Methodological considerations for ghrelin isoforms assay in clinical evaluation in anorexia nervosa.

The growing interest concerning the role of metabolic sensors in various eating disorders requires the implementation of a strict methodology to collect, store and process blood samples in clinical studies. In particular, measurement of isoforms of the appetite-stimulating hormone, ghrelin, has been challenging in clinical settings. Indeed the acyl ghrelin (AG) isoform is rapidly degraded into desacyl ghrelin (DAG) by blood esterases, thus optimal conditions for the conservation of AG and accurate determination of AG/DAG ratio should be used. Here, we compared different protease inhibitors (Aprotinin, PHMB, AEBSF) during blood collection, increasing delays (0-180 min) before centrifugation, plasma supplementation with various HCl concentrations, storage durations of frozen plasma (8 and 447 days) and immunoenzyme-assay procedures (one-step versus sequential) in healthy subjects. Optimal conditions were obtained by collecting blood with aprotinin and supplementation of plasma with 0.1 N HCl with subsequent freezing for at least 8 days and using one-step assay. Under such conditions, different patterns of secretion of ghrelin isoforms were characterized in patients with restrictive-type anorexia nervosa (AN-R) before and after nutritional recovery. We illustrate the pulsatile variations of ghrelin isoforms according to the time around a meal and hunger rates in 3 patients with AN-R. This study offers a comprehensive comparison of various conditions using selective and specific immunoassays for both ghrelin isoforms in order to optimize assay sensitivity and consistency among procedures. These assay conditions could therefore be widely used to elucidate precisely the role of ghrelin isoforms on eating behavior in physiological and pathological situations.

[Depression and professional activity: results of the NEXTEP study]. / Dépression et activité professionnelle : résultats de l'observatoire NEXTEP.

BACKGROUND: 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. OBJECTIVES: To describe the management of depressive patients and assess the impact of treatment on professional activity and sick-leave. METHODS: An epidemiological observational longitudinal study (NEXTEP) performed by TNS Healthcare in private practice psychiatrists. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

[Use of services and treatment adequacy of major depressive episodes in France]. / Recours aux soins et adéquation des traitements de l'épisode dépressif majeur en France.

INTRODUCTION: Though depressive disorders are major problems of public health, general population data about use of services and treatment adequacy are scarce in France. The literature suggests that the percentage of people suffering from mental disorders who are adequately treated is low. AIM OF THE STUDY: The objective of this study was to estimate the 12-month use of services in the French general population suffering from major depressive episodes (MDE) and levels of treatment adequacy. METHOD: This analysis was conducted on data from the Health barometer 2005, an epidemiological survey concerning several health topics. Thirty thousand five hundred and fourteen individuals from 12 to 75 years old were interviewed by telephone from October 2004 to February 2005. Depressive disorders were assessed by a standardized tool, the CIDI-SF, according to DSM-IV classification. RESULTS: The mental health questions were answered by 16,883 individuals; i.e. by 60% of individuals aged 15 or older. One year prevalence of MDE was 7.8%. In this group, 58.2% used services in a 12-month period, though only 21% of the service users received adequate treatment. Amongst those who used services, 2/3 consulted health care professionals (i.e. 1/3 of people presenting a MDE). The remaining percentage - 21.4% - of people presenting a MDE used psychotropic drugs without mentioning any use of services for mental health problems. The vast majority of individuals with MDE who used services (34.6% of those with MDE) consulted a professional trained to treat depression (general practitioner, psychiatrist, psychologist and psychotherapist). Only a small proportion (19.9%) of those consulting a professional went to a non-specialist professional as well; and even less (6%) consulted only a non-specialist professional. Amongst trained professionals, most consultations (61%, or 21.1% of the MDE group) concern general practitioners; another 38.4% (13.3% of the MDE group) involved psychiatrists; and 27.8% (9.6% of the MDE group) went to psychologists or psychotherapists. Amongst the psychologists and psychotherapists, most consultations were with psychologists (74.1%). The proportion with adequate treatment differed according to the type of professional. Consulting a general practitioner is associated with the lowest levels of adequate treatment (37.2%, and for general practitioners only, 21.5%). Consulting a psychiatrist is associated with higher proportions of adequate treatment (65.1%, and for consulting a psychiatrist only, 60.7%). Consulting both a general practitioner and a psychiatrist is associated with the highest levels of adequate treatment (79.7%). Antidepressants (ATD) are used far more frequently than psychotherapy (PT): 33.4% of individuals with MDE used ATD, and among the latter, 58.4% had also used anxiolytic drugs (AXL). Finally, 26.9% of the MDE group used AXL, 7.5% without any use of ATD. For PT, 10.8% used PT, and 8.1% used PT and ATD. DISCUSSION: Improving use of professionals and treatment adequacy are two primary objectives from a public health perspective. Since most adequately treated people used an antidepressant therapy (90%), and only 30% a PT, use of psychotherapeutic approaches might be improved. Moreover, levels of treatment adequacy are very low in people presenting an MDE who did not consult for "mental health reasons". Improving the recognition of symptoms of depression might contribute to better treatment adequacy.

