Frontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuum.

Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signalling or impaired top-down cortical regulation. We used spectral dynamic causal modelling of resting-state functional MRI to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naïve first-episode psychosis patients and 23 controls and an independent sample of 36 patients with established schizophrenia and 100 controls. We also investigated the association between FST effective connectivity and striatal 18F-DOPA uptake in an independent healthy cohort of 33 individuals who underwent concurrent functional MRI and PET. Using a posterior probability threshold of 0.95, we found that midbrain and thalamic connectivity were implicated as dysfunctional across both patient groups. Dysconnectivity in first-episode psychosis patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in established schizophrenia patients. In the healthy 18F-DOPA cohort, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits to those associated with psychotic symptom severity in patients. Overall, our findings indicate that subcortical dysconnectivity is evident in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signalling are closely related to striatal dopamine synthesis capacity, which is a robust marker for psychosis.

Staged treatment and acceptability guidelines in early psychosis study (STAGES): A randomized placebo controlled trial of intensive psychosocial treatment plus or minus antipsychotic medication for first-episode psychosis with low-risk of self-harm or aggression. Study protocol and baseline characteristics of participants.

AIM: It is now necessary to investigate whether recovery in psychosis is possible without the use of antipsychotic medication. This study will determine (1) whether a first-episode psychosis (FEP) group receiving intensive psychosocial interventions alone can achieve symptomatic remission and functional recovery; (2) whether prolonging the duration of untreated psychosis (DUP) in a sub-group according to randomisation will be associated with a poorer outcome and thereby establish whether the relationship between DUP and outcome is causative; and (3) whether neurobiological changes observed in FEP are associated with the psychotic disorder or antipsychotic medication. Baseline characteristics of participants will be presented. METHODS: This study is a triple-blind randomized placebo-controlled non-inferiority trial. The primary outcome is the level of functioning measured by the Social and Occupational Functioning Assessment Scale at 6 months. This study is being conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne and includes young people aged 15 to 24 years with a DSM-IV psychotic disorder, a DUP less than 6 months and not high risk for suicide or harm to others. Strict discontinuation criteria are being applied. Participants are also undergoing three 3-Tesla-MRI scans. RESULTS: Ninety participants have been recruited and baseline characteristics are presented. CONCLUSIONS: Staged treatment and acceptability guidelines in early psychosis will determine whether antipsychotic medications are indicated in all young people with a FEP and whether antipsychotic medication can be safely delayed. Furthermore, the relative contribution of psychotic illness and antipsychotic medication in terms of structural brain changes will also be elucidated. The findings will inform clinical practice guidelines.

Internet-based cognitive behavioural therapy for young people with suicide-related behaviour (Reframe-IT): a randomised controlled trial.

BACKGROUND: Suicide-related behaviours are common in young people and associated with a range of negative outcomes. There are few evidence-based interventions; however, cognitive behavioural therapy (CBT) shows promise. Internet delivery of CBT is popular, with potential to increase reach and accessibility. OBJECTIVE: To test the effectiveness of an internet-based CBT program (Reframe-IT) in reducing suicide-related behaviours, depression, anxiety, hopelessness and improving problem solving and cognitive and behavioural skills in school students with suicide-related behaviours. METHODS: A parallel randomised controlled trial testing the effectiveness of Reframe-IT plus treatment as usual (TAU) compared with TAU alone in reducing suicidal ideation, suicide attempts, depression, hopelessness, symptoms of anxiety, negative problem orientation and cognitive and behavioural skill acquisition was undertaken. We recruited students experiencing suicidal ideation from 18 schools in Melbourne, Australia, between August 2013 and December 2016. The intervention comprised eight modules of CBT delivered online over 10 weeks with assessments conducted at baseline, 10 weeks and 22 weeks. FINDINGS: Only 50 of the planned 169 participants were recruited. There were larger improvements in the Reframe-IT group compared with the TAU group for the primary outcome of suicidal ideation (intervention -61.6, SD 41.6; control -47.1, SD 42.3, from baseline to 22-week follow-up intervention); however, differences were non-significant (p=0.593). There were no increases in distress in the majority of participants (91.1%) after completion of each module. Changes in depression and hopelessness partly mediated the effect of acquisition of CBT skills on suicidal ideation. CONCLUSIONS: The trial was underpowered due to difficulties recruiting participants as a result of the complex recruitment procedures that were used to ensure safety of participants. Although there were no significant differences between groups, young people were safely and generally well engaged in Reframe-IT and experienced decreases in suicidal ideation and other symptoms as well as improvements in CBT skills. The study is the first online intervention trial internationally to include young people demonstrating all levels of suicide risk. CLINICAL IMPLICATIONS: Integration of internet-delivered interventions for young people with suicide-related behaviour may result in reductions in these behaviours. Further research is needed, but researchers should feel more confident about being able to safely undertake research with young people who experience these behaviours. TRIAL REGISTRATION NUMBER: ACTRN12613000864729.