An open label pilot trial of low-dose lithium for young people at ultra-high risk for psychosis.

AIM: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side-effect profile) of lithium in a sample of young people identified at ultra-high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). METHODS: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side-effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. RESULTS: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side-effect assessment indicated that lithium was well-tolerated. 64% (n = 16) of participants in the lithium group were lithium-adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. CONCLUSIONS: With a side-effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort.

Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis.

Importance: Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. Objective: To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads. Design, Settings, and Participants: This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023. Main Outcomes and Measures: Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance. Results: Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression. Conclusion and Relevance: These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.

Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).

Gradients of striatal function in antipsychotic-free first-episode psychosis and schizotypy.

Both psychotic illness and subclinical psychosis-like experiences (PLEs) have been associated with cortico-striatal dysfunction. This work has largely relied on a discrete parcellation of the striatum into distinct functional areas, but recent evidence suggests that the striatum comprises multiple overlapping and smoothly varying gradients (i.e., modes) of functional organization. Here, we investigated two of these functional connectivity modes, previously associated with variations in the topographic patterning of cortico-striatal connectivity (first-order gradient), and dopaminergic innervation of the striatum (second-order gradient), and assessed continuities in striatal function from subclinical to clinical domains. We applied connectopic mapping to resting-state fMRI data to obtain the first-order and second-order striatal connectivity modes in two distinct samples: (1) 56 antipsychotic-free patients (26 females) with first-episode psychosis (FEP) and 27 healthy controls (17 females); and (2) a community-based cohort of 377 healthy individuals (213 females) comprehensively assessed for subclinical PLEs and schizotypy. The first-order "cortico-striatal" and second-order "dopaminergic" connectivity gradients were significantly different in FEP patients compared to controls bilaterally. In the independent sample of healthy individuals, variations in the left first-order "cortico-striatal" connectivity gradient were associated with inter-individual differences in a factor capturing general schizotypy and PLE severity. The presumed cortico-striatal connectivity gradient was implicated in both subclinical and clinical cohorts, suggesting that variations in its organization may represent a neurobiological trait marker across the psychosis continuum. Disruption of the presumed dopaminergic gradient was only noticeable in patients, suggesting that neurotransmitter dysfunction may be more apparent to clinical illness.

Isolating the impact of antipsychotic medication on metabolic health: Secondary analysis of a randomized controlled trial of antipsychotic medication versus placebo in antipsychotic medication naïve first-episode psychosis (the STAGES study).

BACKGROUND: Cardiovascular and metabolic diseases are the leading contributors to the early mortality associated with psychotic disorders. To date, it has not been possible to disentangle the effect of medication and non-medication factors on the physical health of people with a first episode of psychosis (FEP). This study aimed to isolate the effects of antipsychotic medication on anthropometric measurements, fasting glucose and lipids. METHODS: This study utilized data from a triple-blind randomized placebo-controlled trial comparing two groups of antipsychotic-naïve young people with a FEP who were randomized to receive a second-generation antipsychotic medication (FEP-medication group) or placebo (FEP-placebo group) for 6 months. Twenty-seven control participants were also recruited. RESULTS: Eighty-one participants commenced the trial; 69.1% completed at least 3 months of the intervention and 33.3% completed the full 6 months. The FEP-placebo group gained a mean of 2.4 kg (±4.9) compared to 1.1 kg (±4.9) in the control participants (t = 0.76, p = .45). After controlling for multiple analyses, there was no difference in blood pressure, waist circumference or heart rate between the FEP-placebo group and controls. After 6 months, the FEP medication group had gained 4.1 kg (±4.5), higher than those receiving placebo but not statistically significant (t = 0.8, p = .44). There were no differences in fasting glucose or lipids between the FEP groups after 3 months. CONCLUSIONS: While limited by small numbers and high attrition, these findings indicate that some of the metabolic complications observed in psychotic disorders could be attributable to factors other than medication. This emphasizes the need to deliver physical health interventions early in the course of FEP.

