Multimodal Magnetic Resonance Imaging Depicts Widespread and Subregion Specific Anomalies in the Thalamus of Early-Psychosis and Chronic Schizophrenia Patients.

BACKGROUND AND HYPOTHESIS: Although the thalamus has a central role in schizophrenia pathophysiology, contributing to sensory, cognitive, and sleep alterations, the nature and dynamics of the alterations occurring within this structure remain largely elusive. Using a multimodal magnetic resonance imaging (MRI) approach, we examined whether anomalies: (1) differ across thalamic subregions/nuclei, (2) are already present in the early phase of psychosis (EP), and (3) worsen in chronic schizophrenia (SCHZ). STUDY DESIGN: T1-weighted and diffusion-weighted images were analyzed to estimate gray matter concentration (GMC) and microstructural parameters obtained from the spherical mean technique (intra-neurite volume fraction [VFINTRA)], intra-neurite diffusivity [DIFFINTRA], extra-neurite mean diffusivity [MDEXTRA], extra-neurite transversal diffusivity [TDEXTRA]) within 7 thalamic subregions. RESULTS: Compared to age-matched controls, the thalamus of EP patients displays previously unreported widespread microstructural alterations (VFINTRA decrease, TDEXTRA increase) that are associated with similar alterations in the whole brain white matter, suggesting altered integrity of white matter fiber tracts in the thalamus. In both patient groups, we also observed more localized and heterogenous changes (either GMC decrease, MDEXTRA increase, or DIFFINTRA decrease) in mediodorsal, posterior, and ventral anterior parts of the thalamus in both patient groups, suggesting that the nature of the alterations varies across subregions. GMC and DIFFINTRA in the whole thalamus correlate with global functioning, while DIFFINTRA in the subregion encompassing the medial pulvinar is significantly associated with negative symptoms in SCHZ. CONCLUSION: Our data reveals both widespread and more localized thalamic anomalies that are already present in the early phase of psychosis.

Timely N-Acetyl-Cysteine and Environmental Enrichment Rescue Oxidative Stress-Induced Parvalbumin Interneuron Impairments via MMP9/RAGE Pathway: A Translational Approach for Early Intervention in Psychosis.

Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.

Mechanisms of change in brief treatments for borderline personality disorder: a protocol of a randomized controlled trial.

BACKGROUND: Borderline personality disorder (BPD) is one of the most frequent, most debilitating and lethal mental conditions and is associated with a serious burden of disease. Treatment for patients with BPD involves structured psychotherapy, and may involve brief psychiatric treatment as first-line intervention. No controlled study has assessed the effectiveness of such brief intervention. Whereas most psychotherapy studies in patients with BPD focus on the effectiveness of the intervention, we still lack an understanding of how and why these effects are produced from a patient process perspective. It is therefore of utmost importance to study the treatment-underlying mechanisms of change. The present study plans to apply novel measurement methods for assessing change in two central psychobiological processes in BPD: emotion and socio-cognitive processing. The study uses theory-driven and ecologically valid experimental tasks, which take the patient's individual experience as the anchor, by integrating methodology from psychotherapy process and neurofunctional imagery research. METHODS: The aim of this two-arm, randomized controlled study is to test the effects (i.e., symptom reduction) and the underlying mechanisms of change associated with a brief psychiatric treatment (10 sessions over 4 months), compared with treatment as usual. Participants (N = 80 patients with BPD) undergo assessments at four points (intake, 2 months, discharge, and 12-month follow up). In addition to symptom measures, individuals undergo a 2-step assessment for the potential mechanisms of change (i.e., emotion and socio-cognitive processing): (1) behavioral and (2) (for a sub-sample) neurofunctional. We hypothesize that change in the mechanisms explains the treatment effects. DISCUSSION: This study uses an easy-to-implement treatment of BPD, and a sophisticated assessment procedure to demonstrate the critical role of psychobiological change in emotion and socio-cognitive processing in brief treatments. It will help increase the effectiveness of brief treatment for BPD and help diminish the societal burden of disease related to BPD, in these early stages of treatment. TRIAL REGISTRATION {2}: ClinicalTrials.gov: NCT03717818. Registered on 24 October 2018). Protocol version {3} number 2 from 9 February 2018.

N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot Study.

BACKGROUND: There is increasing evidence that redox dysregulation, which can lead to oxidative stress and eventually to impairment of oligodendrocytes and parvalbumin interneurons, may underlie brain connectivity alterations in schizophrenia. Accordingly, we previously reported that levels of brain antioxidant glutathione in the medial prefrontal cortex were positively correlated with increased functional connectivity along the cingulum bundle in healthy controls but not in early psychosis patients. In a recent randomized controlled trial, we observed that 6-month supplementation with a glutathione precursor, N-acetyl-cysteine, increased brain glutathione levels and improved symptomatic expression and processing speed. METHODS: We investigated the effect of N-acetyl-cysteine supplementation on the functional connectivity between regions of the cingulate cortex, which have been linked to positive symptoms and processing speed decline. In this pilot study, we compared structural connectivity and resting-state functional connectivity between early psychosis patients treated with 6-month N-acetyl-cysteine (n = 9) or placebo (n = 11) supplementation with sex- and age-matched healthy control subjects (n = 74). RESULTS: We observed that 6-month N-acetyl-cysteine supplementation increases functional connectivity along the cingulum and more precisely between the caudal anterior part and the isthmus of the cingulate cortex. These functional changes can be partially explained by an increase of centrality of these regions in the functional brain network. CONCLUSIONS: N-acetyl-cysteine supplementation has a positive effect on functional connectivity within the cingulate cortex in early psychosis patients. To our knowledge, this is the first study suggesting that increased brain glutathione levels via N-acetyl-cysteine supplementation may improve brain functional connectivity.

