[Perinatal maternal suicide: How to prevent?] / Suicide maternel périnatal : comment prévenir ?

The sixth report of the National Confidential Survey on Maternal Deaths provides insights into the frequency, risk factors, causes, adequacy of care, and preventability of maternal deaths occurring in 2013-2015 in France. The method developed ensures an exhaustive identification and a confidential analysis of maternal deaths. It was organized in three steps. 1) All deaths occurring during pregnancy or up to 1 year after its end, whatever the cause or mode of termination, being considered 2) A pair of volunteer assessors (midwives, gyneco-obstetricians, anesthesiologists, psychiatrists) was in charge of collecting the information (history of the woman, course of her pregnancy, circumstances of the event that led to the death and management); 3) Review and classification of deaths by the National Committee of Experts on Maternal Mortality which made a collective judgment on the cause of death, on the adequacy of the care provided, and on what could been done to avoid the death depending on the existence of circumstances that could have prevented the fatal outcome. The operation of the committee has been enriched by new resources to further explore these cases. Specifically, a module of the survey questionnaire, the recruitment of psychiatrists whose contribution allows relevant documentation of the suicides, and the participation of a psychiatrist as an associate expert for the analysis of the appropriateness of the management and the variable determining factors of these cases. Suicide becomes one of the two main causes of maternal mortality, (the other cause being cardiovascular pathologies), with 35 suicides on the triennium among the 262 maternal deaths, that is to say 13.4 % of maternal deaths, about 1 per month. In this population, the average age of women who died by suicide was 31.4years. The majority of the women were born in France, 68 % were prima parous, and in 9 % of cases suicide followed a twin pregnancy. Psychiatric history was known in 33.3 % of the suicidal mothers, and 30.3 % had a history of psychiatric care that was unknown to the maternity team.43 % of the women had psychosocial vulnerability factors, a history of violence, and eviction from the home and/or financial difficulties. In 23 % of the cases, the time of occurrence of these suicides was within the first 42days postpartum, and in 77 % between 43 days and one year after birth with a median delay of 126days. Only one suicide occurred during pregnancy. Maternal suicides were mostly violent deaths. Suboptimal care was present in 72 % of cases, where 91 % of potentially preventable deaths related to a lack of multidisciplinary management and/or inadequate interaction between the patient and the health care system. Among these potentially avoidable deaths, we were able to distinguish: women whose psychiatric pathology was known and for whom multidisciplinary management was not optimal, and women whose psychiatric pathology was not known or was not present - for whom it was rather a matter of a failure to detect and identify the signs, particularly by obstetric care providers or general emergency services. Based on the analysis of the cases, strong messages were identified, with the aim of optimizing management: - The screening by structured questioning of psychiatric history from the moment of registration in the maternity ward, repeated at each consultation throughout the pregnancy. - The reassessment of the psychological and somatic state through an early postnatal interview at one month; - The identification of warning symptoms, with screening tools for depression. If necessary, a further recourse to the psychologist and/or psychiatrist of the maternity hospital, organisation of a home hospitalization, and a private midwife to provide a link in the pre- and postpartum period. This, in addition to the earliest possible care in the PMI (Maternal and Infantile Protection, of the French social care system), appointments with mental health professionals,and the link with the attending physician; - The implementation of a coordinated care pathway in case of a known psychiatric pathology with pre conception counselling. This includes a multidisciplinary collaboration, an adaptation of psychotropic treatment, management of comorbidities referral to specialized perinatal psychopathology teams, prenatal meeting with the pediatrician of the maternity hospital, anticipation of the birth, postpartum and discharge options, liaison sheet established for the organization of the delivery and postpartum, and a regular written transmissions between the intervening parties throughout the care; - The generalization of medico-psycho-social staffs, in maternity wards, for all situations identified as at risk. In addition to the need for training and increased awareness on psychological issues during the perinatal period and on the different pathologies encountered by adult mental health professionals and front-line workers, it is necessary to encourage the development of resources in the country. Particularly, joint child psychiatrist-adult psychiatrist consultations at the territorial level, responsible for being resource contacts for maternity wards and local care professionals, as well as the promotion of case pathway referrals.

