Richard Corrigall

Autism Spectrum Disorders and Schizophrenia: Meta-Analysis of the Neural Correlates of Social Cognition

Context Impaired social cognition is a cardinal feature of Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the functional neuroanatomy of social cognition in either disorder remains unclear due to variability in primary literature. Additionally, it is not known whether deficits in ASD and SZ arise from similar or disease-specific disruption of the social cognition network. Objective To identify regions most robustly implicated in social cognition processing in SZ and ASD. Data Sources Systematic review of English language articles using MEDLINE (1995–2010) and reference lists. Study Selection Studies were required to use fMRI to compare ASD or SZ subjects to a matched healthy control group, provide coordinates in standard stereotactic space, and employ standardized facial emotion recognition (FER) or theory of mind (TOM) paradigms. Data Extraction Activation foci from studies meeting inclusion criteria (n = 33) were subjected to a quantitative voxel-based meta-analysis using activation likelihood estimation, and encompassed 146 subjects with ASD, 336 SZ patients and 492 healthy controls. Results Both SZ and ASD showed medial prefrontal hypoactivation, which was more pronounced in ASD, while ventrolateral prefrontal dysfunction was associated mostly with SZ. Amygdala hypoactivation was observed in SZ patients during FER and in ASD during more complex ToM tasks. Both disorders were associated with hypoactivation within the Superior Temporal Sulcus (STS) during ToM tasks, but activation in these regions was increased in ASD during affect processing. Disease-specific differences were noted in somatosensory engagement, which was increased in SZ and decreased in ASD. Reduced thalamic activation was uniquely seen in SZ. Conclusions Reduced frontolimbic and STS engagement emerged as a shared feature of social cognition deficits in SZ and ASD. However, there were disease- and stimulus-specific differences. These findings may aid future studies on SZ and ASD and facilitate the formulation of new hypotheses regarding their pathophysiology.

Increased developmental deviance and premorbid dysfunction in early onset schizophrenia.

Abnormal neurodevelopment and poor premorbid function have been described in schizophrenia. It is unclear whether abnormalities in these domains are increased in patients with early onset schizophrenia (EOS; onset before the 18th birthday) and whether they act to precipitate the earlier onset of the disorder. To address these questions, we collected information based on maternal interviews about the premorbid function of 40 adolescents with recent onset schizophrenia and an equal number of healthy controls using the Developmental Scale Score, the Premorbid Schizoid and Schizotypal Trait Scale (PSST) and Premorbid Adjustment Scale (PAS). Data on the PSST and PAS were also available in 54 patients with adult onset schizophrenia (AOS; onset after the 20th birthday). Compared to healthy controls, EOS patients had (a). delayed speech milestones, difficulties in reading and spelling and greater overall developmental deviance; (b). poor premorbid adjustment in childhood, which became even more deviant in adolescence particularly in boys and (c). more schizophrenia spectrum traits. Both premorbid adjustment and personality traits were more abnormal in patients with increased developmental deviance suggesting the possibility that they represent different manifestations of ongoing abnormalities in developmental processes. EOS patients had more impaired premorbid adjustment in adolescence and schizophrenia spectrum traits compared to AOS cases. Age of onset was related to developmental deviance, premorbid schizophrenia spectrum traits and childhood adjustment in EOS patients only.

EPA-0271 - Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia

BACKGROUND The use of clozapine (CLZ) for treatment-resistant schizophrenia is well established in adults. However, it is seldom used in youth with early onset schizophrenia (EOS) largely because of lack of clarity about its risk benefit ratio. This review synthesises and evaluates available evidence regarding the efficacy and tolerability of CLZ in EOS with the aim to assist clinical decision-making. METHODS We conducted a systematic review of the primary literature on the clinical efficacy and adverse drug reactions (ADRs) observed during CLZ treatment in EOS. We also identified relevant practice guidelines and summarised current guidance. RESULTS CLZ showed superior efficacy than other antipsychotics in treating refractory EOS patients; short-term clinical trials suggest an average improvement of 69% on the Brief Psychiatric Rating Scale that was sustained during long-term follow-up (up to 9 years). No fatalities linked to CLZ treatment were reported. Sedation and hypersalivation were the most common complaints, reported by over 90% of patients. Other common ADRs (reported in 10-60% of patients) were enuresis, constipation, weight gain, and non-specific EEG changes. Less common ADRs (reported in 10-30% of patients) were akathisia, tachycardia and changes in blood pressure. Neutropenia was reported in 6-15% of cases but was usually transient while agranulocytosis was rare (<0.1%). Seizures were also uncommon (<3%). Metabolic changes were relatively common (8-22%) but emergent diabetes was not frequently observed (<6%). Overall the rate of discontinuation was low (3-6%). Current guidelines recommend the use of CLZ in EOS patients who have failed to respond to two adequate trials with different antipsychotics and provide detailed schedules of assessments to evaluate and assess potential ADRs both prior to initiation and throughout CLZ treatment. CONCLUSION Available data although limited in terms of number of studies are consistent in demonstrating that CLZ is effective and generally safe in the treatment of refractory EOS provided patients are regularly monitored.

