Warrick J. Brewer

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.

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.

Spatial working memory ability is a marker of risk-for-psychosis

BACKGROUND Working memory has been identified as a core cognitive deficit in schizophrenia that is associated with negative symptoms, but it is unclear whether it is impaired prior to onset of psychosis in symptomatic patients. METHOD Thirty-eight young people at ultra high-risk (UHR) of developing psychosis (of whom nine later became psychotic) were compared with 49 healthy controls on tests of spatial working memory (SWM) and delayed matching-to-sample (DMTS). RESULTS Both SWM and DMTS performance was significantly poorer in the UHR groups. Those who later became psychotic generally performed more poorly than those who did not, although this did not reach significance for any measure. A significant association between SWM errors and negative symptoms was seen in the later-psychotic group only (P = 0.02). CONCLUSIONS Spatial working memory abilities are impaired in those at high-risk for psychosis. The relationship between working memory and negative symptoms may be useful as a predictive tool.

Efficacy of Using Cognitive Status in Predicting Psychosis: A 7-Year Follow-Up

BACKGROUND Despite extensive early detection research in schizophrenic psychoses, methods for identifying at-risk individuals and predicting their transition to psychosis are still unreliable. Moreover, there are sparse data on long-term prediction. We therefore investigated long-term psychosis transition in individuals with an At Risk Mental State (ARMS) and examined the relative efficacy of clinical and neuropsychological status in optimizing the prediction of transition. METHODS Sixty-four individuals with ARMS for psychosis were identified from all referrals to our early detection clinic between March 1, 2000 and February 29, 2004. Fifty-three (83%) were followed up for up to 7 (mean 5.4) years. RESULTS Twenty-one of the 53 staying in follow-up developed psychosis, corresponding to a transition rate of .34 (Kaplan-Meier estimates). Median time to transition was 10 months (range <1-55). Six of all transitions (29%) occurred only after 12 months from referral. Best transition predictors within this population were selected attenuated psychotic symptoms (suspiciousness), negative symptoms (anhedonia/asociality), and cognitive deficits (reduced speed of information processing). With these predictors in an integrated model for predicting transition to psychosis, the overall predictive accuracy was 80.9% with a sensitivity of 83.3% and a specificity of 79.3%. CONCLUSIONS Follow-up of ARMS subjects should exceed the usual 12 months. Prediction of transitions could be improved by a stronger weighting of certain early symptoms and by introducing neurocognitive tests into a stepwise risk assessment. Confirmatory research will hopefully further improve risk algorithm, including psychopathology and neuropsychological performance, for clinical application in early detection clinics.

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.

Non-reduction in hippocampal volume is associated with higher risk of psychosis

Previous research using MRI scans has shown reduced hippocampal volumes in chronic schizophrenia and first-episode psychosis compared to well subjects. There are few MRI volumetric studies of high-risk cohorts and no studies that have compared structural measures between high-risk subjects who later developed a psychotic illness and those who did not. Therefore, the question of whether structural changes to the hippocampi precede the onset of an acute psychotic episode has not been answered. Hippocampal and whole brain volumes of 60 people at ultra high-risk (UHR) of developing a psychotic episode (identified through state and trait criteria) were obtained through MRI scan and compared with subjects with first episode psychosis (FEP: n=32), and no mental illness (n=139). Thirty-three percent (n=20) of the UHR cohort developed a psychotic disorder during the 12-month period following the MRI scan. The UHR group as a whole, like the FEP group, had significantly smaller left and right hippocampal volumes than the normal comparison group. Contrary to our initial hypothesis, the left hippocampal volume of the UHR subjects who developed a psychotic disorder was larger than the UHR-non-psychotic subgroup and the FEP group, but no differences were found between the UHR-psychotic and normal groups. The right hippocampus of the UHR-non-psychotic group was significantly smaller than the Normal group but not different to the FEP group. Furthermore, a larger left hippocampal volume of the UHR cohort at intake was associated with the subsequent development of acute psychosis rather than smaller volumes. These results contradicted the expected outcomes, which had been influenced by the neurodevelopmental model of the development of psychosis and an earlier study comparing hippocampal volumes of first episode, chronic schizophrenia and normal populations. One implication of these results is that a process of dynamic central nervous system change may occur during the onset phase of schizophrenia and related disorders, rather than earlier in life as suggested by the neurodevelopmental model. Alternatively, selection factors associated with the UHR cohort may have created a bias in the results. Replication of these results is required in other high-risk cohorts.