[Maternal deaths due to suicide in France 2013-2015]. / Mortalité maternelle par suicide en France 2013­2015.

Pregnancy represents a period of significant psychological vulnerability for women. During the perinatal period, twenty percent of them would present with mental disorders ranging from anxiety to depression. In those with pre-existing mental illness, the risk of acute decompensation is significant. For this reason, the World Health Organization recommends classifying suicides occurring during pregnancy and up to one-year post-partum as maternal deaths. Thus, between 2013 and 2015, 35 maternal suicides occurred in France, representing a maternal mortality ratio of 1:4 per 100,000 live births (95% CI: 1.0-2.0). By constituting 13.4% of all maternal deaths for the period, this group is the one of the 2 leading causes of maternal mortality. A total of 23% occurred in the first 42 days post-partum, and 77% between 43 days and one year after birth. 33.3% of the suicidal mothers had a known psychiatric history and 30.3% had a history of psychiatric care, unknown to obstetrical teams. Non-optimal care was present in 72% of cases with 91 % of suicides were potentially preventable, preventability factors beinga lack of multidisciplinary care and inadequate interaction between the patient and the care system. Strong messages were drawn from the analysis of these cases to optimize care: improve knowledge of the psychiatric history from the time of enrolment in maternity units, improve the identification of warning symptoms and the use of the psychologist and/or psychiatrist, set up a specific care pathway and multidisciplinary collaboration in case of known psychiatric disease.

[What support of young presenting a first psychotic episode, when schooling is being challenged?] / Quelle prise en charge du jeune présentant un premier épisode psychotique, quand la scolarité est mise à mal ?