[Factors associated with treatment adequacy of major depressive episodes in France]. / Facteurs associés à l'adéquation des traitements de l'épisode dépressif majeur en France.

INTRODUCTION: Level of treatment inadequacy amongst people suffering from a major depressive episode (MDE) remains an important issue in the literature. Moreover, from a public health perspective, it's important to know how this situation can be improved. AIM OF THE STUDY: The objective of this study was to identify which factors are associated with adequate treatment for depression in France. A More specific objective was to investigate if being adequately treated is associated with the type of health care professionals consulted and, furthermore, to test the specific effect of providers taking sociodemographic and clinical variables into account. METHOD: This study was carried out from the data of the Health Barometer 2005, a random survey on various health topics. Thirty thousand five hundred and fourteen individuals from 12 to 75 years old were interviewed by telephone from October 2004 to February 2005. Depressive disorders were assessed by a standardized tool (CIDI-SF) according to the classification of the DSM-IV (16,883 individuals had answered the questions of mental health: 60% of the individuals aged 15 or older). RESULTS: Levels of treatment adequacy are higher for women, more severe disorders, and for people living in Paris or Central Eastern regions. They are lower for students. Significant differences were found between types of professionals and levels of treatment adequacy. They are higher for psychiatrists than for psychologists and psychotherapists and higher than for general practitioners. Lowest levels of adequate treatment were found for depressed people who used services without considering this recourse being for "mental health reasons". There are also some significant differences in sociodemographic and clinical patient characteristics between health care professionals. The population of depressed people consulting without "mental health reasons" is older and less educated. The population of depressed people consulting a psychiatrist suffers from more severe disorders and is more educated than those consulting a general practitioner. The population of depressed people consulting a psychologist or a psychotherapist is younger and more educated. Taking sociodemographic and clinical variables into account, the probability of receiving an adequate treatment increases when using specialized care only, or conjointly with the primary care sector. To be retired and to be yet another "inactive" is associated with better treatment adequacy, as is living in Mediterranean, Paris or Central Eastern regions. Severe MDE also increases the probability of being adequately treated. DISCUSSION: Levels of treatment adequacy differ between health professionals, even when sociodemographic characteristics of their patients and the severity of their disorders are controlled; specialized care, in particular when associated with primary care use of services, is correlated with the highest rates of adequate treatments, and should therefore be recommended. Geographical areas are associated with adequation of treatments, but not with use of healthcare systems. This suggests that disparities in the organization of the healthcare systems and in the collaboration between professional might exist in the different areas.

In-patient care costs of patients with bipolar I disorder: a comparison between two European centers.

