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Background The prevalence of antibodies to Toxoplasma gondii, a ubiquitous parasitic protozoan causing the infectious disease toxoplasmosis, is increased in patients with psychotic disorders compared to the general population. We have previously shown that antibody titers for T.gondii correlate with the severity of positive symptoms in young people at ultra-high risk (UHR) for psychosis, suggesting that infection with T. gondii may be relevant to the manifestation of psychosis. However, it is unclear if T. gondii antibodies represent a risk factor for psychosis onset or non-psychotic outcome in UHR individuals. The aim of the present study was to examine whether seropositivity for T.gondii is associated with transition to psychosis and other outcomes in young people at UHR for psychosis. Methods The study sample consisted of 96 individuals at UHR for psychosis who were referred to the Personal Assistance and Crisis Evaluation (PACE) clinic in Melbourne, Australia, between 2001 and 2004, consented to optional blood tests for infectious agents and were followed up for up to 10 years after baseline (median (interquartile range) duration of follow-up: 7.15 (3.14 – 7.72) years). Serum IgG antibodies to six viral and parasitic pathogens (Toxoplasma gondii, Herpes Simplex Virus Type 1 and 2, Cytomegalovirus, Epstein Barr Virus, Varicella-Zoster Virus) were measured at baseline. Outcome measures included transition to psychosis, general psychiatric symptomatology and positive psychotic symptoms (BPRS), negative symptoms (SANS), depressive symptoms (HAM-D), anxiety symptoms (HAM-A) and functioning (SOFAS and GAF). Cox proportional hazards regression and linear regression models were used to examine the associations of seropositivity and antibody titers at baseline and transition to psychosis and other outcomes at follow-up. Results A total of 17 individuals (17.7%) were seropositive for Toxoplasma gondii at baseline. The rate of transition to psychosis was higher among seropositive (35.7%) compared to seronegative participants (14.6%), although this was not statistically significant (p=0.101). Antibody titers (IgG) for Toxoplasma gondii were significantly higher at baseline in participants who later transitioned to psychosis (1.34 ± 1.36 vs. 0.79 ± 0.73, p=0.027). Seropositivity for T.gondii IgG at baseline significantly predicted transition to psychosis within the follow-up duration (hazard ratio [HR]=3.61, 95%CI 1.08 – 12.00, p=0.036). Toxoplasma IgG at baseline were significantly associated with higher BPRS scores at follow-up in participants who were seropositive at baseline (Beta=6.38, 95%CI 0.43 – 12.34, p=0.038). No significant associations were found between antibodies to other pathogens and outcome, or between antibodies to Toxoplasma gondii and any other outcomes. Discussion Our findings suggest that the presence of IgG class antibodies for Toxoplasma gondii is associated with a higher risk for psychosis transition in individuals at UHR for psychosis, but not with risk for other long-term outcomes. These observations provide support for the hypothesis that infection with Toxoplasma gondii may be an environmental risk factor for psychosis and suggest that IgG antibodies for Toxoplasma gondii in individuals at UHR for psychosis have prognostic relevance.

Background Neuroimaging studies have found dysconnectivity of frontostriatal circuits across a broad spectrum of psychotic symptoms. However, it is unknown whether dysconnectivity within frontostriatal circuits originates from disrupted bottom-up or top-down control signaling within these systems. Here, we used dynamic causal modelling (DCM) to examine the effective connectivity of frontostriatal systems in first-episode psychosis (FEP). Methods A total of 55 FEP patients (26 males; mean [SD] age = 19.24 [2.89]) and 24 healthy controls (15 males; mean [SD] age = 21.83 [1.93]) underwent a resting-state functional magnetic resonance imaging protocol. Biologically plausible connections between eight left hemisphere regions encompassing the dorsal and ventral frontostriatal systems were modelled using spectral DCM. The regions comprise dorsolateral prefrontal cortex, ventromedial prefrontal cortex, anterior hippocampus, amygdala, dorsal caudate, nucleus accumbens, thalamus, and the midbrain. Effective connectivity between groups were assessed using a parametric Bayesian model. Associations between effective connectivity parameters and positive symptoms, measured by the Brief Psychiatric Rating Scale positive subscale, was assessed in the patient group in a separate Bayesian general linear model. Results DCM shows evidence for differences in effective connectivity between patients and healthy controls, namely in the bottom-down connections distributed in the frontostriatal system encompassing the hippocampus, amygdala, striatum, and midbrain. Compared to healthy controls, patients also demonstrated increased disinhibition of the midbrain. In patients, positive symptoms are associated with increased top-down connections to the midbrain. Outgoing connection from the midbrain to the nucleus accumbens is also increased in association with positive symptoms. Discussion Aberrant top-down connectivity in the frontostriatal system in patients is consistent with top-down dysregulation of dopamine function in FEP, as dopaminergic activity in the midbrain is proposed to be under the control of higher brain areas. In patients, increased self-inhibition of the midbrain, as well as symptom associations in both ingoing and outgoing connections of this region, are congruous with hyperactivity of the midbrain as proposed by the dopamine dysregulation hypothesis. Here, we demonstrate that mathematical models of brain imaging signals can be used to identify the key disruptions driving brain circuit dysfunction, identifying new targets for treatment.

