A systematic review of interventions in the early course of bipolar disorder I or II: a report of the International Society for Bipolar Disorders Taskforce on early intervention.

BACKGROUND: Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II. METHODS: We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the 'early course' of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach. RESULTS: From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course. CONCLUSIONS AND RECOMMENDATIONS: While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.

The impact of aversive personality traits on the psychotic-spectrum of disorders.

OBJECTIVES: Though relatively unexplored in clinical populations, aversive personality traits have been shown to impact the expression, the management, and the outcomes of psychotic disorders. This paper seeks to gather and organize existing evidence of the complex interplay linking social ethics, personality and experiences of psychosis through the lens of the so-called Dark Triad personality model, comprising the three multidimensional constructs Machiavellianism, narcissism and psychopathy. METHODS: A semi-systematic review of major literature databases was conducted; search terms aimed at capturing each of the Dark Triad dimensions and their known relations with both clinical (with single-symptom approach) and non-clinical psychotic experiences. RESULTS: Reviewed studies suggest that all the components of the Dark Triad model present significant clinical implications in the management of psychotic disorders. CONCLUSIONS: Aversive personality traits interact with and modulate the experiences of psychosis. They can be shown to influence the clinical and functional outcomes of psychotic patients. Therefore, further research on this theme seems justified in that it may inform rehabilitative efforts.

[Individual and contextual factors associated with violent behaviours during psychiatric hospitalizations]. / Facteurs individuels et contextuels participant à l'apparition de comportements violents en cours d'hospitalisations psychiatriques.

BACKGROUND: The prevention of Physical Violent Behavior (VB) toward others during psychiatric hospitalization is a major concern of clinicians. These VBs can have a deleterious impact on the victims, inpatients or caregivers, as well as on the therapeutic milieu. Such violence can also have negative consequences for the assailant patients, such as repeatedly being hospitalized under restraint, stigmatization, and difficulties reintegrating into the community. OBJECTIVES: This study explored individual (age, gender, marital status, living status, diagnostic) and institutional (type of admission, length of stay, number of previous hospitalizations) risk factors, and how their interactions could increase the risk of VB during psychiatric hospitalizations. METHOD: The study was carried out over a period of four years in the psychiatry department of the Lausanne University Hospital, on the 15 wards (219 beds) specialized in acute psychiatric care for adults. All the patients admitted to one of these wards during this period (n=4518), aged between 18 and 65 years, were included in the study. The sample was divided in two groups: non-violent patients (NVPs) and violent patients (VPs). VBs, defined as physical aggressions against another person, were assessed by the Staff Observation Aggression Scale - Revised (SOAS - R). Only physical assaults, associated or not with other types of violence, involving hospitalized patients were analyzed. Personal and institutional factors were extracted from the hospital database. Chi2 independence tests were used to assess differences between groups. Logistic regression models were used to identify the links between each factor and the VB. Classification and regression trees were used to study the hierarchical effect of factors, and combinations of factors, on VBs. RESULTS: During the study period, 414 VBs were reported involving 199 patients (4.40 % of all patients). VPs were significantly younger, male, more likely to be unmarried and living in sheltered housing before hospitalization. In this group, the proportion of patients with diagnoses of schizophrenia, and/or schizophrenia with comorbid substance abuse and cognitive impairment, were higher compared to NVPs. VPs were more frequently admitted involuntarily, had a longer average length of stay and a greater number of previous hospitalizations. The logistic regression model performed on individual factors have shown a significant link between age (OR=0.99; CI: 0.97-1.00; P-value=0.024), living in sheltered housing before admission (OR=2.46; CI: 1.61-3.75; P-value<0.000), schizophrenic disorders (OR=2.18; CI: 1.35-3.57; P-value=0.001), schizophrenic disorders with substance abuse comorbidity (OR=2.00; CI: 1.16-3.37; P-value=0.016), cognitive impairment (OR=3.41; CI: 1,21-8.25; P-value=0.010), and VBs. The logistic regression model on institutional factors have shown a significant link between involuntary hospitalization (OR=4.38; CI: 3.20-6.08; P-value<0.000), length of previous stay (OR=1.01; CI: 1.00-1.01; P-value<0.000), number of previous hospitalizations (OR=1.06; CI: 1.00-1.12; P-value=0.031), and VBs. The logistic regression model on individual and institutional factors have shown a significant link between age (OR=0.99; CI: 0.97-1.00; P-value=0.008), living in sheltered housing before admission (OR=2.46: CI: 1.61-3.75; P-value=0.034), cognitive impairment (OR=3.41; CI: 1.21-8.25; P-value=0.074), involuntary hospitalization (OR=3.46; CI: 2.48-4.87; P-value<0.000), length of previous stay (OR=1.01; CI: 1.00-1.01; P-value<0.000), and VBs. The classification and regression trees have shown that the relationship between long length of stay and repeated hospitalizations mainly potentiate the risk of violence. CONCLUSION: The results of this study have shown the existence of a small group of vulnerable patients who accumulate constrained hospital stays during which violence occurs. Exploring the clinical profiles and institutional pathways of patients could help to better identify these patients and promote a more appropriate mode of support, such as intensive clinical case management. This model could facilitate the development of a clinical network and the links between the structures and partners caring for a patient. This would create a continuous support, avoiding or limiting the lack of continuity of care and care disruption.

