[Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatonin- agonist and selective 5HT2c receptors antagonist, in the treatment of major depressive disorders]. / Etude pilote comparant en aveugle l'effet thérapeutique de deux doses d'agomélatine, agoniste des récepteurs de la mélatonine et antagoniste des récepteurs 5HT2C, chez 30 patients présentant un épisode dépressif majeur.

RATIONALE AND METHOD: Two doses of agomelatine (S-20098), a novel potential antidepressant drug with a new pharmacological profile (melatonin agonist and selective 5HT2C antagonist), were compared in a double-blind, randomised, pilot study in order to estimate the antidepressant activity shown in preclinical data. Inpatients suffering from major depressive disorder (DSM III-R criteria) and presenting a minimal score of 25 for MADRS were selected at D-7. After one week of run-in placebo treatment, included patients received one evening dose of agomelatine (either 5 or 100 mg) for 4 to 8 weeks. Hospitalization was required at least for the first 3 weeks. Patients presenting a satisfying response to treatment (MADRS total score < 15 or decrease > or = 40% from inclusion score) could be treated as outpatients. A follow up of 2 weeks was performed after stopping the treatment. The total duration of the treatment period could vary, according to investigator's decision, between 7 and 11 weeks. Evaluation criteria included MADRS, HAMD-17, HAM-A, CGI and AMDP 5 at D0, D7, D14 and D28, and, when applicable, at D35, D42, D49 and D56. Safety evaluations included recording of adverse events, ECG monitoring and biology. RESULTS: Thirty inpatients were selected and 28 included (14 per group). There was no major difference between groups at inclusion, neither for demographic nor evaluation criteria. One patient of each group was excluded of the ITT analysis; 19 patients completed the mandatory period up to D28: 10 in the 5 mg group and 9 in the 100 mg group; 10 patients (5 in each group) carried on the study during the optional period, up to D56 for 7 out of them (4 in the 5 mg group, 3 in the 100 mg group). Efficacy criteria showed a significant improvement in both groups, with highly significant within group evolutions (p < 0.001 whatever the criteria) and without significant difference between groups. However, better results were observed in the 5 mg group compared to the 100 mg group. Total MADRS scores then decreased from 30.7 +/- 3.5 to 14.8 +/- 6.4 in the 5 mg group vs a decrease from 31.6 +/- 4.7 to 18.6 +/- 14.8 in the 100 mg group. Furthermore, significant improvement between D14 and D28 visits were only seen in the 5 mg group. Analysis of somatic complaints (AMDP 5) showed with both treatments a strong decrease of symptoms during the study, especially for items related to sleep disorders (difficulties in falling asleep, interrupted sleep, shortened sleep, early wakening and drowsiness). Acceptability was good for both doses of agomelatine. However, there were slightly more emergent adverse events and severe treatment-related adverse events in the 100 mg group. No modifications of cardio-vascular parameters nor biological abnormalities were observed in both groups. CONCLUSION: Preliminary clinical data with agomelatine confirm the potential antidepressant effect in accordance with positive preclinical results. There was no significant difference between 5 and 100 mg, both for efficacy and for safety. However, the data suggest that 5 mg could be a dose at least as effective and slightly better tolerated than 100 mg. Further double-blind controlled studies versus active comparators and placebo are required in order to confirm these results.

[In utero exposure to benzodiazepine. Is there a risk for anal atresia with lorazepam?]. / Exposition in utero au lorazépam et atrésie anale: signal épidémiologique.