BACKGROUND: Bipolar disorder (BPD) is a disabling disease with high morbidity rates. An international (Spain, France) comparative study about hospitalizations and in-patient care costs associated with BPD I was performed. Centers were included if they had access to a database of computerized patient charts exhaustively covering a defined catchment area. METHODS: Economic evaluation was performed by multiplying the average cumulated annual length of stay (LOS) of hospitalized bipolar patients by a full cost per day of hospitalization in each center to obtain the corresponding annual costs. RESULTS: Hospitalization rates per annum and per 100,000 individuals (general population aged 15+) were similar between France (43.6) and Spain (43.1). There were only slight differences in relation to length of stay (LOS) per patient hospitalized with 18.1 days in Spain and 20.4 days in France. The overall estimated annual hospitalization costs were in the same order of magnitude after adjustment to an adult population of 100,000: euro 232,000 (Spain) and euro 226,500 (France). Mixed episodes had the longest LOS followed by depressive episodes, while manic episodes had the shortest ones. Mania was the most costly disorder representing 53.7% of annual BPD in-patient care costs. CONCLUSIONS: BPD I care requires large resources and frequent hospitalizations, especially during manic episodes. Depressive and mixed episodes require longer hospital stays than manic episodes. Out-patient costs should now be evaluated.

[Evaluation of perturbed body image in eating disorders using the Body Shape Questionnaire]. / Evaluation des préoccupations corporelles dans les troubles des conduites alimentaires par le Body Shape Questionnaire.

INTRODUCTION: Eating disorders are characterized by severe disturbance in eating behavior. A disturbance in perception of body shape and weight is an essential feature of both anorexia nervosa (AN) and bulimia nervosa (BN). Eating disorder patients demonstrate the same characteristic attitude about body image, such as fear of fatness or pursuit of thinness. BACKGROUND: Moreover, perturbed body image is a common diagnostic category of anorexia and bulimia (DSM-IV-TR, CIM-10). Cooper et al. [Int J Eat Disord 6 (1987) 485-94] developed a one-dimensional, 34 items questionnaire in order to measure the worries about weight and shape of the body, called the "Body Shape Questionnaire" (BSQ). Its concurrent validity has been shown using the corporal dissatisfaction subscale of the eating disorders inventory (EDI) [Int J Eat Disord 2 (1983) 15-34], the drive for thinness and body dissatisfaction and the Eating Attitude Test (EAT) [Psychol Med 9 (1979) 273-79]. The total score of the BSQ ranges from 34 to 204. Lower scores indicate lower concerns about body shape. The BSQ provides a means of exploring the role of extreme obsession about the body's appearance in the development, pursuit and treatment of eating disorders. From this point of view, the BSQ is a tool widely used in research on the eating disorders. Recently, It has been validated in a French non-clinical population [Encephale 31 (2005) 161-73]. However, the validity of the BSQ has not been reported in patients with eating disorders in France. This was addressed in the present study. OBJECTIVES: The first aim of this study was to assess perturbed body image with the French version of the BSQ in eating disorder patients. The second aim was to assess the sensitivity to change. METHOD: The sample was composed of patients hospitalized for eating disorders (DSM-IV-TR). During their hospitalization, they were submitted to this questionnaire at the beginning and at the end of their care. The BSQ was compared with commonly used heteroquestionnaires such as the body dissatisfaction and drive for thinness subscale of the Eating Disorder Inventory (EDI-2), the Eating Attitude Test (EAT) and the Clinical Global Impression (CGI). Sensitivity to change was assessed by comparing total score at inclusion and at the end of hospitalization. Statistical analyses included Pearson's correlation coefficients, analysis of variance and t test. As Body Mass Index (BMI) can interfere with the BSQ score, it was included as confounding variables in the model in all analyses. RESULTS: Forty-five patients were included in the study. There were 21 patients with restricting subtype of AN, 17 patients with purging subtype of AN and seven BN. The mean age was 27.2+/-6.8 years, the mean length of hospital stay was 3.7+/-1.4 months, and the mean duration of the disorders was 10.7+/-6.3 years. The global BSQ score was high in the three groups of patients: 131.6+/-11.2. There was no significant difference between groups. There was no influence of the BMI on the BSQ scores. Correlation coefficient was significant for all scales with the BSQ except with the CGI. The higher correlation (r) was 0.58 with the drive for thinness subscale of the EDI-2. The change in scores between Day 0 and the end of hospitalization was significant (p<0.0001). CONCLUSION: The French version of the BSQ thus appears to be valid and accurate and should permit the study of perturbed body image in French eating disorder patients. However, sensitivity to change remains to be confirmed to evaluate response to treatment. Studies measuring this variable at different stages of the illness and recovery should be conducted.