Psychiatric disorders (more specifically mood disorders and psychosis) represent the 1st cause of disability among young people. Unemployment rate between 75 to 95% for the person with schizophrenia. It is correlated to poor social integration and bad economic status, worse symptomatology loss of autonomy as well as global bad functioning. It is responsible of more than half of the overall cost of psychosis. The onset of most of psychiatric disorders occur between the age of 25 and 35 years old, a critical time in young adult life when they should build their professional as well as social future. Without appropriate care, young adult are unable to build satisfactory emotional relationships, continue their studies, live independently or fit into life. They are frequently dependent on their environment. They also have an increased suicide rate and frequent comorbid substance abuse. Despite this context, their care pathway is often marked by a delay or premature stop of care, drug treatments not always suitable and a lack of specific relay post-hospitalization regarding continuity of professional training or studies. All factors impacting future employability of adolescents. Furthermore they spend most of their time in school and school plays a key part in an individual's development including peer relationships, social interactions, academic attainment, cognitive progress, emotional control, behavioral expectations and physical and moral development. These areas are also reciprocally affected by mental illness. The initial phases of FEP are characterized by impaired academic performance, change in social behaviors and increasing absences from school, reflecting the prodrome of the illness that leads to disengagement from education. Functional decline often precedes onset of clinical symptoms and many adolescents and young adults are therefore isolated from school before their illness is recognized. School support staff may fail to recognize those who are functionally impaired because of evolving FEP although school is a key setting for promoting positive mental health, fostering resilience, detecting and responding to emerging mental ill health. So, people with psychotic illness have low levels of secondary school completion. School dropout has been defined as leaving education without obtaining a minimal credential, most often a higher secondary education diploma. In France, the school is compulsory up to the age of 16. Consequences are significant: among young people without a degree out of initial training for one to four years and present on the labour market, 47% are unemployed. School dropout depends on a number of factors, including grades, family and social environment and the relationship with the school, but also the emergence of psychiatric disorders. For first episode psychotic patients, age of onset, lack of family support, longer duration of psychosis, levels of premorbid global functioning and education, negative and cognitive symptoms, addictions, depressive comorbidities and stigma plays an important role in school dropout. However, young adults have historically received less treatment than expected considering prevalence of mental illness at that age. In the last few decades, early intervention programs for psychosis have been developed all around the world in order to promote rehabilitation and prevent long-term disabilities. Early intervention programs focus on the special needs of young people and their families and engage in some form of assertive community treatment, which attempts to treat patients in the community rather than using inpatient services. For early intervention in psychosis programs, the goal is to keep patients engaged with treatment, prevent them from further psychotic episodes and hospitalizations and promote rehabilitation. The additional services of an early intervention program include staff specialized in psychosis treatment, family/group/individual counseling sessions, assertive case management, and low-dose second generation anti-psychotics. In these programs, psychiatric rehabilitation practitioners already use individual counseling and supported education programs (SEd) to improve postsecondary educational outcomes. The goals of SEd are for individuals with serious mental illness to successfully be able to set and achieve an educational goal (e.g., training certificate or degree), to improve educational competencies (literacy, study skills, time management), to navigate the educational environment (e.g., applications, financial assistance), and to improve motivation toward completing educational goals. These approaches are often combined with efforts to support transitions to sustainable employment. Current evidence of these interventions are weak with limited information on specific difficulties experienced by young adults with FEP in educational tasks. Adaptive strategies are needed by young adults with FEP to succeed in educational settings but most studies do not explore it with rigorous methodology. However, common SEd components emerge: specialized and dedicated staffing, one-on-one and group skill-building activities, assistance with navigating the academic setting and coordinating different services, and linkages with mental health counseling. Continued specification, and testing of SEd core components are still needed. It is important that occupational therapy researchers and practitioners develop, and evaluate effective interventions to improve education outcomes for young adults with FEP. The objective of this work is to define school dropout, assess causes and consequences of FEP. How to help young people to maintain education? We will detail measures to support the academic re-insertion in France.

[Stabilisation of post-acute stage schizophrenics: from the hospital to the city]. / Stabilisation des patients schizophrènes en post-aigu : de l'hôpital à la cité

Schizophrenia is a debilitating disease that usually begins in young adulthood, at a time when a person would usually make the transition to independent living, but it can occur at any age. The symptoms and behaviour associated with psychosis and schizophrenia have a distressing impact on the individual, and the family. The course of schizophrenia varies considerably. Although most patients will recover, some will have persisting difficulties or remain vulnerable to future episodes. Therefore, stabilisation of patients in acute phases and avoidance of relapse are major objectives of management throughout the course of this disease. The purpose of this article is to clarify the stabilisation, to study the contributing factors and strategies to implement to achieve stability, through a literature review and key guidelines. Thus, the patient is stabilised when productive symptoms and behavioural problems have decreased. So, the stable phase represents a prolonged period of treatment and rehabilitation during which symptoms are under adequate control and the focus is on improving functioning and recovery. Important predictive criteria of stabilisation include: positive symptoms, the number of previous relapses, cooperation with the patient and family, good adherence to treatment and the use of long acting injectable second-generation antipsychotics. After an acute relapse, the careful organization of the discharge and the development of a proposed ambulatory care in tailored care structures will help consolidate stabilisation and obtain remission. Accepting the idea of continuing treatment is a complex decision in which the psychiatrist plays a central role beside patients and their families. The course of integrated actions on modifiable risk factors such as psychosocial support, addictive comorbidities, identification of prodromes, active information for the therapeutic education of patients and families and access to care will also be supported. This would improve the functional abilities of patients, their social adaptation and particularly their quality of life.

[The imminent peril in the law of July the fifth 2011, two years later: the impact on health?]. / Le péril imminent dans la loi du 5 juillet 2011: quelles implications sur les soins?

