[Three clinical risk profiles of violent behavior in a cohort of early psychosis patients]. / Trois profils cliniques à risque de comportements violents dans une cohorte de patients présentant un premier épisode de psychose.

OBJECTIVE: This study aims to determine whether it is possible to identify clinical profiles at risk of violent behaviors (VB) in the early phase of psychotic disorders, on the basis of the main dynamic psychopathological risk factors and describe characteristics of the groups with highest levels of violent behaviors. METHOD: A total of 265 patients, aged 18 to 35, treated at the Treatment and early Intervention in Psychosis Program (TIPP-Lausanne), a specialized early psychosis program, were included in this study. We conducted a latent-class analysis and a discriminative analysis on the basis of the main dynamic VB risk factors: substance use disorder, impulsivity, positive symptoms, insight, aggression, hostility, anger, emotional instability and adherence to treatment. These factors were evaluated by specialized scales and on the basis of the Positive and Negative Syndrome Scale (PANSS). VB were restricted to physical aggression against people, defined as "serious violence". They were assessed on the basis of a questionnaire listing violent offenses (Swiss Criminal Code) and VB such as assault and battery, information through the forensic psychiatric services and on the basis of the Staff Observation Aggression Scale (SOAS-R scale) during inpatient treatment phase. RESULTS: Four heterogeneous subgroups were identified with respect to the studied clinical characteristics, including two groups with high rates of VB. The first group, comprising 46% of patients with VB, is distinguished by the prevalence of a range of dimensions related to hostility, impulsivity and emotional instability, associated with high levels of substance abuse and positive symptoms. These clinical dimensions are very significant at the statistical level, since they explain 70% of the construction of subgroups (discriminant analysis). The second group with 37% of patients with VB, is characterized by a lack of insight, lack of adherence to treatment and substance use. These two clinical profiles could increase the impairment of cognitive, functional and relational abilities and contribute to the development of VB in this early phase of psychosis. The third subgroup, with a violent behaviors rate of 28.6%, is distinguished by its high proportion of diagnoses of substance abuse (100%) and women (54%). A last subgroup of patients, the largest quantitatively, has a low proportion of VB (15%) and the lowest levels on the studied factors, suggesting that the majority of patients with this profile commit few VB. CONCLUSION: Our results show that it is possible to identify groups at risk of violent behaviors during the early phase of psychosis on the basis of clinical characteristics that may evolve and therefore be the focus of preventive care. These results highlight the need to target substance use, impulsivity and lack of insight at follow-up in order to prevent VB.

Impulsivity in early psychosis: A complex link with violent behaviour and a target for intervention.

BACKGROUND: Violent behaviour (VB) occurs in first episode of schizophrenia and can have devastating impact both on victims and patients themselves. A better knowledge of the underlying mechanisms of VB may pave the way to preventive treatments. OBJECTIVES: 1) To explore the nature of the link between impulsivity and VB in early psychosis (EP) patients; 2) To explore the interactions between impulsivity and substance abuse, insight, and positive symptoms, the main dynamic risk factors of VB described to date. DESIGN AND METHODS: Post hoc analysis of data acquired in the frame of a 36-months EP cohort study. A total of 265 EP patients, aged 18 to 35, treated at TIPP (Treatment and early Intervention in Psychosis Program), at the Department of Psychiatry in Lausanne, Switzerland, were included in the study. Logistic regression analyzes were performed as well as mediation analysis and interaction analysis RESULTS: Our data suggest that impulsivity is a predictor of VB when analyzed independently and as part of a multi-factorial model. Impulsivity continues to differentiate violent patients from non-violent ones at the end of the program. In addition, the relationship between impulsivity and VB is not mediated by substance abuse. Finally, the effect of impulsivity on the probability of VB is potentiated by the interaction of different levels of insight and positive symptoms. CONCLUSIONS: Early intervention strategies in psychotic disorders should include evaluation of impulsivity considering it is linked to increased risk of VB and may respond to treatment.