[Early intervention in bipolar affective disorders: Why, when and how]. / Intervenir précocement dans les stades débutants du trouble bipolaire : pourquoi, quand et comment.

OBJECTIVES: Bipolar disorder (BD) is a chronic and severe psychiatric disease. There are often significant delays prior to diagnosis, and only 30 to 40 % of patients will experience complete remission. Since BD occurs most often at a young age, the disorder can seriously obstruct future socio-professional development and integration. Vulnerability-stress model of BD is considered to be the result of an interaction between vulnerability genes and environmental risk factors, which leads to the onset of the disorder most often in late adolescence or early adulthood. The clinical "staging" model of BD situates the subject in a clinical continuum of varying degrees of severity (at-risk status, first episode, full-blown BD). Given the demonstrated effectiveness of early intervention in the early stages of psychotic disorder, we posit that early intervention for early stages of BD (i.e. at-risk status and first episode mania or hypomania) would reduce the duration of untreated illness and optimize the chances of therapeutic response and recovery. METHODS: We conducted a narrative review of the literature to gather updated data on: (1) features of early stages: risk factors, at-risk symptoms, clinical specificities of the first manic episode; (2) early screening: targeted populations and psychometric tools; (3) early treatment: settings and therapeutic approaches for the early stages of BD. RESULTS: (1) Features of early stages: among genetic risk factors, we highlighted the diagnosis of BD in relatives and affective temperament including as cyclothymic, depressive, anxious and dysphoric. Regarding prenatal environmental risk, we identified peripartum factors such as maternal stress, smoking and viral infections, prematurity and cesarean delivery. Later in the neurodevelopmental course, stressful events and child psychiatric disorders are recognized as increasing the risk of developing BD in adolescence. At-risk symptoms could be classified as "distal" with early but aspecific expressions including anxiety, depression, sleep disturbance, decreased cognitive performance, and more specific "proximal" symptoms which correspond to subsyndromic hypomanic symptoms that increase in intensity as the first episode of BD approaches. Specific clinical expressions have been described to assess the risk of BD in individuals with depression. Irritability, mixed and psychotic features are often observed in the first manic episode. (2) Early screening: some individuals with higher risk need special attention for screening, such as children of people with BD. Indeed, it is shown that children with at least one parent with BD have around 50 % risk of developing BD during adolescence or early adulthood. Groups of individuals presenting other risk factors, experiencing an early stage of psychosis or depressive disorders should also be considered as targeted populations for BD screening. Three questionnaires have been validated to screen for the presence of at-risk symptoms of BD: the Hypomanic Personality Scale, the Child Behavior Checklist-Paediatric Bipolar Disorder, and the General Behavior Inventory. In parallel, ultra-high risk criteria for bipolar affective disorder ("bipolar at-risk") distinguishing three categories of at-risk states for BD have been developed. (3) Early treatment: clinical overlap between first psychotic and manic episode and the various trajectories of the at-risk status have led early intervention services (EIS) for psychosis to reach out for people with an early stage of BD. EIS offers complete biopsychosocial evaluations involving a psychiatric examination, semi-structured interviews, neuropsychological assessments and complementary biological and neuroimaging investigations. Key components of EIS are a youth-friendly approach, specialized and intensive care and client-centered case management model. Pharmaceutical treatments for at-risk individuals are essentially symptomatic, while guidelines recommend the use of a non-antipsychotic mood stabilizer as first-line monotherapy for the first manic or hypomanic episode. Non-pharmacological approaches including psychoeducation, psychotherapy and rehabilitation have proven efficacy and should be considered for both at-risk and first episode of BD. CONCLUSIONS: EIS for psychosis might consider developing and implementing screening and treatment approaches for individuals experiencing an early stage of BD. Several opportunities for progress on early intervention in the early stages of BD can be drawn. Training first-line practitioners to identify at-risk subjects would be relevant to optimize screening of this population. Biomarkers including functional and structural imaging measures of specific cortical regions and inflammation proteins including IL-6 rates constitute promising leads for predicting the risk of transition to full-blown BD. From a therapeutic perspective, the use of neuroprotective agents such as folic acid has shown particularly encouraging results in delaying the emergence of BD. Large-scale studies and long-term follow-up are still needed to achieve consensus in the use of screening and treatment tools. The development of specific recommendations for the early stages of BD is warranted.