In 1938, the French government decided to enact a first legislation to enforce admission of the mentally ill to hospitals. Later in 1990, the law took into consideration the evolution of practices with an increase of free admissions and the right to maintain the mentally ill in cities. Three types of psychiatric hospitalization were defined: free, on third party request and for involuntary confinement. A review had theoretically to be conducted every 5 years. In practice this was not the case, probably due to the balance between individual freedom, patient care and public safety always hard to find. However, considering the imperative European harmonization and the fact the Constitutional Council declared a double unconstitutionality of the law, the Act of July 5th was enacted in a hurry during the summer 2011. The Act defines the "rights and the protection of people subject to psychiatric care and methods of coverage". In this document, we will briefly review the context of this law. We will also explore the clinical implications of the very innovative measure: the "péril imminent". We will use the admissions at the Sainte-Anne hospital in Paris in 2010 to 2012. Three major key points were introduced in the law: a judge controls an agreeable release after 15 days and 6 months of continuous hospitalization. The law let the new possibility to provide ambulatory cares under constraints, and these to make an involuntary confinement without a third party request, using the "imminent peril". This law implies the involvement of the judge and the lawyer. This one has to defend a client who needs care, he controls the formal validity of decisions concerning the patient. To provide treatment without consent in "imminent peril" to someone, conditions are requested: these mental disorders make his consent impossible and his mental state requires immediate care with immediate care of constant medical monitoring justifying a full hospitalization or regular medical monitoring for support under another form of full hospitalization (Article L.3212. 1 of the Code of Public Health). Moreover, a demand for care by a third party has also to be impossible to obtain and an imminent peril to the person's health has to exist, supported by a medical certificate from a doctor who does not belong to the patient's psychiatric hospital. The imminent peril would be an immediate danger to the health or life of the patient. What has been the impact of this law adopted in emergency at Sainte-Anne hospital? This psychiatric hospital is in charge of the population in southern Paris, where reside about 655,000 people. This work observes the evolution of the type of hospitalization and care before and after the adoption of the law. We can observe an overall increase in entries under constraints. There is a decrease in admissions for involuntary confinement for the benefit of imminent peril. This imminent peril corresponds to only a small proportion of hospitalizations without consent but are rising between 2011 and 2012, perhaps in part due to a better understanding of the law. But this progression is to monitor to ensure compliance with the restrictive conditions laid down by this law. Also note that the imminent peril may be used at the refusal of the family or entourage to make the demand for care. The number of hospitalizations at the request of a third party with two certificates is down, which is probably due to a change in status of the CPOA, emergency structure within Sainte-Anne, which is no longer seen as extraterritorial. The imminent peril has advantages: it allows access to the care of people isolated and desocialized, of people whose identity is unknown, of pathological travellers. It avoids hospitalization at the request of the representative of the State for social reasons and not for risks to the safety of persons, even when this type of hospitalization is more stigmatizing and often more difficult to remove. It protects the entourage sometimes, when the family is ambivalent or hostile to care, or has been designated as a persecutor. The imminent peril also has disadvantages. One of them is the risk of its misuse to allow rapid hospitalization without taking the time to seek a third party. The imminent danger made when there is an entourage but which refuses to request care can undermine the development work on information about the disease, the need for care and treatment and the importance of the involvement of the entourage in the care plan. The alliance with the patient may be compromised. In some cases, a decision of care by the request of the representative of the State is more appropriate than the "imminent peril". The "imminent peril" may be preferred because of the administrative burden of prefectural measures when patient presents clinical improvement and we would go up to the ambulatory care in a care program. Yet, the use of a symbolic third, carrying authority, can avoid the too direct confrontation with the patient. Do not use it can complicate the management of the patient. Finally, with desocialized patients, imminent peril can facilitate access to care, but not continuity of care. Indeed, for the care program it is necessary to have an address for the patient. Once the crisis is not to develop a plan of care. Finally in some situations of desocialized patients, the imminent peril can promote access to care but not the continuity of care as to the care program it is necessary to have an address for the patient. Once the crisis is past, it is impossible to implement a program of care. The Law of 5 July 2011 marks a change in the practice of psychiatrists. Take into account the fundamental rights of the patient and to harmonize legislation at EU level was necessary. Some measures are designed to promote access to care as the "imminent peril", we now need to be vigilant to ensure that it is not diverted to promote an increase in care under constraints and that psychiatrists remain in an obligation of means and not of result.