Drugs of the Benzodiazepine family are among the most frequently prescribed in France. Since anxiety disorders, for which these substances are mostly indicated, affect 10% of pregnant women, it is very likely that such a treatment could expose many foetuses to BZD during the first three Months of pregnancy. We know that the teratologic effect is not necessarily based on dose rate, but that it is associated with fetal drug exposure during the first 12 weeks of gestation, when organ formation occurs. Most epidemiologists concur that the baseline incidence of congenital damage is 2-2,5% in Europe. The results from a large number of stu-dies on associations between the use of BZDs in pregnancy and congenital malformations are conflicting. An in-depth analysis of existing literature shows results that are hardly comparable, if not contradictory, due to extreme differences in methodological approaches. In a recent meta-analysis case-control studies and cohort studies were analyzed separately. Among the case-control studies significant associations were found between BZD exposure and both, major malformations and oral clefts, whereas the cohort studies showed no association between BZD and any kind of malformation. The purpose of our study is to search for a specific teratogenic effect of this class of drugs, using data collected (1976-1997) by the French Central-East (FCE) registry of congenital malformations, member of the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) located in Lyon, France. This registry monitor malformations among 100,000 births per Year. We analyzed 13,703 cases where information is available on whether or not the mother took a drug during her first trimester of pregnancy. Among them, 3,603 (28%) actually took a drug, and 262 (6.8%) took some sort of benzodiazepine (BDZ). BZD were divided into 9 categories, 8 being the most frequently present, plus one broad category of "others". Malformations were divided into ten categories: congenital anomalies of heart, cleft lip and/or cleft palate, neural tube defects, other anomalies of central nervous system, hypospadias, urinary malformations, anal atresia, other digestive anomalies, limb reduction defects, and genetic anomalies, including chromosome aberrations and monogenic conditions. Other malformations were grouped in an eleventh category. The interesting aspect of this study is that it takes into account the BZD metabolism. It is worth noting that the hepatic catabolism of benzodiazepine is a very complex one, because it leads to derived molecules which are sometimes active and/or present in the common metabolic route of major commercial drugs. Our hypothesis is that if one BZD is associated specifically to a certain type of congenital defect, we may find this BZD to be overrepresented, as compared with other BZDs, in newborns exhibiting some type of congenital defect. The analysis was run according to a case-control approach. Odd ratios (OR) and their 95% confidence intervals were calculated by logistic regression with adjustment for maternal age and parity. When one category of defects was considered, infants having the corresponding malformation were considered as cases, while infants with other malformations were considered as controls. In a similar way infants having being exposed to a given drug were considered as exposed, while infants exposed to any other drug were considered as unexposed. The analysis then was run in 4 steps. Step 1: full sample. With 13,703 cases. We observed no increased risk for any specific malformation type associated with use of BZD. Step 2: further defining drug exposure as a specific BZD, and all others unexposed, a significant association was seen between lorazepam and anal atresia. OR=6.2 (95% CI2.4-15.7, p=0.01). Step 3: this finding was upheld and no other emerged when exposure was defined as the drug or any of its active metabolites. This step was performed because hepatic catabolism of BDZs leads to derived molecules that are sometimes active and/or present in the common metabolic route of major marketed BZDs. Step 4: similarly, the lorazepam/anal atresia finding was upheld when the analysis was restricted to the 262 malformed infants exposed to BZDs in utero. Six cases of anal atresia were found among all newborns exposed to BZD in utero, and five of them were exposed to lorazepam, representing a hypothesis to be tested in further. We are not aware of other reports of this association, and it should be regarded as preliminary until confirmed in other data sets.

[Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatoninergic agonist and selective 5HT2C receptors antagonist, in the treatment of major depressive disorders]. / Etude pilote comparant en aveugle l'effet thérapeutique de deux doses d'agomélatine - agoniste des récepteurs de la mélatonine et antagoniste des récepteurs 5HT2c - chez 30 patients.