Cannabis, a Significant Risk Factor for Violent Behavior in the Early Phase Psychosis. Two Patterns of Interaction of Factors Increase the Risk of Violent Behavior: Cannabis Use Disorder and Impulsivity; Cannabis Use Disorder, Lack of Insight and Treatment Adherence.

Background: Previous literature suggests that prevalence of cannabis use in the early phase of psychosis is high, and that early psychosis patients are at high-risk for violent behavior. However, the link between cannabis use and violent behavior in early psychosis patients is unclear. We carried out a study on a sample of early psychosis patients, in order to explore the impact of cannabis use on the risk of violent behavior (VB), while taking into account (1) potential confounding factors and, (2) interactions with other dynamic risk factors of VB. Method: In a sample of 265 early psychosis patients, treated at the Treatment and Early Intervention in Psychosis Program (TIPP) in Lausanne, we used logistic regression models to explore the link between various dynamic risk factors of VB [positive symptoms, substance use disorder (drugs including cannabis, alcohol and others drugs), insight, impulsivity, affective instability, and treatment adherence], and VB occurring during treatment. In order to understand hierarchical effects attributable to the combinations of risk factors on VB we conducted a Classification and Regression Tree (CART). Results: Our results show that cannabis use disorder is a risk factor for VB. The associations among risk factors suggest the presence of two patient profiles with an increased rate of VB: the first is composed of patients with cannabis use disorder and impulsivity, and the second of patients combining cannabis use disorder, absence of insight and non-adherence to treatment. The results also show the moderating role of insight and adherence to treatment on the rate of VB in patients with cannabis use disorder. Conclusion: This study suggests that cannabis use disorder is a significant risk factor for VB amongst early psychosis patients, particularly when combined with either impulsivity, lack of insight and non-adherence to treatment. These results suggest that preventive strategies could be developed on the basis of such patient profiles.

N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Treatment in early psychosis with N-acetyl-cysteine for 6months improves low-level auditory processing: Pilot study.

Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.

Predictors of favourable outcome in young people with a first episode psychosis without antipsychotic medication.

INTRODUCTION: Data from the literature suggests that some first episode psychosis (FEP) patients may recover without antipsychotic medication. There is however no reliable way to identify them. In a previous paper we found, in a cohort of 584 FEP patients, that those consistently refusing medication had poorer pre-morbid functioning, less insight, higher rate of substance use and poorer outcome. However, some medication refusers, had a favourable outcome. The study aim was to identify predictors of good short term outcome despite non-exposure to medication. METHODS: The Early Psychosis Prevention and Intervention Centre (EPPIC) admitted 786 FEP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. Data on medication adherence was available in 584 patients. Among the 17.9% of patients who consistently refused medication over the entire treatment phase we compared patients who had a favourable symptomatic and functional outcome with those who did not. RESULTS: Among patients who consistently refused medication, 41% achieved symptomatic remission and 33% reached functional recovery. Predictors of symptomatic remission were a better premorbid functioning level, higher education and employment status at baseline. Predictors of functional recovery were a shorter duration of the prodrome phase, less severe psychopathology at baseline and lower cannabis use. CONCLUSIONS: Despite limitations mainly linked to the fact that non-exposure to antipsychotic medication was based on patient's treatment refusal, this study identified some characteristics which may contribute to the identification of a sub-group of FEP patients who may have good short term outcome without antipsychotic treatment.

Duration of untreated psychosis: a proposition regarding treatment definition.

AIM: Duration of untreated psychosis (DUP) refers to the time elapsing between psychosis onset and treatment initiation. Despite a certain degree of consensus regarding the definition of psychosis onset, the definition of treatment commencement varies greatly between studies and DUP may be underestimated due to lack of agreement. In the present study, three sets of criteria to define the end of the untreated period were applied in a first-episode psychosis cohort to assess the impact of the choice of definition on DUP estimation. METHODS: The DUP of 117 patients admitted in the Treatment and Early Intervention in Psychosis Program Psychosis in Lausanne was measured using the following sets of criteria to define treatment onset: (i) initiation of antipsychotic medication; (ii) entry into a specialized programme; and (iii) entry into a specialized programme and adequate medication with a good compliance. RESULTS: DUP varied greatly according to definitions, the most restrictive criteria leading to the longest DUP (median DUP1=2.2 months, DUP2=7.4 months and DUP3=13.6 months). A percentage of 19.7 of the patients who did not meet these restrictive criteria had poorer premorbid functioning and were more likely to use cannabis. Longer DUP3 was associated with poorer premorbid functioning and with younger age at onset of psychosis. CONCLUSION: These results underline the need for a unique and standardized definition of the end of DUP. We suggest that the most restrictive definition of treatment should be used when using the DUP concept in future research.

Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.