[RÉALITÉ LT, a pharmacoepidemiological study of semiology and therapeutic strategy of patients with schizophrenia treated by antipsychotic loxapine in routine clinical practice]. / RÉALITÉ LT : Recherche Épidémiologique sur l'Activité de la Loxapine et ses Indications en Thérapeutique quotidiennE lors d'une utilisation à Long Terme. Étude pharmacoépidémiologique : sémiologie et stratégie thérapeutique d'une population de patients présentant des troubles schizophréniques traités par loxapine.

INTRODUCTION: Data concerning the clinical and therapeutic characteristics of patients with schizophrenia treated by antipsychotic in naturalistic conditions are useful. Two national pharmacoepidemiological studies were conducted in France, a retrospective survey RÉALITÉ and a prospective study RÉALITÉ LT, to examine the use of loxapine, first in acute and chronic psychotic states and second in long-term treatment prescribed for patients with schizophrenia. AIM OF STUDY: The aim of RÉALITÉ LT is to specify the clinical characteristics of schizophrenic patients treated by loxapine for at least 4 months and the description of the methods of use of this antipsychotic medication during a 6-month follow-up in "real life" conditions. DESIGN OF STUDY: RÉALITÉ LT is an epidemiologic, observational, longitudinal, prospective (during a half-year period), multicenter and national study of the prescription of loxapine in routine clinical practice. For this study, 645 patients with schizophrenia treated by loxapine were recruited, assessed by PANSS, CGI, GAF, MeDra-SOC-PT for side effects and Girerd questionnaire for compliance; statistical analysis used SAS 9.2. RESULTS: Six hundred and forty-five adult patients were included and assessed at inclusion, month 3 and 6. These patients were mostly male (69%), with an average age of 41, inactive (68%), lonely with no child (79%), under psychiatric care for more than 5 years (81%), less than one third were inpatients. The subtypes of schizophrenia were paranoid (59%), disorganised (21%), undifferentiated or residual (10%), the outcome of psychotic illness was episodic (50%) or continuous (33%). The daily mean dosage of loxapine was 168,4 mg/d, in antipsychotic loxapine monotherapy (27%) or in combination with other antipsychotics (63%); it was often associated with psychotropic medications (anxiolytic [72%], antidepressant [21%], normothymic [19%]). The stability of the dosage of loxapine during the 6 months follow-up (60%) was associated with strict loxapine monotherapy or antipsychotic monotherapy (loxapine associated with other psychotropic medication). Safety, side effects and compliance were compared with previous studies. DISCUSSION AND CONCLUSION: These results are discussed, comparing the two pharmacoepidemiological studies RÉALITÉ and RÉALITÉ LT, loxapine is used in compliance with the two indications (smpc) and French guidelines (HAS, Haute Autorité de santé).

Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia.

Three common missense variants of the Disrupted in Schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case-control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.

[A case of Usher's syndrome associated with psychotic symptoms: diagnosis and follow-up in a psychiatric unit]. / A propos d'un cas de syndrome de Usher suivi en psychiatrie : intérêt du diagnostic somatique pour la prise en charge psychiatrique.