Decisional capacity in young people with first episode psychosis, major depressive disorder and no mental disorder.

We aimed to (1) examine decisional capacity for treatment in young people (aged 15 to 25 years) with first-episode psychosis (FEP), Major Depressive Disorder (MDD) and no mental disorder, and (2) determine which theoretically relevant factors are associated with, and predict decisional capacity. We assessed decisional capacity (using MacArthur Competence Assessment Tool-Treatment; MacCAT-T), cognitive abilities, insight and symptom severity in young people with no mental disorder (n = 38), MDD (n = 38) and FEP (n = 18) from inpatient and outpatient services. Most young people with MDD (84.2%) or no mental disorder (86.8%) had adequate decisional capacity to consent to treatment based on recommended cut-off scores, compared with fewer than half of the those with FEP (44.4%). Levels of capacity were not significantly different between young people with MDD and those with no mental disorder (p = .861). However, young people with FEP demonstrated significantly poorer decisional capacity than those with no mental disorder (p = .006) and MDD (p = .009). A hierarchical regression analysis suggested that differences may be better explained by variation in cognitive ability, especially thematic verbal recall. Greater symptom severity and poorer insight were associated with poorer decisional capacity for FEP (p = .008 and p < .001, respectively), but not MDD (p = .050 and p = .805, respectively). Cognitive performance (i.e., predicted IQ, processing speed, mental flexibility and thematic verbal memory) collectively explained 36.6% of the variance in decisional capacity (p < .001). Thematic verbal memory was the strongest predictor of decisional capacity (p < .001). Supports for memory should be implemented to facilitate involvement in treatment decisions during the early course of illness.

Functional Connectivity in Antipsychotic-Treated and Antipsychotic-Naive Patients With First-Episode Psychosis and Low Risk of Self-harm or Aggression: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Altered functional connectivity (FC) is a common finding in resting-state functional magnetic resonance imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotic treatment influences these disturbances, remains unknown. Objective: To investigate longitudinal FC changes in antipsychotic-naive and antipsychotic-treated patients with first-episode psychosis (FEP). Design, Setting, and Participants: This secondary analysis of a triple-blind, randomized clinical trial was conducted over a 5-year recruitment period between April 2008 and December 2016 with 59 antipsychotic-naive patients with FEP receiving either a second-generation antipsychotic or a placebo pill over a treatment period of 6 months. Participants were required to have low suicidality and aggression, to have a duration of untreated psychosis of less than 6 months, and to be living in stable accommodations with social support. Both FEP groups received intensive psychosocial therapy. A healthy control group was also recruited. Participants completed rs-fMRI scans at baseline, 3 months, and 12 months. Data were analyzed from May 2019 to August 2020. Interventions: Resting-state functional MRI was used to probe brain FC. Patients received either a second-generation antipsychotic or a matched placebo tablet. Both patient groups received a manualized psychosocial intervention. Main Outcomes and Measures: The primary outcomes of this analysis were to investigate (1) FC differences between patients and controls at baseline; (2) FC changes in medicated and unmedicated patients between baseline and 3 months; and (3) associations between longitudinal FC changes and clinical outcomes. An additional aim was to investigate long-term FC changes at 12 months after baseline. These outcomes were not preregistered. Results: Data were analyzed for 59 patients (antipsychotic medication plus psychosocial treatment: 28 [47.5%]; mean [SD] age, 19.5 [3.0] years; 15 men [53.6%]; placebo plus psychosocial treatment: 31 [52.5%]; mean [SD] age, 18.8 [2.7]; 16 men [51.6%]) and 27 control individuals (mean [SD] age, 21.9 [1.9] years). At baseline, patients showed widespread functional dysconnectivity compared with controls, with reductions predominantly affecting interactions between the default mode network, limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems; some of these changes correlated with improved clinical outcomes (canonical correlation analysis R = 0.901; familywise error-corrected P = .005). Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain. Conclusions and Relevance: In this secondary analysis of a clinical trial, antipsychotic-naive patients with FEP showed widespread functional dysconnectivity at baseline, followed by an early normalization of default mode network and cortical limbic dysfunction in patients receiving placebo and psychosocial intervention. Antipsychotic exposure was associated with FC changes concentrated on thalamocortical networks. Trial Registration: ACTRN12607000608460.

Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study.

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. In this study, 62 antipsychotic-naïve patients with first-episode psychosis (FEP) received either a second-generation antipsychotic (risperidone or paliperidone) 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. Across the entire patient sample, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. 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.

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.

Does co-occurring borderline personality disorder influence acute phase treatment for first-episode psychosis?

BACKGROUND: This aims of this study were: (1) to determine the prevalence of co-occurring borderline personality disorder (BPD) in a first-episode psychosis (FEP) sample; (2) to determine differences between patients with and without BPD on demographics, comorbidities and clinical risks and other variables; and (3) to examine whether BPD comorbidity influenced treatment received by patients for FEP during their first 3 months after service entry to a specialist early psychosis service. METHODS: A file audit was conducted for 100 consecutive admissions to an early psychosis service. Patients with a clinician-rated co-occurring diagnosis of BPD were compared with patients without clinician-rated BPD on a range of variables. RESULTS: Twenty-two percent of the FEP sample was diagnosed with co-occurring BPD by clinician ratings. The FEP group with co-occurring BPD was found to be younger, more likely to have other comorbidities, and were at higher risk of suicide and violent behaviour. Group differences were found in treatment received for FEP, whereby patients with co-occurring BPD had poorer access to standard treatment, including guideline concordant antipsychotic medication prescription. CONCLUSION: Young people with co-occurring clinician-rated BPD and FEP experienced greater difficulty accessing standard care for FEP and received relatively different treatment, including different pharmacotherapy, compared with those FEP patients without BPD. There is a need to develop new clinical guidelines and effective treatments for this specific subgroup with early psychosis and co-occurring BPD that take into account interpersonal and "premorbid" aspects of their presenting problems.

Predictors of favourable outcome in young people with a first episode psychosis without antipsychotic medication.

INTRODUCTION: Data from the literature suggests that some first episode psychosis (FEP) patients may recover without antipsychotic medication. There is however no reliable way to identify them. In a previous paper we found, in a cohort of 584 FEP patients, that those consistently refusing medication had poorer pre-morbid functioning, less insight, higher rate of substance use and poorer outcome. However, some medication refusers, had a favourable outcome. The study aim was to identify predictors of good short term outcome despite non-exposure to medication. METHODS: The Early Psychosis Prevention and Intervention Centre (EPPIC) admitted 786 FEP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. Data on medication adherence was available in 584 patients. Among the 17.9% of patients who consistently refused medication over the entire treatment phase we compared patients who had a favourable symptomatic and functional outcome with those who did not. RESULTS: Among patients who consistently refused medication, 41% achieved symptomatic remission and 33% reached functional recovery. Predictors of symptomatic remission were a better premorbid functioning level, higher education and employment status at baseline. Predictors of functional recovery were a shorter duration of the prodrome phase, less severe psychopathology at baseline and lower cannabis use. CONCLUSIONS: Despite limitations mainly linked to the fact that non-exposure to antipsychotic medication was based on patient's treatment refusal, this study identified some characteristics which may contribute to the identification of a sub-group of FEP patients who may have good short term outcome without antipsychotic treatment.

Long-term follow-up of a group at ultra high risk ("prodromal") for psychosis: the PACE 400 study.

