Susy Harrigan

Background Clinical outcomesfollowing a first episode of psychosis (FEP) are highly heterogeneous between patients. The identification of prognostic biomarkers would greatly facilitate personalized treatments. Psychosis patients often display brain-wide disruptions of inter-regional functional coupling (FC), with some being linked to symptom severity and remission. FC may thus hold prognostic potential for people experiencing psychosis. Methods Ninety antipsychotic-naïve FEP patients (51% female, 15-25 years) were randomized to receive either antipsychotic or placebo tablets for 6 months alongside psychosocial interventions. A subset of these patients also completed functional magnetic resonance imaging (55 with usable data at baseline and 37 at 3 months), which was used to evaluate whether baseline FC, or 3-month change in FC, could predict 6- and 12-month changes in symptoms and functioning, quantified using the Brief Psychiatric Rating Scale and the Social and Occupational Functioning Assessment Scale, respectively. We considered three different cross-validated prediction algorithms: (i) connectome-based predictive modelling; (ii) kernel ridge regression; and (iii) multilayer meta-matching. Results All algorithms showed poor performance in predicting patients’ 6- and 12-month changes in symptoms and functioning (all r_mean < 0.3), and no model achieved significance via permutation testing (all p > 0.05). Conclusions Our findings suggest that brain-wide measures of FC may not be suitable for predicting extended clinical outcomes over a 6- to 12-month period in FEP patients.

Objective: Cognitive impairment occurs in antipsychotic-naïve first-episode psychosis (FEP), but antipsychotics confound interpretation of the longitudinal course of cognition. The primary aim was to disentangle the effects of illness from antipsychotics on cognition over the first 6-months of FEP treatment. Methods: Randomised, triple-blind placebo-controlled trial (Staged Treatment and Acceptability Guidelines in Early Psychosis; STAGES), where cognition was a secondary outcome. Antipsychotic-naïve FEP patients were allocated to receive risperidone/paliperidone ( N =38) or placebo ( N =40) in addition to intensive psychosocial therapy for 6-months. A healthy control group ( N =42) was also recruited. A cognitive battery assessing attention, working memory, processing speed, verbal fluency, cognitive control and verbal paired-associate learning and memory was administered at baseline and 6-months. Twelve- and 24-month follow-up was also conducted. Results: Over the 6-month trial period, cognitive performance remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. The exception was for verbal paired-associate learning and memory, where a significant group-by-time interaction was observed. The placebo and healthy control groups improved, and the medication group deteriorated on immediate paired-associate recall ( p =0.039) and delayed cued recall ( p =0.005); effect sizes were medium-to-large. Findings were similar when only trial completers were included in the analysis. Conclusions: Risperidone/paliperidone may cause progression of memory impairment in the early months of FEP. Replication is needed in confirmatory trials. The findings support the need for careful consideration of the risks and benefits of various antipsychotics and the importance of accounting for their cognitive effects in longitudinal research. Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ACTRN12607000608460).

Most of the research examining children visiting a parent in prison indicates that visits have a positive impact on children's well‐being, their connection to the imprisoned parent and the parent themselves. However, the COVID‐19 pandemic brought about a significant change to prison visits worldwide, with limits or bans on face‐to‐face contact. Understanding the experiences and needs of children during this period remains limited. This paper presents the findings of a survey of 84 carers of 184 children across Australia, investigating children's experiences of contact with their imprisoned parent both before and during COVID‐19 restrictions. Although most carers reported maintaining contact during restrictions, a range of difficulties were noted: reduced availability; the effect of prison‐based issues, including lockdowns; and the suitability of video/telephone visits for young children. Some described the benefits of videoconferencing, including reduced travel time and cost, and not needing to take children into a prison environment. Despite this, respondents typically described the negative impact of restrictions, and lack of physical contact, on children's emotional well‐being. Our findings suggest that, for video visiting to be successful, it should be complementary to in‐person visits, tailored to the needs of children, with support offered to families.

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 signaling or impaired top-down cortical regulation. Here, we used spectral dynamic causal modelling (DCM) of resting-state functional magnetic resonance imaging (fMRI) to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naïve first-episode psychosis (FEP) patients and 23 controls and an independent sample of 36 patients with established schizophrenia (SCZ) patients and 100 controls. We found that midbrain and thalamic connectivity were implicated across both patient groups. Dysconnectivity in FEP 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 SCZ patients. In another independent sample of 33 healthy individuals who underwent concurrent fMRI and [ ¹⁸ F]DOPA positron emission tomography, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits as those associated with psychotic symptom severity in patients. Our findings thus indicate that subcortical dysconnectivity is salient in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signaling are closely related to striatal dopamine synthesis capacity, which is a robust risk marker for psychosis.

