Alison R. Yung

Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison

BACKGROUND Psychotic disorders, such as schizophrenia, are associated with neuroanatomical abnormalities, but whether these predate the onset of symptoms or develop progressively over the course of illness is unclear. We investigated this issue with MRI to study people with prodromal symptoms who are at ultra high-risk for the development of psychosis. METHODS We did two comparisons, cross-sectional and longitudinal. For the cross-sectional comparison, 75 people with prodromal signs of psychosis were scanned with MRI. After at least 12 months of follow-up, 23 (31%) had developed psychosis and 52 (69%) had not. Baseline MRI data from these two subgroups were compared. For the longitudinal comparison, 21 of the ultra high-risk individuals were scanned again with MRI after at least 12 months. Ten of these had developed psychosis and 11 had not. MRI data from baseline and follow-up were compared within each group of people. FINDINGS In the cross-sectional comparison, compared with people who did not develop psychosis, those who did develop the disorder had less grey matter in the right medial temporal, lateral temporal, and inferior frontal cortex, and in the cingulate cortex bilaterally. In the longitudinal comparison, when re-scanned, individuals who had developed psychosis showed a reduction in grey matter in the left parahippocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri. In those who had not become psychotic, longitudinal changes were restricted to the cerebellum. INTERPRETATION Some of the grey-matter abnormalities associated with psychotic disorders predate the onset of frank symptoms, whereas others appear in association with their first expression.

Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States

Objective: Recognizing the prodrome of a first psychotic episode prospectively creates the opportunity of intervention, which could delay, ameliorate or even prevent onset. Valid criteria and a reliable methodology for identifying possible prodromes are needed. This paper describes an instrument, the Comprehensive Assessment of At-Risk Mental States (CAARMS), which has been designed for such a purpose. It has two functions: (i) to assess psychopathology thought to indicate imminent development of a first-episode psychotic disorder; and (ii) to determine if an individual meets criteria for being at ultra high risk (UHR) for onset of first psychotic disorder. This paper describes the pilot evaluation of the CAARMS.Method: Several methodologies were used to test the CAARMS. First, CAARMS scores in a group of UHR young people and the association between CAARMS scores and the risk of transition to psychotic disorder, were analysed. Second, CAARMS scores in a UHR group were compared to a control group. To asses...

Cognitive Functioning in Prodromal Psychosis: A Meta-analysis

CONTEXT A substantial proportion of people at clinical high risk (HR) of psychosis will develop a psychotic disorder over time. Cognitive deficits may predate the onset of psychosis and may be useful as markers of increased vulnerability to illness. OBJECTIVE To quantitatively examine the cognitive functioning in subjects at HR in the literature to date. DATA SOURCES Electronic databases were searched until January 2011. All studies reporting cognitive performance in HR subjects were retrieved. STUDY SELECTION Nineteen studies met the inclusion criteria, comprising a total of 1188 HR subjects and 1029 controls. DATA EXTRACTION Neurocognitive functioning and social cognition as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS Subjects at HR were impaired relative to controls on tests of general intelligence, executive function, verbal and visual memory, verbal fluency, attention and working memory, and social cognition. Processing speed domain was also affected, although the difference was not statistically significant. Later transition to psychosis was associated with even more marked deficits in the verbal fluency and memory domains. The studies included reported relatively homogeneous findings. There was no publication bias and a sensitivity analysis confirmed the robustness of the core results. CONCLUSIONS The HR state for psychosis is associated with significant and widespread impairments in neurocognitive functioning and social cognition. Subsequent transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.

The initial prodrome in psychosis: Descriptive and qualitative aspects

Objective: This study aimed to describe in detail, using a retrospective approach, the prodromal symptoms in first-episode psychosis patients. This initial prodrome, the period of disturbance preceding a first psychotic episode, is potentially important for early intervention, identification of biological markers, and understanding the process of becoming psychotic. Method: A consecutive series of 21 first-episode patients was recruited from the Early Psychosis Prevention and Intervention Centre, a specialised service for young people aged between 16 and 30 with first-episode psychosis. Subjects were interviewed in the recovery phase after the acute episode, about the period leading up to the psychosis, using a combination of unstructured and semi-structured techniques. Results: A wide variability of phenomena and sequence patterns was found, with symptoms being a mixture of attenuated psychotic symptoms, neurotic and mood-related symptoms, and behavioural changes. Symptoms were often disabling and some, such as suicidal thoughts, potentially life-threatening. Conclusions: The findings highlight the loss of information that has resulted from disregarding early phenomenological studies of the psychotic prodrome and instead focussing on behavioural features. The ground work has been laid for the development of better methodologies for assessing and measuring first psychotic prodromes with increased emphasis on experiential phenomena. This has the potential to lead to the early recognition and more accurate prediction of subsequent psychosis, as well as a deeper understanding of the neurobiology of the onset of psychotic disorder.

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.

