Julia Lappin

Schizophrenia: from developmental deviance to dopamine dysregulation.

Two major theories of schizophrenia are respectively, the neurodevelopmental hypothesis and the dopamine hypothesis. Each of these has recently been revised. Firstly, the classical neurodevelopmental hypothesis has been modified to include the pathogenic effects of psychostimulants and cannabis abuse, and also of chronic social adversity; it is perhaps now more appropriately termed, the developmental hypothesis. Secondly, recent amendments to the dopamine hypothesis suggest that excess striatal dopamine is responsible for increased salience being given to insignificant events and thoughts, and that this underpins the development of psychotic symptoms. Traditionally, it has been thought that this striatal dopamine dysregulation might be secondary to frontal dysfunction. However, recent animal research shows that over-expression of striatal D(2) receptors results in frontal dysfunction manifesting as cognitive difficulties and animal equivalents of so-called negative symptoms. This raises the question whether early intervention may prevent the development of these latter problems. Finally, the two theories are beginning to be integrated through the growing evidence that all the developmental risk factors which increase risk of schizophrenia appear to act by facilitating dopamine dysregulation.

The dopaminergic basis of human behaviors: A review of molecular imaging studies.

This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. Whilst heterogeneity in experimental methods limits meta-analysis, we describe the advantages and limitations of different methodological approaches. Interpretation of experimental results may be limited by regional cerebral blood flow (rCBF) changes, head movement and choice of control conditions. We revisit our original study of striatal DA release during video-game playing [Koepp, M.J., Gunn, R.N., Lawrence, A.D., Cunningham, V.J., Dagher, A., Jones, T., Brooks, D.J., Bench, C.J., Grasby, P.M., 1998. Evidence for striatal dopamine release during a video game. Nature 393, 266-268] to illustrate the potentially confounding influences of head movement and alterations in rCBF. Changes in [(11)C]raclopride binding may be detected in extrastriatal as well as striatal brain regions-however we review evidence which suggests that extrastriatal changes may not be clearly interpreted in terms of DA release. Whilst several investigations have detected increases in striatal extracellular DA concentrations during task components such as motor learning and execution, reward-related processes, stress and cognitive performance, the presence of potentially biasing factors should be carefully considered (and, where possible, accounted for) when designing and interpreting future studies.

Risk factors for schizophrenia--all roads lead to dopamine.

Schizophrenia is a debilitating disease of major public health importance, the incidence of which shows prominent worldwide variation (up to fivefold) and is about 40% greater in men than in women. Furthermore, epidemiological studies have shown that the incidence is higher among those who grow up in urban areas and among migrants. Recent evidence indicates that, although the neurochemical origins of schizophrenia do not necessarily lie in dopamine dysregulation, this operates as the final common pathway underlying positive psychotic symptoms and may also play a role in negative and cognitive symptoms. The last few years have seen the development of a plausible model in which schizophrenia is seen as the consequence of the actions of a number of component causes, such as genes or early environmental hazards that subtly alter subsequent neurodevelopment, thereby predisposing the child to later dopamine dysregulation.

Individualized prediction of illness course at the first psychotic episode: a support vector machine MRI study

Background To date, magnetic resonance imaging (MRI) has made little impact on the diagnosis and monitoring of psychoses in individual patients. In this study, we used a support vector machine (SVM) whole-brain classification approach to predict future illness course at the individual level from MRI data obtained at the first psychotic episode. Method One hundred patients at their first psychotic episode and 91 healthy controls had an MRI scan. Patients were re-evaluated 6.2 years (s.d.=2.3) later, and were classified as having a continuous, episodic or intermediate illness course. Twenty-eight subjects with a continuous course were compared with 28 patients with an episodic course and with 28 healthy controls. We trained each SVM classifier independently for the following contrasts: continuous versus episodic, continuous versus healthy controls, and episodic versus healthy controls. Results At baseline, patients with a continuous course were already distinguishable, with significance above chance level, from both patients with an episodic course (p=0.004, sensitivity=71, specificity=68) and healthy individuals (p=0.01, sensitivity=71, specificity=61). Patients with an episodic course could not be distinguished from healthy individuals. When patients with an intermediate outcome were classified according to the discriminating pattern episodic versus continuous, 74% of those who did not develop other episodes were classified as episodic, and 65% of those who did develop further episodes were classified as continuous (p=0.035). Conclusions We provide preliminary evidence of MRI application in the individualized prediction of future illness course, using a simple and automated SVM pipeline. When replicated and validated in larger groups, this could enable targeted clinical decisions based on imaging data.

Gray matter abnormalities associated with duration of untreated psychosis

PURPOSE A long duration of untreated psychosis (DUP) is associated with relatively poor clinical and social outcomes. In order to identify whether an anatomically mediated mechanism may give rise to poorer outcomes, it is important to identify whether a long DUP is associated with greater brain structural abnormalities. METHOD 81 patients with first-episode psychosis (schizophrenia, affective, and other psychoses) were scanned using high resolution Magnetic Resonance Imaging. DUP was defined as the number of days between first onset of psychotic symptoms and first contact with mental health services. High-resolution MRI images and voxel-based methods of image analysis were used to investigate brain structure in these patients. RESULTS Longer DUP was associated with gray matter reductions in left middle and inferior temporal, left occipital and left fusiform cortices, and with gray matter excess of the left basal ganglia. All findings remained significant when co-varying for exposure to antipsychotic treatment. CONCLUSIONS Temporal gray matter reductions are more marked in patients with a long DUP. This could reflect a progressive pathological process that is active prior to treatment. Alternatively, these abnormalities could be associated with a more insidious onset of illness and a later presentation to services.