[The costs of bipolar disorder]. / Coût du trouble bipolaire: revue de la littérature.

INTRODUCTION: According to the estimates of the World Bank and the World Health Organization bipolar disorder is the sixth leading cause of handicap throughout the world. The burden of this disease is similar to the one of schizophrenia. But cost-of-illness studies are too seldom. Although preventive treatments of bipolar disorder are available for more than fifty years, their economic impact has rarely been studied. LITERATURE FINDINGS: This review shows that the yearly cost of bipolar disorder is between 10,000 and 16,000 euro (12,000 and 18,000 US dollars). Eighty percent are indirect costs, 15% are linked to hospitalization and 5% to drugs. Hospitalization costs are lower in Health Maintenance Organization or general population studies than in studies performed on populations receiving care from psychiatric institutions or with a low socio-economic status. DISCUSSION: The use of mood stabilizers has a substantial impact on direct costs which are halved and consequently on indirect costs. But different surveys all agree on the dramatic under-use of mood stabilizers which may be adequately prescribed to only a quarter of bipolar patients. CONCLUSION: Therefore, the optimization of mental health system resources should prompt incentives to better screen, diagnose, and treat patients with a bipolar disorder.

Olanzapine for schizophrenia.

BACKGROUND: Olanzapine is an atypical antipsychotic reported to be effective without producing disabling extrapyramidal adverse effects associated with older, typical antipsychotic drugs. OBJECTIVES: To determine the clinical effects and safety of olanzapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and schizophreniform psychoses. SEARCH STRATEGY: We updated the first search [Biological Abstracts (1980-1999), The Cochrane Library (Issue 2, 1999), EMBASE (1980-1999), MEDLINE (1966-1999), PsycLIT (1974-1999) and The Cochrane Schizophrenia Group's Register (October 2000)] in October 2004 using the Cochrane Schizophrenia's Group's register of trials. We also searched references of all included studies for further trials, and contacted relevant pharmaceutical companies and authors. SELECTION CRITERIA: We included all randomised clinical trials comparing olanzapine with placebo or any antipsychotic treatment for people with schizophrenia or schizophreniform psychoses. DATA COLLECTION AND ANALYSIS: We independently extracted data and, for homogeneous dichotomous data, calculated the random effects relative risk (RR), the 95% confidence intervals (CI) and the number needed to treat (NNT) on an intention-to-treat basis. For continuous data we calculated weighted mean differences. MAIN RESULTS: Fifty five trials are included (total n>10000 people with schizophrenia). Attrition from olanzapine versus placebo studies was >50% by six weeks, leaving interpretation of results problematic. Olanzapine appeared superior to placebo at six weeks for the outcome of 'no important clinical response' (any dose, 2 RCTs n=418, RR 0.88 CI 0.8 to 0.1, NNT 8 CI 5 to 27). Although dizziness and dry mouth were reported more frequently in the olanzapine-treated group, this did not reach statistical significance. The olanzapine group gained more weight. When compared with typical antipsychotic drugs, data from several small trials are incomplete. With high attrition in both groups (14 RCTs, n=3344, 38% attrition by six weeks, RR 0.81 CI 0.65 to 1.02) the assumptions included in all data are considerable. For the short term outcome of 'no important clinical response', olanzapine seems as effective as typical antipsychotics (4 RCTs, n=2778, RR 0.90 CI 0.76 to 1.06). People allocated olanzapine experienced fewer extrapyramidal adverse effects than those given typical antipsychotics. Weight change data for the short term are not statistically significant but results between three to 12 months suggest a clinically important average gain of four kilograms for people given olanzapine (4 RCTs, n=186, WMD 4.62, CI 0.6 to 8.64). Twenty three percent of people in trials of olanzapine and other atypical drugs left by eight weeks; 48% by three to12 months (11 RCTs, n=1847, RR 0.91 CI 0.82 to 1.00). There is little to choose between the atypicals, although olanzapine may cause fewer extrapyramidal adverse effects than other drugs in this category. Olanzapine produces more weight gain than other atypicals with some differences reaching conventional levels of statistical significance (1 RCT, n=980, RR gain at 2 years 1.73 CI 1.49 to 2.00, NNH 5 CI 4 to 7). There are very few data for people with first episode illness (1 RCT, duration 6 weeks, n=42). For people with treatment-resistant illness there were no clear differences between olanzapine and clozapine (4 RCTs, n=457). AUTHORS' CONCLUSIONS: The large proportion of participants leaving studies early in these trials makes it difficult to draw firm conclusions on olanzapine's clinical effects. For people with schizophrenia it may offer antipsychotic efficacy with fewer extrapyramidal adverse effects than typical drugs, but more weight gain. There is a need for further large, long-term randomised trials with more comprehensive data.