[Sexual and physical abuse during childhood; what is the impact on outcome in first episode psychosis patients?] / Traumatisme sexuel ou physique dans l'enfance : quel impact sur l'évolution d'un premier épisode psychotique ?

BACKGROUND: If exposure to childhood trauma increases the risk to later develop a psychotic disorder, the impact of such events on clinical presentation and outcome after a first psychotic episode deserves attention both in order to identify specific patients' needs and to develop adapted therapeutic interventions. METHODS: Three hundred and sixty-two patients treated at TIPP-Lausanne, a specialized program for the treatment of the early phase of psychotic disorders, were assessed prospectively, from baseline and every six months until the end of the 36 months of treatment. We compared characteristics of patients exposed to childhood sexual and/or physical abuse to those of non-exposed patients. RESULTS: One hundred and eight patients (29.8 %) were exposed to at least one episode of physical and/or sexual abuse during childhood. Exposed patients displayed higher levels of positive and depressive symptoms and had lower levels of functioning throughout the entire three year follow-up period. CONCLUSIONS: The prevalence of exposure to major traumatic events during childhood in early psychosis patients is very high, and it has an important impact on symptomatic and functional outcome. However, when clinical care is adapted, such patients seem to have a great potential for recovery. This justifies the implementation of specialized early psychosis programs and additional research in order to develop specific and adapted therapeutic strategies for such patients.

[Validation of a French version of the 16-item Prodromal Questionnaire (fPQ16) in adolescents and young adults seeking help]. / Validation d'une version française du 16-items Prodromal Questionnaire (fPQ16) chez des adolescents et jeunes adultes consultant en psychiatrie.

INTRODUCTION: The duration of untreated psychosis has been largely associated with poor outcomes in psychosis. Actual diagnostic tools may be used by very specialized teams and need sustained evaluation. We present a French version of a self-report questionnaire: the 16-item Prodromal Questionnaire (fPQ16). Our objective was to evaluate its predictive value for an ultra-high-risk state (UHR) or psychosis. The population enrolled was consulting in a young adults and adolescents center in Sainte-Anne hospital, Paris, France. METHODS: PQ16 had first been translated into French and independently back translated and validated by the original authors. Between November 2016 and May 2018, every C'JAAD consulting patient was proposed to fill in the fPQ16. Each patient was next evaluated with the French version of the comprehensive assessment of at-risk mental state (CAARMS), which detects UHR or psychosis. Statistical analysis of fPQ16 concurrent validity was performed using ROC curves. fPQ16 acceptability was studied by four additional questions especially designed for that purpose. RESULTS: One hundred participants were included. Mean age was 19.85years (SD 3.3 y). Fifty-eight percent of patients included were diagnosed with UHR (40%) or psychotic (18%) state after CAARMS evaluation. Mean score at fPQ16 was 5.7 (SD 3.8). Best cut-off score was 4 positive items, with excellent sensibility (91%) and correct specificity (60%). Positive predictive value of fPQ16 was 76%. Area under the curve was 0.85 (P<0.0001). fPQ16 showed good acceptability. DISCUSSION: fPQ16 had good screening performances in our population. Cut-off score was lower than in previous studies, but performances were equal or better. As a well-accepted and short questionnaire, the fPQ16 could be a great screening tool in primary care. A version with 18-items, including two items focused on thought content and disorganization that are missing in PQ16, is under evaluation.