Economic impact of early intervention in people at high risk of psychosis

Background Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis. Method The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model. Results Over the initial 12 months from presentation, the costs of the OASIS intervention were £1872 higher than CAU. However, after 24 months they were £961 less than CAU. Conclusions This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.

Insight, grey matter and cognitive function in first-onset psychosis

BACKGROUND Several studies have suggested that neuropsychological and structural brain deficits are implicated in poor insight. Few insight studies however have combined neurocognitive and structural neuroanatomical measures. AIMS Focusing on the ability to relabel psychotic symptoms as pathological, we examined insight, brain structure and neurocognition in first-onset psychosis. METHOD Voxel-based magnetic resonance imaging data were acquired from 82 individuals with psychosis and 91 controls assessed with a brief neuropsychological test battery. Insight was measured using the Schedule for the Assessment of Insight. RESULTS The principal analysis showed reduced general neuropsychological function was linked to poor symptom relabelling ability. A subsequent between-psychosis group analysis found those with no symptom relabelling ability had significant global and regional grey matter deficits primarily located at the posterior cingulate gyrus and right precuneus/cuneus. CONCLUSIONS The cingulate gyrus (as part of a midline cortical system) along with right hemisphere regions may be involved in illness and symptom self-appraisal in first-onset psychosis.

Reappraising the Long-term Course and Outcome of Psychotic Disorders: The ÆSOP-10 Study

BACKGROUND Studies of the long-term course and outcome of psychoses tend to focus on cohorts of prevalent cases. Such studies bias samples towards those with poor outcomes, which may distort our understanding of prognosis. Long-term follow-up studies of epidemiologically robust first-episode samples are rare. METHOD AESOP-10 is a 10-year follow-up study of 557 individuals with a first episode of psychosis initially identified in two areas in the UK (South East London and Nottingham). Detailed information was collated on course and outcome in three domains (clinical, social and service use) from case records, informants and follow-up interviews. RESULTS At follow-up, of 532 incident cases identified, at baseline 37 (7%) had died, 29 (6%) had emigrated and eight (2%) were excluded. Of the remaining 458, 412 (90%) were traced and some information on follow-up was collated for 387 (85%). Most cases (265, 77%) experienced at least one period of sustained remission; at follow-up, 141 (46%) had been symptom free for at least 2 years. A majority (208, 72%) of cases had been employed for less than 25% of the follow-up period. The median number of hospital admissions, including at first presentation, was 2 [interquartile range (IQR) 1-4]; a majority (299, 88%) were admitted a least once and a minority (21, 6%) had 10 or more admissions. Overall, outcomes were worse for those with a non-affective diagnosis, for men and for those from South East London. CONCLUSIONS Sustained periods of symptom remission are usual following first presentation to mental health services for psychosis, including for those with a non-affective disorder; almost half recover.

Duration of untreated psychosis and ethnicity in the ÆSOP first-onset psychosis study

BACKGROUND There is a common assumption that Black patients with a psychotic mental illness experience longer treatment delays during a first episode. We sought to investigate this issue in a large cohort of patients with a first episode of psychosis. METHOD All patients with a first episode of psychosis presenting to secondary mental health services within tightly defined catchment areas in south-east London and Nottingham over a 2-year period were included in the study. Data relating to duration of untreated psychosis (DUP) and clinical and sociodemographic characteristics were collected from patients, relatives and case-notes. RESULTS There was no evidence that African-Caribbean or Black African patients experienced longer periods of untreated psychosis than White British patients prior to first contact with services. There was evidence that Black African patients experienced shorter periods of untreated psychosis than White British patients. CONCLUSIONS Contrary to what is commonly assumed, our study suggests that Black patients with a psychotic mental illness do not experience longer treatment delays prior to first contact with services than White British patients. This suggests that strategies to reduce treatment delays targeted specifically at Black patients will be of limited value.

Mortality in Schizophrenia and Other Psychoses: A 10-Year Follow-up of the ӔSOP First-Episode Cohort

The excess mortality in people with psychotic disorders is a major public health concern, but little is known about the clinical and social risk factors which may predict this health inequality and help inform preventative strategies. We aimed to investigate mortality in a large epidemiologically characterized cohort of individuals with first-episode psychosis compared with the general population and to determine clinical and social risk factors for premature death. All 557 individuals with first-episode psychosis initially identified in 2 areas (Southeast London and Nottinghamshire, United Kingdom) were traced over a 10-year period in the ӔSOP-10 study. Compared with the general population, all-cause (standardized mortality ratio [SMR] 3.6, 95% confidence interval [CI] 2.6–4.9), natural-cause (SMR 1.7, 95% CI 1.0–2.7) and unnatural-cause (SMR 13.3, 95% CI 8.7–20.4) mortality was very high. Illicit drug use was associated with an increased risk of all-cause mortality (adj. rate ratio [RR] 2.31, 95% CI 1.06–5.03). Risk of natural-cause mortality increased with a longer time to first remission (adj. RR 6.61, 95% CI 1.33–32.77). Family involvement at first contact strongly reduced risk of unnatural-cause mortality (adj. RR 0.09, 95% CI 0.01–0.69). Our findings suggest that the mortality gap in people with psychotic disorders remains huge and may be wider for unnatural-cause mortality than previously reported. Efforts should now focus on further understanding and targeting these tractable clinical and social risk factors of excess mortality. Early intervention and dual diagnosis services may play a key role in achieving more rapid remission and carer involvement and addressing substance use problems to reduce excess mortality in psychosis.