INTRODUCTION: Usher's syndrome is a heterogeneous autosomal recessive disorder characterised by dual sensory impairment: profound congenital hearing impairment and progressive visual loss due to retinitis pigmentosa, sometimes associated with vestibular dysfunction. Some patients develop a psychotic illness, the etiology of which is still debated. Diagnosis may be difficult, and there are only a few reports in the psychiatric literature. CASE REPORT: The present case reports a 57-year-old man, double diagnosed with sensory impairment and psychosis. The severity of his psychosis required several hospitalisations in a psychiatric in-unit, even under third party decision or compulsory hospitalisation, for acute states with disruptive behaviour, aggressiveness against his mother, persecutory delusion and auditory hallucinations, self-talking, major anxiety, and depressive affects, without dissociation. Deafness had been diagnosed when he was six years old; he was able to attend school and learn to read and speak, using hearing aids, and was able to hold a job for three months. Severe psychotic symptoms appeared when he was 18 years old and contributed in confirming the diagnosis. Progressive loss of vision until blindness began later, between the age of 40 to 50. No specific abnormal results were revealed during the neuroradiological check-up. Treatment consisted in antipsychotics, notably depot, first in a mental health care in-unit and subsequently in an out-patient unit: although he denied psychotic symptoms, he became compliant with medication and could go on with treatment, associated with multidisciplinary interventions at home, in order to improve his quality of life. DISCUSSION: Usher's syndrome is the most frequent cause of combined deafness and blindness in adults (three and five individuals per 100,000), but difficulties in communication need to increase clinical awareness of this disorder, especially for psychiatrists. Three subtypes are recognized by the International Usher Syndrome Consortium: Type 1 is characterised by profound congenital deafness, retinal degeneration beginning in childhood, and progressive vestibular dysfunction; Type 2 is characterised by moderate to severe hearing impairment, later onset of retinal degeneration, and normal vestibular function; Type 3 is characterised by progressive hearing loss and variable age of onset of retinal degeneration. Although nearly 23% may have psychotic symptoms, the aetiology remains unclear: sensory deprivation associated with environmental stress, organic changes such as cerebral abnormalities, genetic link (two genetic loci for both Usher's syndrome and psychotic illness are very close). Treatment of psychiatric symptoms is based on antipsychotics, well tolerated by the patients, who improve change of behaviour and communication abilities. Genetic counselling may be useful for parents. CONCLUSION: Access to mental health services is particularly difficult for deaf and deaf-blind people, and difficulties in communication are a challenge for patients and for caregivers too. Antipsychotic medications are helpful for associated psychotic symptoms. Potential link between Usher syndrome and psychosis is still unclear and needs further studies.

Motor threshold in transcranial magnetic stimulation: comparison of three estimation methods.

AIMS: Motor threshold (MT) is an important parameter for the practice of transcranial magnetic stimulation. Our goal was to compare three methods to estimate MT in a clinical setting. METHODS: Comparison of three MT estimation algorithms: 1) the Rossini-Rothwell method consists in lowering stimulus intensity until only five positive responses out of 10 trials are recorded, defining MT; 2) the Mills-Nithi method considers the MT as the mean of an upper threshold (10 positive out of 10 trials) and a lower threshold (0 out of 10 trials); 3) the supervised parametric method estimates the MT by fitting (mathematically and graphically) a sigmoid function on raw data obtained by stimulation at variable intensities. Six MT estimations (two per method) were recorded in a single session in 10 healthy subjects. RESULTS: The within-subject variation of MT (expressed as % of the mean MT+/-standard deviation) during a single session was of 8.5+/-7.2% for the Rossini-Rothwell method, 8.7+/-5.7% for the Mills-Nithi method and 9.5+/-4.0% for the supervised parametric method. No significant differences in variability of MT estimation were found between the methods, but the Rossini-Rothwell method was significantly shorter (half the number of stimuli compared to the two other methods). CONCLUSION: In our setting, Rossini-Rothwell method was superior to the two other methods. The variability of MT estimation measured in our study is important, yet acceptable for clinical applications. However, this variability can be a source of considerable errors in excitability studies and should be a focus of future research.