Rational and method - Two doses of agomelatine (S-20098), a novel potential antidepressant drug with a new pharmacological profile (melatonin agonist and selective 5HT2C antagonist -MASSA), were compared in a double-blind, randomised, pilot study in order to estimate the antidepressant activity shown in preclinical data. Inpatients suffering from major depressive disorder (DSM III-R criteria) and presenting a minimal score of 25 for MADRS were selected at D -7. After one week of run-in placebo treatment, included patients received one evening dose of agomelatine (either 5 or 100 mg) for 4 to 8 weeks. Hospitalization was required at least for the first 3 weeks. Patients presenting a satisfying response to treatment (MADRS total score<15 or decrease 40% from inclusion score) could be treated as outpatients. A follow up of 2 weeks was performed after stopping the treatment. The total duration of the treatment period could vary, according to investigator's decision, between 7 and 11 weeks. Evaluation criteria included MADRS, HAMD-17, HAM-A, CGI and AMDP 5 at D0, D7, D14 and D28, and, when applicable, at D35, D42, D49 and D56. Safety evaluations included recording of adverse events, ECG monitoring and biology. Results - Thirty inpatients were selected and 28 included (14 per group). There was no major difference between groups at inclusion, neither for demographic nor evaluation criteria. One patient of each group was excluded of the ITT analysis; 19 patients completed the mandatory period up to D28: 10 in the 5 mg group and 9 in the 100 mg group; 10 patients (5 in each group) carried on the study during the optional period, up to D56 for 7 out of them (4 in the 5 mg group, 3 in the 100 mg group). Efficacy criteria showed a significant improvement in both groups, with highly significant within group evolutions (p<0.001 whatever the criteria) and without significant difference between groups. However, better results were observed in the 5 mg group compared to the 100 mg group. Total MADRS scores then decreased from 30.7 3.5 to 14.8 6.4 in the 5 mg group vs a decrease from 31.6 4.7 to 18.6 14.8 in the 100 mg group. Furthermore, significant improvement between D14 and D28 visits were only seen in the 5 mg group. Analysis of somatic complaints (AMDP 5) showed with both treatment a strong decrease of symptoms during the study, especially for items related to sleep disorders (difficulties for falling asleep, interrupted sleep, shortened sleep, early wakening and drowsiness). Acceptability was good for both doses of agomelatine. However, there were slightly more emergent adverse events and severe treatment-related adverse event in the 100 mg group. No modifications of cardio-vascular parameters nor biological abnormalities were observed in both groups. Conclusion - Preliminary clinical data with agomelatine confirm the potential antidepressant effect in accordance with positive preclinical results. There was no significant difference between 5 and 100 mg, both for efficacy and for safety. However, the data suggest that 5 mg could be a at least as effective and slightly better tolerated dose than 100 mg. Further double-blind controlled studies versus active comparators and placebo are required in order to confirm these results.

WCST performance and schizotypal features in the first-degree relatives of patients with schizophrenia.

Since the findings concerning the Wisconsin Card Sorting Test (WCST) performance of healthy first-degree relatives of patients with schizophrenia are equivocal, it still remains unclear whether the WCST may serve as a neuropsychological indicator of vulnerability to schizophrenia. The aim of this study was to evaluate whether the first-degree relatives' schizotypal features could account for these discrepancies. The subjects were 24 schizophrenic probands, 49 of their first-degree relatives and 41 normal controls. The computerized version of the WCST was used and schizotypy features were assessed using four of Chapman's scales. The patient group performed worse on the WCST and had higher scores of schizotypy than the control group. The relatives group did not significantly differ from the control, neither on the WCST performance nor on the scores of schizotypy. However, the subgroup of relatives and the subgroup of patients with high scores on the negative dimension of schizotypy showed a worse performance on the WCST than the subgroups with low scores. There were no differences on the WCST performance between the subgroups with high vs. low scores on the positive dimension of schizotypy. Thus, discrepancies across studies could be explained by a confounding factor represented by the negative dimension of schizotypy.

[Vulnerability to schizophrenia: neuropsychological performance and schizotypal personality traits]. / Vulnérabilité à la schizophrénie: performances neuropsychologiques et traits de personnalité schizotypique.