[Prevalence of depression in multiple sclerosis: a review and meta-analysis]. / Prévalence de la dépression dans la sclérose en plaques. Revue et méta-analyse.

INTRODUCTION: The aim of this paper was to review and summarize the data about the frequency of depression during multiple sclerosis (MS). MATERIAL AND METHODS: We performed a metaanalysis to combine the results of the studies which compared the frequency of depression in MS patients with the prevalence in patients with other chronic diseases. Eight controlled studies were identified via manual and computerized search of the Medline and PsychInfo databases. Given the various ways these studies reported their results, we used statistical procedures based on the combination of significance levels (the method of adding Zs and the method of adding ts). An additional statistical procedure, Cohen's d, was performed to estimate the effect of size. RESULTS: The two statistical methods yielded highly significant summary statistics: z=4.15 and z=3.98, respectively (p<0.0001). The effect of size (Cohen's d), which ranged from 0.02 to 0.70 with an average of 0.29 (95 percent confidence interval: 0.09-0.49), can be considered as medium and hence clinically meaningful. CONCLUSION: These results suggest that the association between MS and depression is specific, that is not just casual nor due to the nonspecific factors inherent in every chronic disease.

Alexithymia in insulin-dependent diabetes mellitus is related to depression and not to somatic variables or compliance.

OBJECTIVES: To assess the prevalence of alexithymia in insulin-dependent diabetic mellitus (IDDM) outpatients. To examine whether alexithymia is associated with diabetic somatic variables, depression, and compliance. METHOD: Our sample comprised 69 diabetic outpatients followed in a university hospital. We assessed the prevalence of alexithymia (26-item Toronto Alexithymia Scale, TAS-26) and the relationships among alexithymia, depression (13-item Beck Depression Inventory, BDI-13), somatic diabetic variables (glycosylated hemoglobin, number of mild or severe hypoglycemia, somatic complications), and compliance (observer-rater scale completed by diabetologist). RESULTS: The prevalence of alexithymia in IDDM patients was low (14.4%). Alexithymia and depression, as measured by TAS-26 and BDI-13 scores, respectively, correlated with each other. Alexithymia was not correlated with glycemic control, somatic complications, or compliance. CONCLUSION: In our sample, alexithymia was related to depression and not to somatic factors or compliance.