[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.

[Has the concept of staging modified treatment of schizophrenia yet ?] / Le concept de staging a-t-il changé la prise en charge de la schizophrénie ?

The concept of staging is applied in medicine since many years, in order to better adapt treatment to patients' needs. Some authors have suggested one should also apply this concept to psychiatric disorders. If this approach seems to make sense, concrete progress in the domain are still limited. It is in the field of psychosis that most development have occurred, in the favorable context of early intervention programs. Some very detailed models have recently been proposed where successive stages of psychotic disorders are defined and corresponding treatment options are proposed. However, the limited reliability of clinical diagnoses systems and the absence of biomarkers allowing a more objective delineation of these various stages still hampers the concrete application of such strategies. Despite these limitations, the staging concept has already started to modify the mental health offer, especially for adolescents and young adults, for example through the development of the Headspace centers in Australia and other countries. These centers constitute accessible entry point for help seekers with mental health issues where treatment is defined according to the stage of illness. If such programs seem promising, a better understanding of the mechanisms underlying the development of psychiatric disorders seems important in order to facilitate the identification of stages and define the nature of the treatment needed for each of them, considering such knowledge has been the crucial for the development of the staging model in somatic disorders.

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.

Age at the time of onset of psychosis: A marker of specific needs rather than a determinant of outcome?

BACKGROUND: While there is suggestion that early onset of psychosis is a determinant of outcome; knowledge regarding correlates of later onset age is more limited. This study explores the characteristics of patients developing psychosis after age 26, towards the end of the usual age range of early intervention programs, in order to identify potential specific needs of such patients. METHODS: Two hundred and fifty-six early psychosis patients aged 18-35 were followed-up prospectively over 36 months. Patients with onset after 26 ("later onset", LO) were compared to the rest of the sample. RESULTS: LO patients (32% of the sample) had shorter DUP, were less likely to be male, had better premorbid functioning and were more likely to have been exposed to trauma. They had greater insight at presentation and less negative symptoms overall. The trajectories for positive and depressive symptoms were similar in both groups. Evolution of functional level was similar in both groups, but while LO patients recovered faster, they were significantly less likely to return to premorbid functional level. CONCLUSIONS: Later psychosis onset correlates with better premorbid functioning and higher rate of trauma exposure; the latter should therefore be a treatment focus in such patients. LO patients were less likely to return to premorbid functional level, which suggests that current treatment strategies may not be efficient to help patients maintain employment. The possibility of distinct illness mechanisms according to onset age and the more central role for trauma in patients with onset after age 26 needs to be further explored.

Predictors of functional status at service entry and discharge among young people with first episode psychosis.

OBJECTIVE: Most patients with first episode psychosis (FEP) are neither studying nor employed (have a poor functional status) when first accessing care. Knowledge of the characteristics of patients with poor functioning and the features influencing functional status over time may pave the way to better treatment. METHOD: A medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics on 661 FEP patients who consecutively attended the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia, between 1998 and 2000. Functional status was ascertained using the modified vocational status index and was rated at baseline (poor or good) and according to its evolution over the treatment period (stable good, stable poor, deteriorating or improved functional status). RESULTS: 52.0% of patients had a poor functional status at service entry. They were more likely to be male with a non-affective psychosis. They also had lower levels of premorbid global functioning and education, and were more likely to have self-reported histories of learning disability, forensic issues, traumatic experiences and substance use. At service entry, they had more severe symptoms and poorer global functioning. 37% of these patients maintained a poor functional status at discharge, and 18% of those with a good functional status at service entry experienced a decline. CONCLUSIONS: Although psychosocial interventions might assist a young person with FEP with working towards functional goals, for some, the impact of factors such as ongoing substance use and forensic issues on functional status needs to be addressed.

Insight as a social identity process in the evolution of psychosocial functioning in the early phase of psychosis.