IMPORTANCE: The ultra high-risk (UHR) criteria were introduced to prospectively identify patients at high risk of psychotic disorder. Although the short-term outcome of UHR patients has been well researched, the long-term outcome is not known. OBJECTIVE: To assess the rate and baseline predictors of transition to psychotic disorder in UHR patients up to 15 years after study entry. DESIGN: Follow-up study of a cohort of UHR patients recruited to participate in research studies between 1993 and 2006. SETTING: The Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service for UHR patients in Melbourne, Australia. PARTICIPANTS: Four hundred sixteen UHR patients previously seen at the PACE clinic. MAIN OUTCOMES AND MEASURES: Transition to psychotic disorder, as measured using the Comprehensive Assessment of At-Risk Mental States, Brief Psychiatric Rating Scale/Comprehensive Assessment of Symptoms and History, or state public mental health records. RESULTS: During the time to follow-up (2.4-14.9 years after presentation), 114 of the 416 participants were known to have developed a psychotic disorder. The highest risk for transition was within the first 2 years of entry into the service, but individuals continued to be at risk up to 10 years after initial referral. The overall rate of transition was estimated to be 34.9% over a 10-year period (95% CI, 28.7%-40.6%). Factors associated with transition included year of entry into the clinic, duration of symptoms before clinic entry, baseline functioning, negative symptoms, and disorders of thought content. CONCLUSIONS AND RELEVANCE: The UHR patients are at long-term risk for psychotic disorder, with the highest risk in the first 2 years. Services should aim to follow up patients for at least this period, with the possibility to return for care after this time. Individuals with a long duration of symptoms and poor functioning at the time of referral may need closer monitoring. Interventions to improve functioning and detect help-seeking UHR patients earlier also may be indicated.

Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: twelve-month outcome.

OBJECTIVE: The ultra-high risk clinical phenotype is associated with substantial distress and functional impairment and confers a greatly enhanced risk for transition to full-threshold psychosis. A range of interventions aimed at relieving current symptoms and functional impairment and reducing the risk of transition to psychosis has shown promising results, but the optimal type and sequence of intervention remain to be established. The aim of this study was to determine which intervention was most effective at preventing transition to psychosis: cognitive therapy plus low-dose risperidone, cognitive therapy plus placebo, or supportive therapy plus placebo. METHOD: A double-blind, randomized, placebo-controlled 12-month trial of low-dose risperidone, cognitive therapy, or supportive therapy was conducted in a cohort of 115 clients of the Personal Assessment and Crisis Evaluation Clinic, a specialized service for young people at ultra-high risk of psychosis located in Melbourne, Australia. Recruitment commenced in August 2000 and ended in May 2006. The primary outcome measure was transition to full-threshold psychosis, defined a priori as frank psychotic symptoms occurring at least daily for 1 week or more and assessed using the Comprehensive Assessment of At-Risk Mental States. Secondary outcome measures were psychiatric symptoms, psychosocial functioning, and quality of life. RESULTS: The estimated 12-month transition rates were as follows: cognitive therapy + risperidone, 10.7%; cognitive therapy + placebo, 9.6%; and supportive therapy + placebo, 21.8%. While there were no statistically significant differences between the 3 groups in transition rates (log-rank test P = .60), all 3 groups improved substantially during the trial, particularly in terms of negative symptoms and overall functioning. CONCLUSIONS: The lower than expected, essentially equivalent transition rates in all 3 groups fail to provide support for the first-line use of antipsychotic medications in patients at ultra-high risk of psychosis, and an initial approach with supportive therapy is likely to be effective and carries fewer risks.

Randomized controlled trial of interventions for young people at ultra high risk for psychosis: 6-month analysis.

