Multimodal prevention of first psychotic episode through N‐acetyl‐l‐cysteine and integrated preventive psychological intervention in individuals clinically at high risk for psychosis: Protocol of a randomized, placebo‐controlled, parallel‐group trial

Abstract

Aim Meta‐analyses indicate positive effects of both antipsychotic and cognitive‐behavioural interventions in subjects clinically at high risk (CHR) for psychosis in terms of a delay or prevention of psychotic disorders. However, these effects have been limited regarding social functioning and the relative efficacy of both types of interventions remains unclear. Furthermore, neuroprotective substances seem to be a promising alternative agent in psychosis‐prevention as they are associated with few and weak side‐effects. Methods In this multi‐centre randomized controlled trial (RCT), we investigate the effects of two interventions on transition to psychosis and social functioning: (a) an integrated preventive psychological intervention (IPPI) including stress‐/symptom‐management and social‐cognitive remediation; (b) N‐acetyl‐l‐cysteine (NAC) as a pharmacological intervention with glutamatergic, neuroprotective and anti‐inflammatory capabilities. Results This is a double‐blind, placebo‐controlled RCT with regard to NAC and a single‐blind RCT with regard to IPPI using a 2 × 2‐factorial design to investigate the individual and combined preventive effects of both interventions. To this aim, a total of 200 CHR subjects will be randomized stratified by site to one of four conditions: (a) IPPI and NAC; (b) IPPI and Placebo; (c) NAC and psychological stress management; (d) Placebo and psychological stress management. Interventions are delivered over 26 weeks with a follow‐up period of 12 months. Conclusion This paper reports on the rationale and protocol of an indicated prevention trial to detect the most effective and tolerable interventions with regard to transition to psychosis as well as improvements in social functioning, and to evaluate the synergistic effects of these interventions.

General psychopathology links burden of recent life events and psychotic symptoms in a network approach

“…Overall, our results suggest that life events may be one driving force of unspecific, general psychopathology described as characteristic of early phases of mental disorders, corroborating previous considerations 11,14,15,19,31 . Early transdiagnostic pathways from life events to general psychopathology also align with the idea of multifinality in the emergence of psychopathology following recent stressful life events, similar to early trauma 12,22,39,40 .…”

“…One viable strategy may involve reducing certain types of burdensome life events, such as conflicts in the family or partnership, through appropriate interventions, e.g. assertive community treatment or family-focused therapy, to reduce stress in the social environment of patients 20,31,48,49 .…”

“…In the current study, we use network analysis to investigate pathways between the cumulative burden of a comprehensive set of recent life events and individual positive, negative and general symptoms in the early psychosis spectrum. Based on previous literature 12,21,31 , we hypothesize that burden of recent life events will not be connected to positive and negative symptoms directly, but indirectly via general symptoms. In a control analysis, we examine whether childhood trauma can explain links between burden of recent life events and symptoms.…”

Exploring the Interplay Between Adversity, Neurocognition, Social Cognition, and Functional Outcome in People With Psychosis: A Narrative Review

“…With regards to biology, addressing studies in the future testing biological mediating mechanisms between adversity and neurocognitive and social cognitive domains will allow exploration of new potential pharmacological targets that could be used as add-on to enhance interventions addressing cognitive deficits (91). In this line, a plausible pathway is related to oxidative stress, which could potentially be corrected with antioxidants, such as N-Acetyl Cysteine (NAC), making it a promising add-on to therapies targeting SC and NC (92). This is of particular interest given evidence showing that traumatized individuals with a better redox status (lower oxidation) showed better cognitive domains as compared with traumatized subjects with higher oxidation and to non-traumatized subjects in terms of cognitive functioning (49).…”

Cognitive behavioural social skills training: Methods of a randomized controlled trial for youth at risk of psychosis

“…Interestingly, an excellent, more detailed protocol was very recently published (Schmidt et al, 2019) that aims to investigate the effect of an integrated preventive psychological intervention or a psychological stress management intervention on both transition to psychosis and social functioning. In addition, N‐acetyl‐L‐cysteine (NAC) or placebo is combined with each psychological intervention using a 2 x 2 design to investigate the combined and individual effects of the interventions.…”