[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.

[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.