OBJECTIVE: Cognitive therapy and/or low-dose antipsychotic administered during the prodromal phase of schizophrenia may prevent or delay the onset of full-blown illness. However, it is unclear which of these treatments are most effective, how long treatment should be given, and whether effects will be sustained over a prolonged period. METHOD: In order to examine these issues, we conducted a randomized controlled trial of cognitive therapy + risperidone; cognitive therapy + placebo; and supportive therapy + placebo in young people at ultra high risk for developing a psychotic disorder (that is, putatively prodromal). The main outcome was transition to psychotic disorder, with level of symptoms and functioning the secondary outcomes. This article reports the interim 6-month follow-up results. The study was conducted from August 2000 to May 2007. RESULTS: Of a possible 464 eligible ultra high risk individuals, 115 were recruited to the randomized controlled trial (cognitive therapy + risperidone, n = 43; cognitive therapy + placebo, n = 44; and supportive therapy + placebo, n = 28). An additional 78 individuals agreed to follow-up assessments but not to randomization ("monitoring group," n = 78). At 6 months, 8 of the 115 participants (7.0%) and 4 of the monitoring group (5.1%) had developed psychotic disorder. There were no significant differences between the 3 randomized groups (log rank test, P = .92) or between all 4 groups (log rank test, P = .93). There was also no difference between the 4 groups in secondary measures, with all groups showing a reduction in symptoms and increased functioning. CONCLUSIONS: Rates of transition to psychosis were lower than expected, particularly in the control supportive therapy + placebo group. This may have accounted for the negative finding, as the sample was therefore underpowered to find any difference between groups. Alternatively, it may be that all treatments were equally effective or equally ineffective at 6 months. TRIAL REGISTRATION: http://www.anzctr.org.au Identifier: ACTRN012605000247673.

Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: study design and baseline characteristics.

OBJECTIVE: Intervention during the pre-psychotic period of illness holds the potential of delaying or even preventing the onset of a full-threshold disorder, or at least of reducing the impact of such a disorder if it does develop. The first step in realizing this aim was achieved more than 10 years ago with the development and validation of criteria for the identification of young people at ultra-high risk (UHR) of psychosis. Results of three clinical trials have been published that provide mixed support for the effectiveness of psychological and pharmacological interventions in preventing the onset of psychotic disorder. METHOD: The present paper describes a fourth study that has now been undertaken in which young people who met UHR criteria were randomized to one of three treatment groups: cognitive therapy plus risperidone (CogTher + Risp: n = 43); cognitive therapy plus placebo (CogTher + Placebo: n = 44); and supportive counselling + placebo (Supp + Placebo; n = 28). A fourth group of young people who did not agree to randomization were also followed up (monitoring: n = 78). Baseline characteristics of participants are provided. RESULTS AND CONCLUSION: The present study improves on the previous studies because treatment was provided for 12 months and the independent contributions of psychological and pharmacological treatments in preventing transition to psychosis in the UHR cohort and on levels of psychopathology and functioning can be directly compared. Issues associated with recruitment and randomization are discussed.

Intervention in individuals at ultra-high risk for psychosis: a review and future directions.

OBJECTIVE: Over the last 15 years, a focus on early intervention in psychotic disorders has emerged. Initially, the early psychosis movement focused on timely recognition and phase-specific treatment of first-episode psychosis. However, early psychosis researchers suspected that pushing the point of intervention even further back to the prodromal phase of psychotic disorders may result in even better outcomes. This article reviews intervention research in the ultra-high-risk phase of psychotic disorders. DATA SOURCES: A literature search of intervention trials with ultra-high-risk cohorts published after 1980 was conducted on PubMed with the search terms prodrome and intervention. STUDY SELECTION: All published intervention trials with ultra-high-risk cohorts. DATA SYNTHESIS: The first generation of intervention trials indicated that both pharmacologic and psychological intervention strategies may be of value in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. CONCLUSIONS: Further controlled intervention trials with larger sample sizes are required in order to confirm and extend these findings. We argue that the clinical staging model provides a framework for the rationale and design of such studies, with simpler, safer, and more benign interventions being better candidates for first-line treatment, while more complex and potentially harmful treatments should be reserved for those cases in which response has failed to occur. Recent evidence indicates that neuroprotective agents, such as essential fatty acids, may be a suitable form of intervention for the ultra-high-risk phase of psychotic disorders, with a positive risk-benefit balance. Ethical aspects have become more salient given the recently observed declining transition rate in ultra-high-risk samples. We outline the key questions for the next generation of ultra-high-risk intervention trials.

Strategies used by psychotic individuals to cope with life stress and symptoms of illness: a systematic review.

