Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Impact of the first wave of the COVID-19 pandemic on French Health students.

CONTEXT: In France, care workers and health students have been intensely mobilized during the first wave of the COVID-19 pandemic. But few studies have evaluated psychological distress on non-medical health students, in addition to the challenges posed by pedagogical continuity while universities are closed following health and safety regulations. OBJECTIVES: This study aims to assess COVID-19's impact on health students in France on different levels: psychological, educational and social. METHODS: An online national cross-sectional study, from April 11 to May 30 2020, included sociodemographic, work conditions and numeric scales. RESULTS: A total of 4411 students answered. Regarding the K6 scale, 39% of students had moderate distress, and 21% had a high level of distress. Risk factors of psychological distress included being a woman (P<0.001), being between 19 and 21 years old (P<0.001), living alone (P=0.008), and not having the ability to isolate (P<0.001). Students on the frontline had less psychological distress (57 vs 62%, P=0.003), better quality of sleep (34% vs 28% high quality, P<0.001) but a higher consumption of medical (8.5% vs 6.5%, P=0.044) and non-medical (18% vs 10%, P<0.001) psychotropic drugs. Nurse and medical students had more distress and used more non-medical psychotropic substances than other health students (15% vs 9.2%). DISCUSSION: COVID-19' crisis had an important impact on health students' mental health, social life and training with discrepancies regarding the speciality whether they were on the frontline or not. There is an urgent need for psychological and pedagogical support for students, and even more so regarding the prolongation of the COVID-19 epidemic.

[Student's mental health: better measurement and considereration of the challenges]. / La santé mentale des étudiants : mieux prendre la mesure et considérer les enjeux.

Mental health represents a high cost for society, estimated at 109 billion euros per year in France, 80 % of which are indirect costs. Mental diseases start before the age of 24 for 75 % of patients. Students, whose age is predominantly between 18 and 25, are a particularly high-risk population and for whom mental illness can have very serious consequences. The Observatoire de la vie Etudiante surveys from 2016 found a 12 month prevalence of depression of 15 % with suicidal thoughts in 8 % of the students higher than what is observed in the French general population, respectively 10 % and 5 %. The confinement itself and its consequences both economic (unemployment, difficulty for young people to find a job…) and social (isolation) could have a very bad effect on their mental health. The survey made by a governmental organization (Santé Publique France) revealed a significant increase in the prevalence of anxiety disorders at the start of confinement in the general population. This prevalence decreased during confinement but remained significantly higher than in 2017. Economic simulated data indicate that prevention in mental health could not only be effective but also profitable. In France, reimbursement by national health insurance of 12 sessions of psychologists for young people (between 11 to 21) is being tested in order to further and widely implement psychological prevention strategies rather than relying on already widely reimbursed pharmacological treatments. There are, however, several issues to discuss. First of all, is the need to define what psychopathology is considered to be. Then, it should be understood how measures of these concepts are created, how tools are constructed and how they operate in their environment. For depression, many different scales exist and even if the most used one are taken into account, they have very little content or symptoms in common. In addition, for the same scale, many different cut-offs exist to define whether a case should be considered as pathological or not, and so it is with the period of time studied being considered that may vary, both leading to consequences such as the differences observed in prevalence. Other biases should also be considered such as the age of the participants, the gender, the size of the sample, the response rate, the method of assessment and recruitment. Finally, it is necessary to question the assumptions and models used concerning the causes of psychic pathologies. Biological hypotheses on the origin of depression involve genetics and inflammation, but sociological and psychological factors must also be considered as well as the underlying complexity both in their nature and interactions at different structural levels of space and time. We should avoid drifting towards a biological or a sociological reductionism and move forward through complex systems approaches and models. With regard to student mental health in France, unfortunately, quality data are still lacking, and existing studies are difficult to compare as some may also have methodological issues. This article leads to the conclusion that there is a need for policies to assess student mental health at both local and national levels with a reflexional thinking on the tools and scales to use as measurements of these phenomena. This approach does not require being too assertive, but should have full transparency on the way the measures were designed and obtained. Measures are as much needed as are the needs for coordinated prevention and care in mental health.

[Management of cardiovascular co-morbidities in young patients with early onset psychosis: State of the art and therapeutic perspectives]. / Prise en charge des comorbidités cardio-vasculaires chez les jeunes patients souffrant d'une psychose débutante : état des lieux et perspectives thérapeutiques.