Changes in brain volume are a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and numerous longitudinal studies suggest that volume deficits progress with illness duration. However, a major unresolved question concerns whether these changes are driven by the underlying illness or represent iatrogenic effects of antipsychotic medication. Here, we report MRI findings from a triple-blind randomised placebo-controlled study where 62 antipsychotic-naïve patients with first episode psychosis (FEP) received either an atypical antipsychotic or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n=27) was also recruited. Structural MRI scans were obtained at baseline, 3-months and 12- months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum (p < 0.05 FWE-corrected), such that patients receiving antipsychotic medication showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. In patients, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. We additionally found preliminary evidence for illness- related volume reductions in prefrontal cortices at 12 months and medication-related volume reductions in cerebellum at both 3-months and 12-months. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotic medications may be primarily mediated through their effects on the basal ganglia.

First episode psychosis (FEP) has been consistently associated with changes within grey matter. No prospective study to date has been able to distinguish the differential effects of antipsychotic medication from the natural progression of psychosis on these changes. We conducted a triple-blind randomised placebo-control trial where 90 people aged between 15 to 24 with FEP received either an atypical antipsychotic or a placebo pill over a treatment period of 6 months, with a sub-group (N=62) undergoing neuroimaging. Both FEP groups received intensive psychosocial therapy. A healthy control group (n=27) were also recruited. T1-w structural MRI scans at 3-Tesla were taken at baseline, 3-months and 12-months. Longitudinal Voxel-Based-Morphometry was used to identify grey matter areas where the rate of change between the three groups was significantly different across timepoints. Using robust non-parametric methods, and after controlling for baseline age, sex, total intracranial volume and medication dose following treatment conclusion, a cluster within the medial and inferior temporal cortex showed a significant group x time interaction (k = 213, p < 0.05 FWE-corrected). Within the medication group, the volume of this area normalised to that of the healthy control group at the 3-month time point, then continued to increase to a size greater than that of the healthy control group at the 12-month follow-up. Volume remained reduced within the placebo group at the 3-month timepoint but trended towards normalisation at the 12-month timepoint. Additionally, the rate of change between baseline and three months within this cluster was significantly correlated (r = -.53, p < 0.01) with the primary trial outcome measure: The Social an Occupational Functional Assessment Scale. Antipsychotic medication normalises the initially reduced volume of the temporal cortex. However, a similar pattern of normalization may be seen over a longer period of time in those who received placebo. Additionally, greater change within the same area is associated with poorer functional outcome, suggesting that the processes and networks supported medial and inferior temporal cortex may play a primary role in maintaining social and occupational functioning.

Antipsychotic medication has been the mainstay of treatment for psychotic illnesses for over 60 years. This has been associated with improvements in positive psychotic symptoms and a reduction in relapse rates. However, there has been little improvement in functional outcomes for people with psychosis. At the same time there is increasing evidence that medications contribute to life shortening metabolic and cardiovascular illnesses. There is also uncertainty as to the role played by antipsychotic medication in brain volume changes.Aim: The primary aim of the study is, in a population of young people with first‐episode psychosis, to compare functional outcomes between an antipsychotic dose reduction strategy with evidence‐based intensive recovery treatment (EBIRT) group (DRS+) and an antipsychotic maintenance treatment with EBIRT group (AMTx+) at 24‐months follow‐up.Methods: Our single‐blind randomized controlled trial, within a specialist early psychosis treatment setting, will test the whether the DRS+ group leads to better vocational and social recovery than, the AMTx+ group over a 2‐year period in 180 remitted first‐episode psychosis patients. Additionally, we will examine the effect of DRS+ vs AMTx+ on physical health, brain volume and cognitive functioning. This study will also determine whether the group receiving DRS+ will be no worse off in terms of psychotic relapses over 2 years follow‐up.Results: This paper presents the protocol, rationale and hypotheses for this study which commenced recruitment in July 2017.Conclusion: This study will provide evidence as to whether an antipsychotic dose‐reduction recovery treatment leads to improved functioning and safer outcomes in first‐episode psychosis patients. In addition, it will be the first‐controlled experiment of the effect of exposure to antipsychotic maintenance treatment on brain volume changes in this population.