Implication of the glutamate-cystine antiporter xCT in schizophrenia cases linked to impaired GSH synthesis.

xCT is the specific chain of the cystine/glutamate antiporter, which is widely reported to support anti-oxidant defenses in vivo. xCT is therefore at the crossroads between two processes that are involved in schizophrenia: oxidative stress and glutamatergic neurotransmission. But data from human studies implicating xCT in the illness and clarifying the upstream mechanisms of xCT imbalance are still scarce. Low glutathione (GSH) levels and genetic risk in GCLC (Glutamate-Cysteine Ligase Catalytic subunit), the gene of limiting synthesizing enzyme for GSH, are both associated with schizophrenia. In the present study, we aimed at determining if xCT regulation by the redox system is involved in schizophrenia pathophysiology. We assessed whether modulating GCLC expression impact on xCT expression and activity (i) in fibroblasts from patients and controls with different GCLC genotypes which are known to affect GCLC regulation and GSH levels; (ii) in rat brain glial cells, i.e., astrocytes and oligodendrocytes, with a knock-down of GCLC. Our results highlight that decreased GCLC expression leads to an upregulation of xCT levels in patients' fibroblasts as well as in astrocytes. These results support the implication of xCT dysregulation in illness pathophysiology and further indicate that it can result from redox changes. Additionally, we showed that these anomalies may already take place at early stages of psychosis and be more prominent in a subgroup of patients with GCLC high-risk genotypes. These data add to the existing evidence identifying the inflammatory/redox systems as important targets to treat schizophrenia already at early stages. SCHIZOPHRENIA: ANTIOXIDANT DEFICIT INCREASES A KEY NEUROTRANSMITTER TRANSPORTER: Deficit of antioxidant synthesis in schizophrenia leads to oxidative stress and changes in neurotransmitter transporter. Led by Kim Do, a team of researchers from Lausanne University in Switzerland investigated the role of the cell-surface transport protein xCT in schizophrenia. They found that an enzyme responsible for antioxidant production is disturbed in patients. This leads to decreased antioxidant levels and consequently to oxidative stress-i.e. the accumulation of reactive oxygen molecules, damaging the cells component and impairing cell functioning-which in turn affects the functioning of the antioxidant pathway, including xCT. xCT, which exports the neurotransmitter glutamate, is thus overproduced in schizophrenia. The resulting increase of neurotransmitter activity, alongside the increase in oxidative stress, is thought to play a major role in the pathophysiology of schizophrenia, including at early stages of the disease.

Impaired fornix-hippocampus integrity is linked to peripheral glutathione peroxidase in early psychosis.

Several lines of evidence implicate the fornix-hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix-hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix-hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms.

Childhood sexual and physical abuse: age at exposure modulates impact on functional outcome in early psychosis patients.

BACKGROUND: Evidence suggests a relationship between exposure to trauma during childhood and functional impairments in psychotic patients. However, the impact of age at the time of exposure has been understudied in early psychosis (EP) patients. METHOD: Two hundred and twenty-five patients aged 18-35 years were assessed at baseline and after 2, 6, 18, 24, 30 and 36 months of treatment. Patients exposed to sexual and/or physical abuse (SPA) were classified according to age at the time of first exposure (Early SPA: before age 11 years; Late SPA: between ages 12 and 15 years) and then compared to patients who were not exposed to such trauma (Non-SPA). The functional level in the premorbid phase was measured with the Premorbid Adjustment Scale (PAS) and with the Global Assessment of Functioning (GAF) scale and the Social and Occupational Functioning Assessment Scale (SOFAS) during follow-up. RESULTS: There were 24.8% of patients with a documented history of SPA. Late SPA patients were more likely to be female (p = 0.010). Comparison with non-SPA patients revealed that: (1) both Early and Late SPA groups showed poorer premorbid social functioning during early adolescence, and (2) while patients with Early SPA had poorer functional level at follow-up with lower GAF (p = 0.025) and lower SOFAS (p = 0.048) scores, Late SPA patients did not. CONCLUSION: Our results suggest a link between exposure to SPA and the later impairment of social functioning before the onset of the disease. EP patients exposed to SPA before age 12 may present long-lasting functional impairment, while patients exposed at a later age may improve in this regard and have a better functional outcome.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.