[Bipolar I disorder in France: prevalence of manic episodes and hospitalisation-related costs]. / Le trouble bipolaire I en France: prévalence des épisodes maniaques et coût des hospitalisations pour ce motif.

Bipolar disorder is a chronic, highly disabling illness. However, few studies have evaluated the economic impact of this illness. The objective of this study was to estimate: 1) the annual number of manic episodes in patients with bipolar I disorder, and 2) the costs of hospitalisations related to manic episodes in France. We only included data on bipolar I disorder, as there is greater consensus and better documentation for this subgroup of patients with bipolar disorder. The prevalence of manic episodes was estimated using published epidemiological data. A computerised literature search was performed using the traditional scientific and medical databases. Additional epidemiological references were identified from published studies and textbooks. For hospitalisation data, we used the statistics of the Medical Information Department of a large psychiatric hospital in Paris for the year 1999. We estimated the annual number of manic episodes in France based on: 1) the lifetime prevalence of bipolar I disorder, 2) the average cycle duration, 3) the proportion of rapid cycling patients, and 4) the proportion of depressive vs. manic episodes for patients with bipolar I disorder. In order to estimate the prevalence of bipolar I disorder, we conducted a random effects meta-analysis using published international data. Results of the meta-analysis, which was based on a total of 62 736 patients, showed the lifetime prevalence of bipolar I disorder to be 0.82% [95% CI: 0.42, 1.21]. Applied to the adult population in France, this prevalence implies that the number of persons who have ever experienced a bipolar I -disorder is approximately 390,000 [95% CI: 200,000, 575,000]. Few studies provide information on the duration of cycles in patients with bipolar I disorder. Available estimates suggest the cycle duration to be approximately 12 months. Regarding the proportion of rapid cyclers, data from the meta-analysis by Tondo et al. show that 18% of patients with bipolar disorder experience at least four episodes of mood disorder per year. Finally, based on findings provided by cohort studies, the number of depressive episodes appears to be roughly equal to the number of manic episodes during the course of bipolar disorder. A rapid cycling rate of 18% and a cycle duration of 12 months imply that, on average, among 100 bipolar patients, 18 will have a 3-month cycle duration and 82 a 14-month cycle duration. Given an equal proportion of manic and depressive episodes, the annual number of manic episodes would then be 68 for a cohort of 100 bipolar patients (0.68 episode per patient per year). Applying this figure to the estimate of the total number of patients with bipolar I disorder in France suggests that the annual number of manic episodes in France is 265,000 [95% CI: 136,000, 391,000]. Based on data from a psychiatric hospital in Paris, the proportion of manic episodes that require hospitalisation was estimated to be around 63% with an average length of stay of 32.4 days. Hence the annual number of hospitalisations for manic episodes in France is estimated to be 167 000 [95% CI: 86 000, 246 000] and the hospitalisation-related costs 1,3 billion euros approximately. Our review of literature highlights the lack of medical and economic data at the national level on the frequency and hospitalisation-related costs of manic episodes in patients with bipolar I disorder in France. Given the lifetime prevalence of bipolar I disorder which may be as high as 3% among adults, further studies are required in order to provide representative national data and to allow economic evaluations of costs related to bipolar disorder in France.

Olanzapine for schizophrenia.