Patients with psychiatric disorders have a decrease in their life expectancy. Excess mortality of patients with schizophrenia was demonstrated by a meta-analysis in the late 1990s and has not decreased for the past 30years. A recent meta-analysis including nearly 250,000 patients with schizophrenia found an average decrease in life expectancy of 14.5years (CI95: 11,2-17,8), more important for men than for women: 15.9 (CI95: 13,8-18,0) vs 13.6 (CI95: 11,4-15,8). A closer look at the somatic comorbidities, including metabolic syndrome, and investigation of causes of death of these patients highlighted already well-known factors, namely late diagnosis and insufficient treatment of physical diseases, side effects of antipsychotics, unhealthy lifestyle (poor diet, smoking, excessive alcohol consumption and lack of exercise), and higher risk of suicide and accident. Concerning ultra-high risk (UHR) patients, a 2016 meta-analysis of 47 studies evaluated the cardiovascular risk factors. They reported a higher prevalence of smoking in UHR (odds ratio 2,3) and a lower level of physical activity associated with a normal BMI (Body Mass Index) compared to the control population. A meta-analysis about patients with a first episode of psychosis (FEP) found reduced total and LDL cholesterol levels and an increased triglyceride level compared to the control population. One study found alteration of the fasting plasmatic levels of glucose and insulin, as well as insulin resistance in FEP patients, compared to controls albeit the HbA1c level was not significantly different. A meta-analysis reported a prevalence of metabolic syndrome of 10 % in FEP or drug naïve patients versus 35 % and 20 % in treated and untreated patients with chronic schizophrenia respectively. Somatic comorbidities usually appear during the first two years of the disease. Some interventions have proven their efficacy in reducing the occurrence of metabolic syndrome and other cardiovascular risk factors. For instance, metformin, a treatment for type 2 diabetes that is allowed from the age of 10, has shown benefits in children and adolescents receiving second-generation antipsychotics in a recent meta-analysis, with a mean weight loss of 3.23kg (IC95 % -5.59 -0.86) after 16 weeks. Dietary-hygienic interventions are also effective in reducing cardiovascular risk. Other interventions such as omega-3 supplementation, vitamin D, N-acetylcysteine, and fasting have not proven to be effective. Comprehensive care programs have been developed to promote somatic care in psychiatric patients, such as the Canadian HeAL (Healthy Active Lives) program. These programs are more effective when proposed from the beginning of the disease and the introduction of antipsychotics. In this review, because there is no French recommendation, we translate a tool for the prescription of metformin and the Canadian recommendations from the HeAL program. Generalization of these programs to all young psychotic patients could improve their life expectancy and reduce the overall mortality. Prevention of cardiovascular risk factors and cardio-metabolic monitoring of treatments must be part of the standard of care in early psychosis. These programs aim at providing patients with the quality of somatic and mental care they are entitled to. This requires the involvement of all stakeholders, including patients and their families but also psychiatrists and other caregivers.

[Neurodevelopment and cannabis]. / Cannabis et neurodéveloppement.

Brain development is a complex phenomenon, stretching from fetal life to adolescence, during which brain maturation proceeds through a series of ordered events including critical periods of plasticity. The brain is particularly sensitive to the environment during these changes. The endocannabinoid system participates directly and indirectly in these plasticity and maturation processes. The main psychoactive component of cannabis, the delta-9-tetrahydrocanabinol, can cross the placental barrier, is present in breastmilk and diffuses in the brain. It interacts with the endocannabinoid signaling, especially through the activation of cannabinoid receptors 1 CB1R, which can lead to abnormal neurodevelopmental processes and neuronal circuits functions. Therefore, exposure to cannabis in utero, in perinatal phase, as well as during the adolescence disrupts the brain maturation and can cause disturbances on the cognitive, psychotic and addictive levels that persist far beyond the period of exposure. Several factors modulate the risk of such complications, but studies performed in animal models as well as in human cohorts have shown that exposure during both the critical perinatal and adolescence phases is a risk factor per se. Current knowledge encourages the dissemination of objective information to young people, to prevent and limit early exposure and its consequences.

[Membrane lipids in schizophrenia and early phases of psychosis: Potential biomarkers and therapeutic targets?] / Lipides membranaires dans la schizophrénie et la psychose débutante : de potentiels biomarqueurs et pistes thérapeutiques ?

The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.

[Which interventions improve the well-being of medical students? A review of the literature]. / Quelles interventions pour améliorer le bien-être des étudiants en médecine ? Une revue de la littérature.