Progressive Gray Matter Reduction of the Superior Temporal Gyrus During Transition to Psychosis

CONTEXT Longitudinal magnetic resonance imaging studies have shown progressive gray matter reduction in the superior temporal gyrus during the earliest phases of schizophrenia. It is unknown whether these progressive processes predate the onset of psychosis. OBJECTIVE To examine gray matter reduction of the superior temporal gyrus over time in individuals at risk for psychosis and in patients with first-episode psychosis. DESIGN Cross-sectional and longitudinal comparisons. SETTING Personal Assessment and Crisis Evaluation Clinic and Early Psychosis Preventions and Intervention Centre. PARTICIPANTS Thirty-five ultrahigh-risk individuals (of whom 12 later developed psychosis [UHRP] and 23 did not [UHRNP]), 23 patients with first-episode psychosis (FEP), and 22 control subjects recruited from the community. MAIN OUTCOME MEASURES Volumes of superior temporal subregions (planum polare, Heschl gyrus, planum temporale, and rostral and caudal regions) were measured at baseline and follow-up (mean, 1.8 years) and were compared across groups. RESULTS In cross-sectional comparisons, only the FEP group had significantly smaller planum temporale and caudal superior temporal gyrus than other groups at baseline, whereas male UHRP subjects also had a smaller planum temporale than controls at follow-up. In longitudinal comparison, UHRP and FEP patients showed significant gray matter reduction (approximately 2%-6% per year) in the planum polare, planum temporale, and caudal region compared with controls and/or UHRNP subjects. The FEP patients also exhibited progressive gray matter loss in the left Heschl gyrus (3.0% per year) and rostral region (3.8% per year), which were correlated with the severity of delusions at follow-up. CONCLUSIONS A progressive process in the superior temporal gyrus precedes the first expression of florid psychosis. These findings have important implications for underlying neurobiologic features of emerging psychotic disorders and emphasize the importance of early intervention during or before the first episode of psychosis.

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.

Psychotic-like experiences in a community sample of adolescents: implications for the continuum model of psychosis and prediction of schizophrenia

Objective: Studies conducted in community samples suggest that psychotic-like experiences are common in the general population, leading to suggestions that they are either variations of normal personality or are different expressions of underlying vulnerability to psychotic disorder. Different types of psychotic symptoms may exist, some being normal variants and some having implications for mental health and functioning. The aim of the present study was to determine if different subtypes of psychotic-like experiences could be identified in a community sample of adolescents and to investigate if particular subtypes were more likely to be associated with psychosocial difficulties, that is, distress, depression and poor functioning, than other subtypes. Method: Eight hundred and seventy-five Year 10 students from 34 schools participated in a cross-sectional survey that measured psychotic-like experiences using the Community Assessment of Psychic Experiences; depression using the Centre for Epidemiologic Studies Depression Scale; and psychosocial functioning using the Revised Multidimensional Assessment of Functioning Scale. Factor analysis was conducted to identify any subtypes of psychotic experiences. Results: Four subtypes of psychotic-like experiences were identified: Bizarre Experiences, Perceptual Abnormalities, Persecutory Ideas, and Magical Thinking. Intermittent, infrequent psychotic experiences were common, but frequent experiences were not. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas were strongly associated with distress, depression and poor functioning. Magical Thinking was only weakly associated with these variables. Overall these findings may suggest that infrequent psychotic-like experiences are unlikely to be a specific risk factor for onset of a psychotic disorder in community samples. Conclusions: Given that the different subtypes had varying associations with current difficulties it is suggested that not all subtypes confer the same risk for onset of psychotic disorder and poor outcome. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas may represent expressions of underlying vulnerability to psychotic disorder, but Magical Thinking may be a normal personality variant.

Preventing a first episode of psychosis: Meta-analysis of randomized controlled prevention trials of 12 month and longer-term follow-ups

Over the last decade many studies were conducted to assess the feasibility of early detection of people at risk of developing psychosis and intervention to prevent or delay a first psychotic episode. Most of these studies were small and underpowered. A meta-analysis can demonstrate the effectiveness of the efforts to prevent or postpone a first episode of psychosis. A search conducted according the PRISMA guideline identified 10 studies reporting 12-month follow-up data on transition to psychosis, and 5 studies with follow-ups varying from 24 to 48 months. Both random and fixed effects meta-analyses were conducted. The quality of the studies varied from poor to excellent. Overall the risk reduction at 12 months was 54% (RR=0.463; 95% CI=0.33-0.64) with a Number Needed to Treat (NNT) of 9 (95% CI=6-15). Although the interventions differed, there was only mild heterogeneity and publication bias was small. All sub-analyses demonstrated effectiveness. Also 24 to 48-month follow-ups were associated with a risk reduction of 37% (RR=.635; 95% CI=0.44-0.92) and a NNT of 12 (95% CI=7-59). Sensitivity analysis excluding the methodologically weakest study showed that the findings were robust. Early detection and intervention in people at ultra-high risk of developing psychosis can be successful to prevent or delay a first psychosis. Antipsychotic medication showed efficacy, but more trials are needed. Omega-3 fatty acid needs replication. Integrated psychological interventions need replication with more methodologically sound studies. The findings regarding CBT appear robust, but the 95% confidence interval is still wide.

Pituitary Volume Predicts Future Transition to Psychosis in Individuals at Ultra-High Risk of Developing Psychosis

BACKGROUND We examined pituitary volume before the onset of psychosis in subjects who were at ultra-high risk (UHR) for developing psychosis. METHODS Pituitary volume was measured on 1.5-mm, coronal, 1.5-T magnetic resonance images in 94 UHR subjects recruited from admissions to the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia and in 49 healthy control subjects. The UHR subjects were scanned at baseline and were followed clinically for a minimum of 1 year to detect transition to psychosis. RESULTS Within the UHR group, a larger baseline pituitary volume was a significant predictor of future transition to psychosis. The UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (+12%; p = .001) baseline pituitary volume compared with UHR subjects who did not go on to develop psychosis (UHR-NP, n = 63). The survival analysis conducted by Cox regression showed that the risk of developing psychosis during the follow-up increased by 20% for every 10% increase in baseline pituitary volume (p = .002). Baseline pituitary volume of the UHR-NP subjects was smaller not only compared with UHR-P (as described above) but also compared with control subjects (-6%; p = .032). CONCLUSIONS The phase before the onset of psychosis is associated with a larger pituitary volume, suggesting activation of the HPA axis.