BACKGROUND: Olanzapine is an atypical antipsychotic that is reported to be effective without producing the disabling extrapyramidal side effects associated with the older, typical antipsychotic drugs. OBJECTIVES: To determine the clinical effects and safety of olanzapine as compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and schizophreniform psychoses. SEARCH STRATEGY: The reviewers undertook electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 2, 1999), EMBASE (1980-1999), MEDLINE (1966-1999), PsycLIT (1974-1999) and The Cochrane Schizophrenia Group's Register (October 2000). References of all identified studies were searched for further trials, and the reviewers contacted relevant pharmaceutical companies and authors of trials. SELECTION CRITERIA: All randomised clinical trials comparing olanzapine to placebo or any antipsychotic treatment for those with schizophrenia or schizophreniform psychoses. DATA COLLECTION AND ANALYSIS: Data were independently extracted. For homogeneous dichotomous data the random effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data the reviewers calculated weighted mean differences. MAIN RESULTS: Twenty one trials are included. Attrition from olanzapine versus placebo studies was so great (olanzapine - 61%, placebo - 73% by six weeks, RR 0.85 CI 0.7-0.98, NNT 8 CI 5-40) that interpretation of results is problematic. Olanzapine appeared superior to placebo at six weeks for the outcome of 'no important clinical response' (RR 0.88 CI 0.8-0.98, NNT 8 CI 5-27) and global mental state scores. Although dizziness and dry mouth were reported more frequently in the olanzapine-treated group, this did not reach statistical significance. Tthe olanzapine group gained more weight. When compared to typical antipsychotic drugs, data from several small trials are incomplete; but, for the short term outcome of 'no important clinical response', olanzapine seem as effective as typical antipsychotics (n=2778, RR 0.9 CI 0.76-1.06). Brief Psychiatric Rating Scale (BPRS) data tended to be equivocal but Positive and Negative Syndrome Scale (PANSS) rating of total score and negative and positive symptom sub-scores favoured olanzapine. With high attrition in both groups (olanzapine - 36%, typical drug - 49% by 6 weeks, n=2738, RR 0.85 CI 0.66-1.1; olanzapine - 83%, typical drug - 90% by 1 year, n=2738, RR 0.9 CI 0.86-1.02), the assumptions included in all continuous data are considerable. Participants allocated olanzapine experienced fewer extrapyramidal side effects than people given haloperidol. Weight change data for the short term are not conclusive (n=2455, WMD 0.8kg CI -0.6-2.2) but the three to 12 month results suggest an average gain of four kilograms (n=233, WMD 4 CI 0.3-7.8). It is difficult to distinguish between olanzapine and other atypical drugs, although it may cause fewer extrapyramidal side effects than risperidone (n=339, RR 0.6 CI 0.4-0.9, NNH 8 CI 4-29). Olanzapine did cause more weight gain than its comparators but current data are not statistically significant (3-12 months, n=535, WMD 2.2kg CI -0.6-5). One study (n=180) found no clear differences between olanzapine and clozapine for people with treatment-resistant illness. REVIEWER'S CONCLUSIONS: The large proportions of participants leaving the studies early, in the large multi-centre trials makes it difficult to draw firm conclusions on clinical effects. For people with schizophrenia olanzapine may offer antipsychotic efficacy with fewer extrapyramidal side effects than typical drugs but more weight gain. Large, long-term randomised trials with participants, interventions and primary outcomes that are familiar to those wishing to help those with schizophrenia are long overdue.

[Tricyclic antidepressants dosage and depressed elderly inpatients: a retrospective pharmaco-epidemiologic study]. / Posologie des tricycliques au cours du traitement de la dépression chez le sujet âgé: une étude pharmaco-épidémiologique rétrospective.