Physician's psychological distress has been known for more than a century. A meta-analysis found an increase in the suicide rate among physicians, compared to the general population, with a relative risk of 1.41 for men and 2.27 for women. Among interns, the prevalence of depression or depressive symptoms is estimated at 28.8% (IC 95%=25.3%-32.5%). The suffering of medical students prior to internship has been recognized more recently. But now there are many studies, and a few meta-analyses, which have evaluated the prevalence of anxiety, depression, burnout and, more generally, the lack of well-being. Among medical students, the prevalence of depression or depressive symptoms is estimated at 27.2% (IC 95%=24.7-29.9) and that of suicidal ideation of 11.2% (CI at 95%=9.0-13.7). Another meta-analysis found a prevalence of burnout of 44.2 % (IC 95%=33.4-55.0). Since the problem has been known researchers have tested interventions to improve the well-being of students. Our work aims to review interventions to help medical students and use validated scales. A review was published in 2016 about interventions on the learning environment, and the well-being of medical students was published; 28 studies were identified. But they did not systematically use validated questionnaires allowing a quantitative approach. Interventions included: pass/fail scoring systems (n=3), mental health programs (n=4), psycho-corporal skills programs (n=7), curriculum structure (n=3), multi-component program reform (n=5), wellness programs (n=4), and counseling/mentoring programs (n=3). We chose to focus only on studies using validated questionnaires. A search was performed in the MEDLINE biomedical electronic database until July 31, 2018. The inclusion criteria were: original study, in French or English, concerning medical students prior to internship involving an intervention to improve the well-being of medical students by measuring at least one criterion of psychological distress (anxiety, burnout, depression…) using a validated scale. Thirty-six studies were included in this review. The quality of the studies is very heterogeneous. We can distinguish three types of intervention: institutional (modification of the system of notation, classification…), in-group (management of the stress, therapy full of conscience, relaxation, psychoeducation…) or individual (screening and support custom). These interventions encompass all levels of prevention (primary, secondary and tertiary). There is limited effectiveness of group interventions. This effectiveness disappeared after SIX months with the exception of institutional interventions. The data set encourages us not to favor a single type of intervention but to promote a global intervention acting at all levels. In particular, researchers can draw on studies of doctors and interns. France is late to come to the issue with few published studies on interventions to improve the well-being of students, but recent awareness seems to have taken place. Our study has some limitations: restriction to French and English, the choice to select only comparative studies using validated scales which limited the number of studies selected but also the type of interventions not all of which allow a quantitative evaluation. In the interventions not taken into account in this review, several seem promising. They mainly involve secondary prevention: improving the training of staff and students in the detection of symptoms of depression, burnout and psychological stress, screening at-risk populations, and communication campaigns to combat the stigma of psychiatric disorders and encourage students to consult. But tertiary prevention is also of interest: have psychologists and psychiatrists in the faculties accessible to students who feel the need and can also accommodate. Finally, a certain number of faculties have set up vocational guidance and selection aids that are appreciated by students but have not been evaluated for their impact on students' health. Recent studies and meta-analyses indicate a significant prevalence of outstanding medical students, however, there is reason to be optimistic. Many health professionals and researchers are interested in the problem as well as the means to remedy it. Most studies are effective in the short term. However, the methodological limitations (low number of subjects, limited follow-up time…) and the heterogeneity of studies concerning interventions (mindfulness, psychoeducation…) on students do not allow us to conclude that they are effective in the long term. It should therefore rather move towards comprehensive care acting on the three levels of prevention: primary (institutional interventions/speech groups/psycho education), secondary (screening of subjects at risk, speech groups/psycho education/others) and tertiary (individual interventions).

Membrane lipidomics in schizophrenia patients: a correlational study with clinical and cognitive manifestations.

Schizophrenia is a severe mental condition in which several lipid abnormalities-either structural or metabolic-have been described. We tested the hypothesis that an abnormality in membrane lipid composition may contribute to aberrant dopamine signaling, and thereby symptoms and cognitive impairment, in schizophrenia (SCZ) patients. Antipsychotic-medicated and clinically stable SCZ outpatients (n=74) were compared with matched healthy subjects (HC, n=40). A lipidomic analysis was performed in red blood cell (RBC) membranes examining the major phospholipid (PL) classes and their associated fatty acids (FAs). Clinical manifestations were examined using the positive and negative syndrome scale (PANSS). Cognitive function was assessed using the Continuous Performance Test, Salience Attribution Test and Wisconsin Card Sorting Test. Sphingomyelin (SM) percentage was the lipid abnormality most robustly associated with a schizophrenia diagnosis. Two groups of patients were defined. The first group (SCZ c/SM-) is characterized by a low SM membrane content. In this group, all other PL classes, plasmalogen and key polyunsaturated FAs known to be involved in brain function, were significantly modified, identifying a very specific membrane lipid cluster. The second patient group (SCZ c/SM+) was similar to HCs in terms of RBC membrane SM composition. Compared with SCZ c/SM+, SCZ c/SM- patients were characterized by significantly more severe PANSS total, positive, disorganized/cognitive and excited psychopathology. Cognitive performance was also significantly poorer in this subgroup. These data show that a specific RBC membrane lipid cluster is associated with clinical and cognitive manifestations of dopamine dysfunction in schizophrenia patients. We speculate that this membrane lipid abnormality influences presynaptic dopamine signaling.