Luis Alameda

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.

Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

BACKGROUND Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the γ-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu. METHODS Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. RESULTS Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes. CONCLUSIONS GCLC high-risk genotypes are associated with low [GSHmPFC], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.

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

Abstract 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.

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.

Age at the time of exposure to trauma modulates the psychopathological profile in patients with early psychosis.

OBJECTIVE To examine the potential differential impact of childhood trauma, according to the age at the time of exposure, on the psychopathological profile of patients with early psychosis treated in a specialized 3-year program during the early phase of the disease. METHODS 196 subjects with early psychosis aged 18-35 years were followed up prospectively over 36 months of treatment between 2004 and 2010. Patients who had faced at least 1 experience of abuse (physical, sexual, or emotional) or neglect (physical or emotional) were classified according to age at the time of the first exposure (early trauma: before 12 years of age; late trauma: from age 12 through 16 years) and then compared with unexposed patients (nontrauma). The level of symptoms was assessed using the Positive and Negative Syndrome Scale, the Young Mania Rating Scale, and the Montgomery-Asberg Depression Rating Scale. RESULTS Exposure to 1 or more forms of trauma before 16 years of age was present in 31.63% of patients. Comparisons over the 3 years of treatment with the nontrauma patients revealed that (1) patients with early trauma showed consistently higher levels of positive (P = .006), depressive (P = .001), manic (P = .006), and negative (P = .029) symptoms and (2) patients with late trauma showed only more negative symptoms (P = .029). CONCLUSIONS These results suggest that the age at the time of exposure to trauma has a modulating effect on symptoms in patients with early psychosis. Various biological and psychological hypotheses can be proposed to explain this observation, and they need to be investigated in an experimental setting in order to develop therapeutic avenues.

Assertive outreach for "difficult to engage" patients: A useful tool for a subgroup of patients in specialized early psychosis intervention programs.

PURPOSE Most specialized Early Psychosis (EP) programs include assertive outreach (AO) principles, either for all patients or as an intensive case management (ICM) subprogram in selected situations. The objective of this study is to examine prevalence, characteristics and outcomes of patients who needed additional ICM in a specialized EP program. METHODS In a 3-year prospective naturalistic study of 229 consecutive EP patients treated at TIPP-Lausanne we compared characteristics of those who needed ICM and those who did not. RESULTS 60 (26.2%) TIPP patients needed ICM. At baseline, ICM-patients showed a poorer academic premorbid functioning (p=0.019); lower level of insight (p<0.001); had a previous history of alcohol (p=0.043) and cannabis (p=0.040) use. ICM-patients were less likely to be adherent to medication during the early phase of treatment but differences disappeared during follow-up. ICM-patients showed globally a poorer functional level and higher level of positive and negative symptoms during the follow-up. CONCLUSIONS About one quarter of EP patients needed a combination of ICM and assertive outreach. Despite the high treatment adherence in both groups, psychotic symptoms remained higher in ICM-patients. In a real live setting with limited resources, combination of ICM and AO in selected situations seems a valid solution.

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.

Insight et comportements violents dans une cohorte de patients souffrant de premiers épisodes de psychose

Objectives: An important proportion of patients with first episode psychosis behave in a violent, hetero-aggressive manner. This study aims to explore the association between insight and violent behavior (VB), and insight evolution in the follow-up period. Method: The study was carried out with a prospective cohort of 265 patients recruited from the early treatment and intervention for psychotic disorders program, and followed for a 3-year period. Insight assessing is based on a 3-item scale and the insight item in Positive and Negative Syndrome Scale (PANSS). VBs were evaluated by case managers, information from forensic services and through a record of VBs noted during hospitalization. Univariate and multivariate logistic regression analyses, t-tests and correlations were conducted. Results: The significant effect of insight as a factor associated with VBs that was found in univariate analyses disappears after controlling for the effect of positive symptoms, substance addiction diagnosis, impulsivity and treatment compliance. Conclusion: If patient insight in their illness develops positively during treatment, our results suggest that the risk of VBs occurring is not influenced by insight level. On the other hand, it is significantly linked to substance abuse and impulsivity, which might implicate focusing on these 2 dimensions in preventive strategies. Insight impact on VB should be further explored in more focused prospective analyses.Objectifs: Une proportion importante de patients présentant un premier épisode psychotique commettent des actes violents hétéro-agressifs. L’objectif de cette étude est d’explorer l’association entre insight et comportement violent (CV) et l’évolution de l’insight durant la période de suivi. Méthode: L’étude est conduite sur une cohorte prospective de 265 patients recrutés au sein du programme de traitement et d’intervention précoce dans les troubles psychotiques et suivis sur une période de 3 ans. L’évaluation de l’insight est basée sur une échelle d’insight en 3 points et l’item de l’insight à la Positive and Negative Syndrome Scale (PANSS). Les CV ont été évalués par les case-managers, par les informations provenant des services forensiques et par l’intermédiaire d’un relevé des CV en cours d’hospitalisation. Des analyses de régression logistique uni-variées et multi-variées, des tests-t et des corrélations ont été réalisés. Résultats: L’effet significatif de l’insight comme facteur associé aux CV trouvé dans les analyses uni-variées disparaît après avoir contrôlé l’effet des symptômes positifs, du diagnostic de dépendance aux substances, de l’impulsivité et de l’adhésion au traitement. Conclusion: Si la prise de conscience des patients à l’égard de leur maladie évolue positivement au cours du traitement, nos résultats suggèrent que le risque de survenue de CV n’est pas influencé par le degré d’insight. Il est par contre significativement lié à l’abus de substances et à l’impulsivité, impliquant de cibler ces deux dimensions dans les stratégies préventives. L’impact de l’insight sur le CV doit être l’objet d’analyses prospectives plus précises.

Treatment in early psychosis with N-acetyl-cysteine for 6 months 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.

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.