UNLABELLED: It is recommended to reduce by one half the dosages of tricyclic antidepressants for patients over 65 years of age, in order to avert the occurrence of side-effects. The question we studied was: is it rightful to prescribe tricyclic antidepressants at half-dose to hospitalized elderly people? It is important, for the following reasons, to specify the rules of prescription of tricyclics in elderly patients: 1) The elderly population is on the increase; 2) There is a high prevalence of depression in elderly patients; 3) Depression exposes the elderly person to an increased risk of suicide; 4) Depression influences the prognosis of associated organic disorders 5) Recourse to tricyclic antidepressants is often necessary within this population group because of treatment resistant forms of depression which impose the use of different families of antidepressants and thus resort to tricyclics despite their lower tolerance. OBJECTIVES AND METHODS: The aim of our study is to evaluate whether the half doses of tricyclics recommended for an elderly person are sufficient in the case of an hospitalized patient. In order to provide some answer to this question, we have carried out a retrospective study. We have studied a sample of patients over-65, hospitalized at the Clinique des Maladies Mentales et de l'Encéphale, over a period of two years, with a ICD 10 diagnosis of moderate or severe intensity major depressive episode, and treated effectively with return to the euthymia. Creatinemia was prescribed systematically to each patient on entry. Only patients with normal renal function were retained. Laboratory norms are between 45 and 120 micromol/liter. The routine practice of imipraminic blood dosages allowed the comparison of blood levels obtained among patients treated with posologies inferior or equal to 75 mg/day imipraminic, to those treated with more than 75 mg/day imipraminic for a least a week. The percentage observed were compared using the Khi2 test with Yates correction. We retained the blood concentrations of the mother molecule for tertiary amines (imipramine, clomipramine and amitriptyline). The samples were taken after at least seven days of treatment at the same dose, and twelve to thirteen hours after the last taking. The maxima of blood levels were respectively: desipramine 200 ng/ml, clomipramine 258 ng/ml, imipramine 163 ng/ml, amitriptyline 129 ng/ml. Research for evidence in favor of toxicity (fall, delirium, convulsion, reduction of dosage before discharge), was done through revision of patients' clinical files. RESULTS: The test group consisted of 87 individuals. The average age was 71.3 years (SD: 5.09). Mean creatinemia was 83.73 mmol/l (SD: 26.89). The population thus selected divided into 4 groups: 61 (70.1%) were given imipraminics, 10 (11.5%) serotonin recapture inhibitors, 11 (12.7%) other antidepressants essentially of mianserine and 5 (5.7%) treatment by electroconvulsivotherapy. The imipraminics prescribed were desipramine, imipramine, clomipramine and amitriptyline. Among the 61 patients treated with imipramine, blood level dosage was practised on 48 patients (79%). Two subgroup were distinguished: 13 (21%) received dosages inferior ou equal to 75 mg/day and 48 (79%) superior to 75 mg/day. The mean dosage found in the sub-group of patients treated with dosages superior to 75 mg/day was 140 mg/day (SD: 30). The subgroup treated with dosages superior to 75 mg/day was more frequently monitored than the subgroup receiving dosages inferior or equal to 75 mg/day, respectively 40/48 (83%), and 8/13 (62%). This difference is statistically nonsignificant (p > 0.10). The analysis of dosages used showed that:--among the dosages effected upon patients receiving doses inferior or equal to 75 mg/day, 1 (12.5%) exceeded the maximal value of therapeutic range.--Among the dosages effected upon patients receiving dosages superior to 75 mg/day, 9 (22%) exceeded the maximal value of the therapeutic range. The difference is statistically significant (p < 0.001). On revision of clinical files, no patient presented any element that might lead one to suspect toxicity such as defined in "Objectives and Methods". CONCLUSION: In our study, patients were hospitalized and so benefited from closer observation than one can expect in outpatients. In this particular context, the dosages used are close to those advocated for the general population. With the elderly subject, the systematic prescription of half-dose tricyclics runs the risk of infratherapeutic dosage. It is thus preferable to resort to blood level dosage and to look for a maximum dose tolerance before concluding ineffectuality. This allows one to monitor whether the blood levels obtained are included in the therapeutic range; to avoid toxic doses and to check weak compliance in the elderly patient. Our findings do not oppose the use, for the elderly hospitalized depressive, of doses of imipraminics close to those of a young subject. To confirm these results it would be desirable to carry out o prospective study, including a systematised evaluation of adverse effects and a comparison of clinical effectiveness for parallel groups of elderly patients receiving different doses of imipraminic antidepressants.