Although some neuropsychological deficits and a high rate of schizotypal personality disorders have been found in the first-degree relatives of patients with schizophrenia, few studies have looked for a link between those two types of potential marker of vulnerability to this disease. The aims of this study were: 1) to confirm some executive/attentional deficits in a group of first-degree relatives including not only siblings but also parents; 2) to evaluate the schizotypal traits using the French version of 4 self-reporting scales proposed by Chapman and his colleagues; 3) to look for a dependence or independence between the neuropsychological performance and the scores on the scales of schizotypy. Twenty four patients with schizophrenia, 48 of their first-degree relatives and 31 controls were included in the study. Both attentional tests (a Digit Symbol Substitution Test and a Degraded Stimulus-Continuous Performance Test) confirmed a worse performance in the patient and in the first-degree relative groups than in the control group. On the opposite side, the executive performance assessed by the Wisconsin Sorting Card Test, was poorer in the patient group only. Scores of the first-degree relative group on the social anhedonia, physical anhedonia and perceptual aberrations scales were at an intermediate level between those of the patient and control groups; moreover, only scores on the social anhedonia scale tended to be significantly higher in the first-degree relative group than in the control group. Among the first-degree relative group, the only significant correlation found was between the number of perseverative errors on the WCST and the scores on the physical anhedonia scale.

Consensus on the Practical Use of Amisulpride, an Atypical Antipsychotic, in the Treatment of Schizophrenia.

Clinical expectations in schizophrenia treatment have greatly increased since the introduction of new atypical antipsychotics, but the choice of therapeutic strategy has become more complex and reference guidelines are scarce. This paper summarizes the consensus of a broad range of professionals after long-term commercialization in France of an atypical antipsychotic, amisulpride. Participants were from psychiatric hospitals, private clinics, out-patients settings and research; all were experienced with the drug. Discussions focused on the practical use of amisulpride, as, in addition to the double-blind trials information, it may be useful for psychiatrists of other countries to intuitively understand the therapeutic properties of amisulpride. The topics selected include acute psychotic episodes, short- and long-term follow-up, feasibility of treating the initial phase, the elderly and switching treatments. The French experience emphasizes the central role of amisulpride as a first-line treatment of schizophrenia.

[Comparative study of paroxetine and mianserin in depression in elderly patients: efficacy, tolerance, serotonin dependence]. / Etude comparative de la paroxétine et de la miansérine dans la dépression du sujet âgé: efficacité, tolérance, sérotoninodépendance.

The primary objective of this multicentre, randomized, double-blind study carried out in France was to compare the efficacy and safety of a 6-week treatment with paroxetine (20 mg/day) or mianserine (30 mg/day) in geriatric hospitalized or ambulatory patients (> or = 60 years) treated for a major depressive disorder (according to DSM III-R). A secondary objective was to discriminate those items predicting the response to an agent according to its serotoninergic or noradrenergic pharmacologic profile. The tool used for this latter purpose was the Aubin-Jouvent-Rating-Scale (AJRS) which was designed to assess the deficit of serotonin: this is a scale with 10 items, some of them regrouped into a "general" factor (irritability, sudden mood change, impatience, aggressivity) or a "depression" factor (pain, anxiety, suicidal ideas) with additional items related to sleep disorders, abnormalities in eating behavior and inability to tolerate isolation. In the perspective of this assessment, paroxetine was chosen due to its potential to inhibit serotonin re-uptake, as compared to mianserin which blocks presynaptic alpha-adrenergic receptors with negligible action on serotonin. This was a multicenter study carried out in France in 50 hospital or private practice psychiatrists. The assessment criteria included the MADRS, the AJRS, the COVI's anxiety scale, the Folstein's Mini-mental state (MMS) as well as a global assessment by the investigator at the end of the study. Safety was measured with a nondirective questionnaire, routine laboratory tests as well as a global assessment by the investigator. The primary efficacy criteria was the change in the MADRS global score. Statistical analysis included chi-square or Fisher's test as well as Student's and Wilcoxon tests for comparability at baseline, and analysis of variance for the changes in scores as during the study. A total of 116 patients was randomised (paroxetine: 54; mianserine: 62), of whom 96 completed the study (paroxetine: 43; mianserine: 53). With the exception of MADRS moderately higher in the paroxetine group, both groups were comparable at baseline. After 6 weeks of treatment, a marked improvement was recorded in both groups for all criteria except MMS; there was a consistent tendency favouring paroxetine which reached statistical significance for the COVI' scale (p = 0.001). For a given criterion, the difference paroxetine versus mianserine appeared related to the score at baseline; it was also more marked in those patients with a AJRS baseline score > or = 20 with a difference for MADRS reduction of marginal significance in favor of paroxetine (p = 0.061). As regards safety, at least one adverse event was reported in 31.5% of the patients receiving paroxetine versus 41.9% in those receiving mianserin (NS); premature withdrawal related to an adverse event was reported in 11.1% of the patients in the paroxetine group versus 12.9% in the mianserin group. No abnormality of clinical significance was reported in either group concerning laboratory tests. In conclusion, this study confirmed the therapeutic value and good safety of paroxetine as an antidepressant in geriatric populations, especially when exist a concomitant anxiety or symptoms likely to reflect a deficit of serotonine (irritability, emotional lability, restlessness, aggressivity) and to predict a good response to an agent such as this one.

[Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine]. / Hypothèse glutamatergique de la schizophrénie: apports des recherches cliniques sur la kétamine.

Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in schizophrenia pathophysiology. Post-mortem studies have revealed a lower density of glutamatergic receptors in patients with schizophrenia. Other studies of cerebrospinal fluid reported lower levels of glutamate in patients with schizophrenia in healthy comparison subjects. The most compelling evidence is provided by the psychomimetic effects of the NMDA antagonists phencyclidine and ketamine. Recently, much interest has been given to the study related to the role of NMDA receptor in pathophysiology of schizophrenia by administration of sub-anesthetic doses of ketamine. A phencyclidine hydrochloride derivate, ketamine, is a dissociative anesthetic and a non competitive antagonist of the NMDA receptor. In healthy subjects, ketamine produces: 1) positive symptoms of psychosis, such as illusions, thought disorder and delusions; 2) negative symptoms similar to those associated with schizophrenia including blunted emotional responses, emotional detachment, and psychomotor retardation; 3) cognitive impairments, in particular impairments on tests of frontal cortical function including increased distractibility, reduced verbal fluency and poorer performance on the Wisconsin Card Sorting Test. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities which are among the characteristics of schizophrenia. In patients with schizophrenia, the administration of ketamine produces an activation of their psychotic symptoms, which have striking similarities to symptoms of their usual psychotic episodes. Ketamine effects on memory and other cognitive functions in schizophrenic patients are controversial. The psychomimetic effects of ketamine are transitional, reversible and influenced by time, dose and administration conditions. Susceptibility to the psychotomimetic effects of ketamine is minimal or absent in children and becomes maximal in early adulthood. The similarity between ketamine effects and endogenous psychoses created interest in the capacity of antipsychotic medications to block ketamine effects. Haloperidol failed to block this ketamine-induced psychomimetic effects in healthy subjects and in schizophrenic patients. However, clozapine, the prototype of atypical antipsychotic agents significantly reduced the ketamine-induced increase in positive symptoms in schizophrenic patients. Recently, lamotrigine significantly decreased ketamine-induced positive and negative symptoms in healthy subjects. Brain regions responsible for NMDA-mediated psychosis have not been established. Using positron emission tomography and [18F] fluorodeoxyglucose, the sub-anesthetic ketamine administration produces bilateral increases in metabolic activity in the prefrontal cortex. In a [15O] H2O positron emission tomography study, ketamine selectively increases cerebral blood flow in the anterior cingulate cortex and reduces cerebral blood flow in the hippocampus and primary visual cortex. The mechanism of neuropsychiatric effects of sub-anesthetic ketamine is not clear. A dysfunction in glutamate-dopaminergic interactions has been suggested as a mechanism for these effects of ketamine. Ketamine has been reported to primarily block NMDA receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. In addition, ketamine caused increases in cortical and striatal synaptic dopamine concentrations. The effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia.