Duration of untreated psychosis and cognitive deterioration in first-episode schizophrenia

Cognitive impairment is an important clinical feature in many individuals with schizophrenia. Factors associated with cognitive deficit are not well established. Duration of untreated psychosis (DUP) has recently gained interest as a prognostic factor in schizophrenia. This study reports on the association between DUP and cognitive function. Subjects comprised 42 individuals (30 males, 12 females) who experienced a first-episode of DSM-III-R schizophrenia or schizophreniform disorder. Cognitive function was determined at clinical stabilization using the WAIS-R. An estimate of cognitive deterioration was based on the WAIS-R subtest profile. Longer DUP, male gender, higher premorbid IQ and younger age at admission independently predicted cognitive deterioration. Poorer performance on Digit Symbol and Comprehension subtests was associated with longer DUP. The findings suggest that untreated psychosis compromises some aspects of cognitive function. Studies investigating the association between DUP and outcome should control for potentially confounding variables. Early treatment of psychosis could help to reduce the prominent cognitive deficit in first-episode schizophrenia.

Neurocognitive predictors of functional outcome two to 13 years after identification as ultra-high risk for psychosis

BACKGROUND AND AIM Little is known about the relationship between neurocognitive performance and functional outcome before the onset of frank psychosis. This longitudinal study aimed to investigate neurocognitive predictors of poor functional outcome in a group identified as ultra-high risk (UHR) for psychosis between two and 13 years prior. METHOD Individuals (N=230) identified as UHR for psychosis at the PACE Clinic in Melbourne completed assessment of psychopathology, functioning and neurocognition at baseline and follow-up. The mean length of follow-up was 7.26 years (SD 3.05). RESULTS Forty-one individuals with the poorest functional outcome were identified. Only 48.8% of this group had transitioned to psychosis. Poor functional outcome was associated with reduced performance at baseline in the specific neurocognitive domains of verbal learning and memory, processing speed and attention, and verbal fluency, but not global cognitive impairment. Reduced performance on a verbal story recall task, in combination with higher negative symptoms at baseline, was the best predictor of later poor outcome. Baseline positive psychotic symptoms and GAF scores were not associated with later poor outcome. DISCUSSION To date, this is the longest follow-up study of an UHR sample. Poor functional outcome was associated with specific neurocognitive decrements, regardless of transition to psychosis. The detection of individuals with poor functioning at follow-up, against a background of previously identified risk factors for psychotic disorder, may yield a valid group in which to study biomarkers and treatment of schizophrenia.

A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia

Brain abnormalities have been identified in patients with schizophrenia, but what is unclear is whether these changes are progressive over the course of the disorder. In this longitudinal study, hippocampal and temporal lobe volumes were measured at two time points in 30 patients with first episode psychosis (mean follow-up interval=1.9 years, range 0.54-4.18 years) and 12 with chronic schizophrenia (mean follow-up interval=2.3 years, range 1.03-4.12 years) and compared to 26 comparison subjects (mean follow-up interval 2.2 years, range 0.86-4.18 years). Hippocampal, temporal lobe, whole-brain and intracranial volumes (ICV) were estimated from high-resolution magnetic resonance images. Only whole-brain volume showed significant loss over the follow-up interval in both patient groups. The rate of this volume loss was not different in the first episode group compared to the chronic group. There were no changes in either hippocampal or temporal lobe volumes. The negative findings for the hippocampus and temporal lobes may mean that the abnormalities in these regions are stable features of schizophrenia. Alternatively, the period before the onset of frank psychotic symptoms may be the point of greatest risk for progressive change.

Understanding Drug Addiction: A Neuropsychological Perspective

The purpose of the present review is to describe the neuropsychological correlates of long-term substance abuse and to discuss the findings within the context of premorbid vulnerabilities, comorbidity and adolescent neurodevelopment. The authors critically review key findings from the neuropsychological literature related to the long-term sequelae of alcohol, cannabis, inhalant, opiates, psychostimulants and ecstasy use. Leading electronic databases such as PubMed were searched to identify relevant studies published in the past 20 years. References identified from bibliographies of pertinent articles and books in the field were also collected and selectively reviewed. Across substances, individuals with long-term abuse consistently demonstrate neuropsychological impairments of executive (inhibitory) control, working memory and decision making, together with neurobiological abnormalities involving frontotemporal and basal ganglia circuits. In some instances these deficits are dose dependent, implying that they are a direct consequence of prolonged drug exposure. However, comorbid behavioural, personality and mental health problems are common among drug-using populations and are associated with similar neuropsychological deficits. Presented herein is a neuropsychological model of addictive behaviour that highlights the complex interplay between cognition, brain maturation, psychopathology and drug exposure.