[Psychotropic drugs induced weight gain: a review of the literature concerning epidemiological data, mechanisms and management]. / Prise de poids pharmaco-induite par les psychotropes et sa prise en charge: revue des données de la littérature.

Weight gain is associated with the use of many psychotropic medications, including antidepressants, mood stabilizers, antipsychotic drugs, and may have serious long term consequences: it can increase health risks, specifically from overweight (BMI = 25-29.9 kg/m2) to obesity (BMI > or =30 kg/m2), according to Body Mass Index (BMI), and the morbidity associated therewith in a substantial part of patients (hypertension, coronary heart desease, ischemic stroke, impaired glucose tolerance, diabetes mellitus, dyslipidemia, respiratory problems, osteoarthritis, cancer); according to patients, psychosocial consequences such as a sense of demoralization, physical discomfort and being the target of substantial social stigma are so intolerable that they may discontinue the treatment even if it is effective. The paper reviews actual epidemiological data concerning drug induced weight gain and associated health problems in psychiatric patients : there is a high risk of overweight, obesity, impaired glucose tolerance, diabetes mellitus, premature death, in patients with schizophrenia or bipolar disorder; and the effects of specific drugs on body weight: Tricyclic Antidepressants (TCA) induced weight gain correlated positively with dosage and duration of treatment, more pronounced with amitriptyline ; Selective Serotonin Reuptake Inhibitors (SSRI) decrease transiently bodyweight during the first few weeks of treatment and may then increase bodyweight; weight gain appears to be most prominent with some mood stabilizers (lithium, valproate); atypical antipsychotics tend to cause more weight gain than conventional ones and weight gain, diabetes, dyslipidemia, seem to be most severe with clozapine and olanzapine. Conceming the underlying mechanisms of drug induced weight gain, medications might interfere with central nervous functions regulating energy balance; patients report about: increase of appetite for sweet and fatty foods or "food craving" (antidepressants, mood stabilizers, antipsychotic drugs) and weight gain despite reduced appetite which can be explained by an altered resting metabolic rate (TCA, SSRI, Monoaminoxidase Inhibitors MAO I). According to current concepts, appetite and feeding are regulated by a complex of neurotransmitters, neuromodulators, cytokines and hormones interacting with the hypothalamus, including the leptin and the tumor necrosis factor system. The pharmacologic mechanisms underlying weight gain are presently poorly understood: maybe the different activities at some receptor systems may induce it, but also genetic predisposition. Understanding of the metabolic consequences of psychotropic drugs (weight gain, diabetes, dyslipidemia) is essential: the insulin-like effect of lithium is known; treatment with antipsychotic medications increases the risk of impaired glucose tolerance and diabetes mellitus. Several management options of weight gain are available from choosing or switching to another drug, dietary advices, increasing physical activities, behavioural treatment, but the best approach seems to attempt to prevent the weight gain : patients beginning maintenance therapy should be informed of that risk, and nutritional assessment and counselling should be a routine part of treatment management, associated with monitoring of weight, BMI, blood pressure, biological parameters (baseline and three months monitoring of fasting glucose level, fasting cholesterol and triglyceride levels, glycosylated haemoglobin). Psychiatrics must pay attention to concomitant medications and individual factors underlying overweight and obesity. Weight gain has been described since the discovery and the use of the firstpsychotropic drugs, but seems to intensify with especially some of the second generation antipsychotic medications ; understanding of the side effects of psychotropic drugs, including their metabolic consequences (weight gain, diabetes, dyslipidemia) is essential for the psychiatrics to avoid on the one hand a risk of lack of compliance, a discontinuation of the pharmacological medication and also a risk of relapse and rehospitalization, and on the other hand to avoid acute life threatening events (diabetic ketoacidocetosis and non ketotic hyperosmolar coma, long term risk complications of diabetes and overweight).