Background While antipsychotic medication (AP) is a very effective treatment for positive psychotic symptoms in first-episode psychosis (FEP), it is also associated with risks. These include adverse neurological and metabolic effects and measurable changes in brain structure. APs may even be associated with poorer functional recovery. Due to advances in the detection of, and psychosocial treatments for FEP, it is now ethically feasible to study the relative risks and benefits of offering AP as a first line treatment, and conversely, of withholding it, on a background of comprehensive evidence-based psychosocial care. This non-inferiority design randomised double blind placebo controlled study examines whether a (low-risk) subgroup of people with FEP can recover without AP, and considers the effects on functioning, physical health, cognition, and brain structure of AP versus withholding AP. Methods Young people with FEP were screened for study eligibility and invited to participate if they met stringent inclusion criteria indicating low-risk of harm to self or others, and adequate social support. Hence a large proportion of patients were assumed a priori to be too high risk to withhold antipsychotic medication. Participants were randomly assigned to receive either low dose AP (MIPT group) or placebo (PIPT group) for six months, and all participants received intensive psychosocial treatment. Randomisation was stratified with three levels of DUP and gender creating six cells. Assessments of psychopathology, neurocognitive performance, and neuroimaging occurred regularly until two years after study entry. Results 90 young people were randomised and 81 commenced trial medication. They were 44% male and mean age 18.5 years (SD = 2.7). Thirty-four percent of participants completed the six month medication phase and there were more completers in the placebo group than the medication group. On the primary outcome measure of SOFAS there was significant evidence that the placebo group was not inferior to the medication group (SOFAS: MIPT mean = 61.5, SD = 13.4; PIPT mean = 61.7, SD = 16.8). The two groups were found to be very similar on all psychopathology assessments and measures of functioning at both baseline and following treatment, suggesting that the outcomes of the two treatment regimes were not different with respect to symptoms and functioning. Discussion The results of this study demonstrate that it is feasible and acceptable to conduct AP-free research in carefully selected FEP to examine the risk-benefit ratio of current treatments under carefully controlled conditions that prioritise patient outcomes and safety. Although only one-third of the participants completed the six month trial intervention period, more of those on placebo completed the trial phase and they had higher mean, minimum and maximum time in the experimental intervention phase than those on medication. In addition, there were no differences between the groups on measures of psychopathology and functioning, suggesting that the intensive psychosocial intervention provided to all participants is complementary and may be more important than antipsychotic medication in the early phases of psychotic illness for a subgroup of young people. However this subgroup is very small as a % of total FEP patients treated during the study period. Further analysis of physical health and neuroimaging data and completion of the 24 month follow-up assessments will allow detailed examination of the risk-benefit ratio regarding antipsychotic medication in FEP.

There is growing interest in the prodromal stage of psychotic disorders, with many services now providing care for these "ultra high risk" (UHR) individuals. However, a reduction in the rate of transition to psychosis has been suspected over the last few years. This has implications for the use of interventions in this population and for the validity of research findings. This study examined the transition rate in one UHR service, the Personal Assessment and Crisis Evaluation Clinic, over the years 1995-2000 and investigated possible causes for the transition rate reduction. There was evidence for a declining transition rate, with each successive year showing a rate 0.80 times that of the preceding year. Functioning and symptom level were not responsible for the change. The decreased transition rate was partly explained by a reduction in the duration of symptoms of patients prior to receiving help. That is, UHR individuals are being detected and provided with care earlier than in the past. Thus, the decline in transition rate may be due to treatment being more effective at this very early stage of illness or it may be due to finding more false positives who were never at risk of psychosis, ie, a "dilution" effect. Given that it is not possible to distinguish between these alternatives at least phenotypically at present, perhaps it is time to rethink the role and practice of UHR clinics. Patients presenting to them need help. It may be that we need to aim to prevent a range of target syndromes.

Cognitive deficits are a core feature of established psychotic illnesses. However, the association between cognition and emerging psychosis is less understood. While there is some evidence that cognitive deficits are present prior to the onset of psychosis, findings are not consistent. In this article we provide an overview of the more general cognitive findings available from genetic high-risk studies, retrospective studies, and birth cohort studies. We then focus the review on neuropsychological performance in clinically "at-risk" groups. Overall, general cognitive ability as assessed by established batteries appears to remain relatively intact in these ultra-high risk cohorts and is a poor predictor close to illness onset relative to other vulnerability factors. Further decline may occur with illness progression, more consistent with state relative to trait factors. In addition, most established cognitive tasks involve several relatively discrete cognitive subprocesses, where findings from general batteries of subtests may mask specific deficits. In this context, our review suggests that relatively specific olfactory identification and spatial working memory deficits exist prior to illness onset and may be more potent trait markers for psychosis than cognitively dense tasks such as verbal memory. Suggestions for further research address the importance of standardization of inclusion criteria and the maintenance of basic neuropsychological assessment to allow better comparison of findings across centers. Further, in order to better understand the aetiopathology of cognitive dysfunction in psychosis, more experimental, hypothesis-driven measures of discrete cognitive processes are required. Delineation of the relationship between specific cognitive ability and symptoms from data-driven approaches may improve our understanding of the role of cognition during psychosis onset.