Psychological models of schizophrenia and other psychotic disorders suggest that poor coping responses to life stressors and to symptoms of illness is central to their development and maintenance and influences recovery. These models are widely accepted and inform psychological treatments for psychotic disorders. In this paper, 85 studies that explore how individuals with established psychotic disorders cope with symptoms associated with their illness, and with independent life events and stressors are comprehensively reviewed. Reviewed research included cross-sectional and longitudinal investigations of self-initiated coping. Despite limitations in the existing research, it is concluded that most individuals experiencing psychosis implement at least one strategy to cope with symptoms, and life events and most implement more than one strategy. It appears that having a repertoire of strategies to employ leads to greater effectiveness than simply relying on one strategy. This suggests that treatment strategies that aim to enhance the coping of individuals with psychosis should emphasize the development of a range of coping strategies. It also seems that there is no one coping strategy that is universally effective and situational, or other factors may influence both the choice of coping strategy implemented and its efficacy.

Does disturbance of self underlie social cognition deficits in schizophrenia and other psychotic disorders?

AIM: Although the different approaches to psychosis research have made significant advances in their own fields, integration between the approaches is often lacking. This paper attempts to integrate a strand of cognitive research in psychotic disorders (specifically, social cognition research) with phenomenological accounts of schizophrenia and other psychotic disorders. METHOD: The paper is a critical investigation of phenomenological models of disturbed selfhood in schizophrenia in relation to cognitive theories of social cognition in psychotic disorders. RESULTS: We argue that disturbance of the basic sense of self, as articulated in the phenomenological literature, may underlie the social cognition difficulties present in psychotic disorders. This argument is based on phenomenological thinking about self-presence ('ipseity') being the primary or most basic ground for the intentionality of consciousness - that is, the directedness of consciousness towards others and the world. A disruption in this basic ground of conscious life has a reverberating effect through other areas of cognitive and social functioning. We propose three routes whereby self-disturbance may compromise social cognition, including dissimilarity, disruption of lived body and disturbed mental coherence. CONCLUSIONS: If this model is supported, then social cognition difficulties may be thought of as a secondary index or marker of the more primary disturbance of self in psychotic disorders. Further empirical work examining the relationship between cognitive and phenomenological variables may be of value in identifying risk markers for psychosis onset, thus contributing to early intervention efforts, as well as in clarifying the essential psychopathological features of schizophrenia and other psychotic disorders.

Identifying the ultra-high risk (prodromal) population: evaluation of training workshops with mental health services.

OBJECTIVE: Recent years have witnessed widespread interest in the early phase of psychotic disorders. The most widely used approach to identify individuals in the prodromal phase is the ultra-high risk (UHR) approach, which combines known trait and state risk factors for psychotic disorder. The Personal Assessment and Crisis Evaluation Clinic introduced the Comprehensive Assessment of At Risk Mental States (CAARMS) in order to assess UHR status. A training DVD and manual in the use of the CAARMS was recently developed in order to assist with UHR identification. The current paper reports the outcome of a series of training workshops with mental health professionals based around this DVD. The research aim was to investigate whether the training workshops assisted mental health professionals in their confidence and ability to accurately identify UHR cases and distinguish these from non-UHR and first-episode psychosis (FEP) cases. METHOD: A total of 137 mental health workers participated in the training sessions across eight training sites. The training sessions consisted of four modules: theoretical background; rating written vignettes for UHR, non-UHR or FEP status; viewing and discussing the CAARMS Training DVD; and re-rating matched written vignettes for UHR, non-UHR or FEP status. RESULTS: Participants' confidence in identifying UHR cases and in using the CAARMS increased as a result of the workshop. Participants' ability to correctly identify UHR-positive cases did not improve as a result of the workshop. This may have been the result of a ceiling effect due to the baseline ability to identify UHR-positive cases being high. But there was a trend for participants' ability to correctly identify UHR-negative cases to improve as a result of the workshop. CONCLUSIONS: UHR training workshops are a valuable means of increasing mental health workers' confidence in identifying UHR patients. Future UHR training programmes with experienced mental health professionals should pay particular attention to the correct identification of UHR-negative cases.