Pharmacoclinical strategy in neuroleptic resistant schizophrenic patients treated by clozapine: clinical evolution, concentration of plasma and red blood cell clozapine and desmethylclozapine, whole blood serotonin and tryptophan.

1. The aim of the study was to determine if a more rational therapeutic approach could be devised for neuroleptic resistant psychotic patients treated for months and years with clozapine. Clozapine is an atypical antipsychotic medication, but its therapeutic benefit has been limited by a high incidence of agranulocytosis and seizures. 2. The study has been performed in an open setting and included 12 patients. Some of them developed a secondary depression and were treated with fluoxetine. 3. Pharmacokinetic analysis were conducted at the same time as clinical evaluations, grading using the BPRS, the PDS, and QLS, and determinations of plasma and red blood cell clozapine and desmethylclozapine, plasma and RBC fluoxetine and norfluoxetine, whole blood serotonin and tryptophan. 4. A positive linear correlation was found only between RBC concentration and the evolution of the QLS. 5. Clozapine is efficacious both on positive and negative symptoms but its mechanism of action remains unclear. Positive symptoms disappear more quickly, sometimes followed by a post psychotic depression. Negative symptoms improve more slowly but regularly. They seem to be correlated with serotoninergic mechanisms. For whole blood 5HT, an important increase was seen about 4 weeks after Cloza administration, and then a decrease. 6. Therapeutic drug monitoring (on the same sample drawn for haematological monitoring providing) could play a useful role in the management of patients treated by clozapine: compliance, lowest dose, possible toxicity, drug interaction, lack of efficacy, relapse predictivity.

Neuroleptic-resistant schizophrenic patients treated by clozapine: clinical evolution, plasma and red blood cell clozapine and desmethylclozapine levels.

The aim of this open study was to determine a more rational therapeutic approach for psychotic patients treated with clozapine for several months, using measurement of plasma and red blood cell levels (P, RBC) of clozapine (cloza) and N-desmethylclozapine (descloza), the major metabolite of clozapine, which has been reported to be less active but more toxic (agranulocytosis) than clozapine itself. The RBC concentration may be considered as more representative of the free fraction drug. The study concerned 7 patients suffering from chronic paranoid schizophrenia according to the DSM-IV criteria. All of them were treatment-refractory schizophrenic inpatients (4 men, 3 women, mean age +/- SD: 38.2 +/- 8.4 years; mean duration of illness +/- SD: 14.4 +/- 5.1 years). They had received at least two different neuroleptics, for 6 weeks, before entering the study. Treatment started in our hospitalization unit with clozapine 25 mg up to a maximum of 900 mg/d (mean stabilized daily dose +/- SD: 507 +/- 211 mg and mean daily dose per kg: 6.91 +/- 3.08 mg). Clinical evaluations (Quality of Life Scale: QLS), regular blood monitoring and biological samples were conducted at the same time, weekly for 18 weeks and then monthly (duration of the study: 4 to 38 months; mean +/- SD: 12.9 +/- 11.5 months). Plasma and RBC (after lysis) levels were determined by reversed phase HPLC and UV detection after extraction with hexane. All the patients improved very quickly after the first week of treatment and six were able to leave the hospitalization unit and start outpatient care such as daily hospitalization, returning home or in sheltered accommodation. With the following plasma (P) and RBC levels: mean cloza +/- SD: (P = 294 +/- 146 ng/ml; RBC = 110 +/- 82 ng/ml) and mean descloza +/- SD: (P = 173 +/- 106 ng/ml; RBC = 76 +/- 54 ng/ml); none of the seven patients developed agranulocytosis. The blood levels, ensuring better surveillance, have a predictive value for clinical improvement. A linear pharmacoclinical correlation was only found between RBC cloza concentrations and the evolution of the QLS scores. Clozapine fulfils the criteria for therapeutic drug monitoring, and determination of plasma, and more particularly RBC, cloza and descloza levels may help to find the lowest effective dose with the fewest side effects.