BACKGROUND: Awareness of illness (insight) has been found to have contradictory effects for different functional outcomes after the early course of psychosis. Whereas it is related to psychotic symptom reduction and medication adherence, it is also associated with increased depressive symptoms. In this line, the specific effects of insight on the evolution of functioning over time have not been identified, and social indicators, such as socio-occupational functioning have barely been considered. Drawing from social identity theory we investigated the impact of insight on the development of psychosocial outcomes and the interactions of these variables over time. METHOD: The participants, 240 patients in early phase of psychosis from the Treatment and Early Intervention in Psychosis Program (TIPP) of the University Hospital of Lausanne, Switzerland, were assessed at eight time points over 3 years. Cross-lagged panel analyses and multilevel analyses were conducted on socio-occupational and general functioning [Social and Occupational Functioning Assessment Scale (SOFAS) and Global Assessment of Functioning (GAF)] with insight, time and depressive symptoms as independent variables. RESULTS: Results from multilevel analyses point to an overall positive impact of insight on psychosocial functioning, which increases over time. Yet the cross-lagged panel analysis did not reveal a systematic positive and causal effect of insight on SOFAS and GAF scores. Depressive symptoms seem only to be relevant in the beginning of the treatment process. CONCLUSIONS: Our results point to a complex process in which the positive impact of insight on psychosocial functioning increases over time, even when considering depressive symptoms. Future studies and treatment approaches should consider the procedural aspect of insight.

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.

A single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: A 12-month follow-up study.

BACKGROUND: Cognitive deficits have been reported during the early stages of bipolar disorder; however, the role of medication on such deficits remains unclear. The aim of this study was to compare the effects of lithium and quetiapine monotherapy on cognitive performance in people following first episode mania. METHODS: The design was a single-blind, randomised controlled trial on a cohort of 61 participants following first episode mania. Participants received either lithium or quetiapine monotherapy as maintenance treatment over a 12-month follow-up period. The groups were compared on performance outcomes using an extensive cognitive assessment battery conducted at baseline, month 3 and month 12 follow-up time-points. RESULTS: There was a significant interaction between group and time in phonemic fluency at the 3-month and 12-month endpoints, reflecting greater improvements in performance in lithium-treated participants relative to quetiapine-treated participants. After controlling for multiple comparisons, there were no other significant interactions between group and time for other measures of cognition. CONCLUSION: Although the effects of lithium and quetiapine treatment were similar for most cognitive domains, the findings imply that early initiation of lithium treatment may benefit the trajectory of cognition, specifically verbal fluency in young people with bipolar disorder. Given that cognition is a major symptomatic domain of bipolar disorder and has substantive effects on general functioning, the ability to influence the trajectory of cognitive change is of considerable clinical importance.

Olanzapine or chlorpromazine plus lithium in first episode psychotic mania: An 8-week randomised controlled trial.

BACKGROUND: Treatment strategies for mental disorders may vary according to illness stage. However no data currently exist to guide treatment in first episode psychotic mania. The aim of this study was to compare the safety and efficacy profile of chlorpromazine and olanzapine, as add-on to lithium, in patients with a first episode of psychotic mania, expecting better safety profile and adherence to olanzapine but similar efficacy for both treatments. METHODS: Data from 83 patients were collected in an 8-week randomised controlled trial on clinical variables, side effects, vital signs, and weight. Analyses of treatment differences over time were based on intent-to-treat principles. Kaplan-Meier estimated survival curves were used to analyse time-to-event data and mixed effects models repeated measures analysis of variance were used to determine treatment group differences over time on safety and efficacy measures. RESULTS: Ethics committee approval to delay informed consent procedure until recovery from the acute episode allowed the inclusion of 83 patients highly representative of those treated in the public sector. Contrary to our hypotheses, safety profile of both medications was similar. A signal for higher rate (P=.032) and earlier occurrence (P=.043) of mania remission was observed in the olanzapine group which did not survive correction for multiple comparisons. CONCLUSIONS: Olanzapine and chlorpromazine have a similar safety profile in a uniquely representative cohort of patients with first episode psychotic mania. The possibility for a greater impact of olanzapine on manic symptoms leading to earlier remission of the episode needs exploration in a large sample.

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.

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity.

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.

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.