Poor performance in smooth pursuit and antisaccadic eye-movement tasks in healthy siblings of patients with schizophrenia.

This study examines the area of eye movement dysfunctions as an indicator of vulnerability to schizophrenia. Eye movement performance was investigated with three different paradigms: Smooth Pursuit Eye Movements (SPEM); Visually Guided Saccades (VGS); and Antisaccades (AS) in 21 clinically stable patients with schizophrenia, 21 of their healthy, biological full siblings and 21 healthy control subjects. The three groups did not differ on VGS performance, whereas both patients and their siblings showed lower SPEM gain, an increased catch-up Saccades (CUS) rate, reduced AS accuracy and an increased number of AS errors in comparison to control subjects. In addition, patients with schizophrenia exhibited increased AS latency. Among the patients with schizophrenia, eye movement abnormalities did not correlate with age, gender, clinical state or duration of illness. These data suggest that abnormalities of SPEM and AS may represent neurobiological markers of the vulnerability to schizophrenia in individuals at high genetic risk for the disease.

Defective recognition of one's own actions in patients with schizophrenia.

OBJECTIVE: The possibility that delusions of influence could be related to abnormal recognition of one's own actions was investigated in persons with schizophrenia. METHOD: Schizophrenic patients with (N=6) and without (N=18) delusions of influence were compared with normal subjects (N=29) on an action recognition task. The image of a virtual right hand holding a joystick was presented to the subjects through a mirror so that the image was superimposed on their real hand holding a real joystick. Subjects executed discrete movements in different directions. Angular biases and temporal delays were randomly introduced in some trials, such that the movement of the virtual hand departed from the movement executed by the subjects. After each trial, subjects were asked whether the movement they saw was their own. RESULTS: Compared with normal subjects, both patient groups made significantly more recognition errors in trials with temporal delays. In trials with angular biases, the error rate of patients with delusions of influence significantly differed from that of comparison subjects and from that of patients without delusions of influence. CONCLUSIONS: The findings support the hypothesis that delusions of influence are associated with a quantifiable difficulty in correct self-attribution of actions. This difficulty may be related to a specific impairment of a neural action attribution system.

Abnormal peripheral auditory asymmetry in schizophrenia.

OBJECTIVE: Auditory processing difficulties have been reported in schizophrenia. This study explores peripheral auditory function in patients with schizophrenia in whom certain early disturbances of auditory message filtering have been found and may be associated with certain abnormalities which are particularly localised in the left temporal lobe. METHODS: Otoacoustic emissions, including click evoked and spontaneous emissions and measurements of functioning of the medial olivocochlear efferent system were obtained from 12 chronic schizophrenic patients and compared with normative data recorded from 12 normal controls. RESULTS: Otoacoustic emission amplitudes and medial olivocochlear functioning were similar between the normal controls and schizophrenic patients; the schizophrenic patients did, however, differ from the normal controls in otoacoustic emission intensity and in medial olivocochlear asymmetry. A tendency to a higher number of spontaneous peaks, and a significantly higher click evoked otoacoustic emission response amplitude were found in the right ear compared with the left ear of schizophrenic patients. For the medial olivocochlear system, whereas normal controls showed greater attenuation in the right than in the left ear, schizophrenic patients lacked such an asymmetry. CONCLUSION: In the absence of any attention task, the findings show disturbed peripheral lateralisation in schizophrenia of mechanisms involved in auditory information filtering. Such a lack of right ear advantage in medial olivocochlear functioning may thus be a peripheral reflection of central lateralisation anomalies.