Abnormal Functional Activation and Connectivity in the Working Memory Network in Early-Onset Schizophrenia

OBJECTIVE Disruption within the working memory (WM) neural network is considered an integral feature of schizophrenia. The WM network, and the dorsolateral prefrontal cortex (DLPFC) in particular, undergo significant remodeling in late adolescence. Potential interactions between developmental changes in the WM network and disease-related processes for schizophrenia remain unclear. The aim of this study was to determine whether DLPFC activation and functional connectivity are impaired during WM in patients with early-onset schizophrenia (EOS; age of onset <18 years). METHOD We used functional magnetic resonance imaging and psychophysiological interaction analysis to respectively measure blood oxygenation level-dependent signal and to derive functional connectivity estimates in response to the two-back WM task from 25 youths with EOS and 20 matched healthy adolescents. RESULTS Compared with healthy adolescents, patients with EOS showed reduced engagement of the DLPFC, the anterior cingulate cortex (ACC), and frontal operculum, and had reduced DLPFC connectivity within the WM network. Patients with EOS showed abnormal reduction in the coupling of the DLPFC with the ACC, the inferior parietal lobule, and the middle occipital gyrus. In contrast to healthy adolescents, patients with EOS expressed age-related decrease in the activity of the DLPFC and an increase in its connectivity with the ACC. CONCLUSIONS Patients with EOS show dysfunctional engagement and reduced integration within the WM neural network. The pattern of abnormal age-related correlations in DLPFC activity and connectivity suggests that schizophrenia-related processes have an impact on brain regions that show significant late developmental changes.

Global and Temporal Cortical Folding in Patients With Early-Onset Schizophrenia

OBJECTIVE Adult-onset schizophrenia has repeatedly been associated with disturbances in the temporal lobes and alterations in cortical folding, which are thought to reflect neurodevelopmental impairment. Early-onset schizophrenia (EOS; onset before 18 years) is considered to involve even more pronounced neurodevelopmental deviance across a wide range of brain structural measures. We hypothesized that overall alteration of cortical folding also applies to EOS, and EOS involves prominent structural aberrations in superior temporal and collateral sulci. METHOD Magnetic resonance T1 images of 51 patients with EOS and 59 healthy participants were investigated. A fully automated method was applied to the images to extract, label, and measure the sulcus area in the whole cortex. Cortical folding was assessed by computing global sulcal indices (the ratio between total sulcal area and total outer cortex area) for each hemisphere and local sulcal indices (the ratio between the area of labeled sulcus and total outer cortex area in the corresponding hemisphere) for superior temporal and collateral sulci. RESULTS Relative to healthy individuals, patients with EOS had significantly lower global sulcal indices in both hemispheres and a lower local sulcal index in the left collateral sulcus. CONCLUSIONS Reduced hemispheric sulcation appears to be a feature of schizophrenia, irrespective of age at onset. Structural aberration involving the left collateral sulcus may contribute to neurobiological substrate of EOS.

Deficits in visual sustained attention differentiate genetic liability and disease expression for Schizophrenia from Bipolar Disorder

BACKGROUND There is mounting evidence for shared genetic liability to psychoses, particularly with respect to Schizophrenia (SZ) and Bipolar Disorder (BD), which may also involve aspects of cognitive dysfunction. Impaired sustained attention is considered a cardinal feature of psychoses but its association with genetic liability and disease expression in BD remains to be clarified. METHODS Visual sustained attention was assessed using the Degraded Symbol Continuous Performance Test (DS-CPT) in a sample of 397 individuals consisting of 50 remitted SZ patients, 119 of their first degree relatives, 47 euthymic BD patients, 88 of their first degree relatives and 93 healthy controls. Relatives with a personal history of schizophrenia or bipolar spectrum disorders were excluded. Performance on the DS-CPT was evaluated based on the response criterion (the amount of perceptual evidence required to designate a stimulus as a target) and sensitivity (a signal-detection theory measure of signal/noise discrimination). RESULTS We found no effect of genetic risk or diagnosis for either disorder on response criterion. In contrast, impaired sensitivity was seen in SZ patients and to a lesser degree in their relatives but not in BD patients and their relatives. These findings were not attributable to IQ, medication, age of onset or duration of illness. CONCLUSIONS Our results argue for the specificity of visual sustained attention impairment in differentiating SZ from BD. They also suggest that compromised visual information processing is a significant contributor to these deficits in SZ.

A preliminary investigation of schematic beliefs and unusual experiences in children

BACKGROUND In cognitive models of adult psychosis, schematic beliefs about the self and others are important vulnerability and maintaining factors, and are therefore targets for psychological interventions. Schematic beliefs have not previously been investigated in children with distressing unusual, or psychotic-like, experiences (UEDs). The aim of this study was firstly to investigate whether a measure of schematic beliefs, originally designed for adults with psychosis, was suitable for children; and secondly, to examine the association of childhood schematic beliefs with internalising and externalising problems and with UEDs. METHOD Sixty-seven children aged 8-14 years, with emotional and behavioural difficulties, completed measures of UEDs, internalising (depression and anxiety), and externalising (conduct and hyperactivity-inattention) problems, together with the Brief Core Schema Scales (BCSS). RESULTS The BCSS was readily completed by participants, and scale psychometric properties were good. Children tended to view themselves and others positively. Internalising and externalising problems and UEDs were all associated with negative schematic beliefs; effect sizes were small to medium. CONCLUSIONS Schematic beliefs in young people can be measured using the BCSS, and negative schematic beliefs are associated with childhood psychopathology and with UEDs. Schematic beliefs may therefore form a useful target in psychological interventions for young people with UEDs.

Psychological interventions for adolescent psychosis: A pilot controlled trial in routine care

PURPOSE Evidence for the recommendation to deliver Cognitive Behavioural Therapy (CBT) and Family Interventions (FI) to under-18s with psychosis derives from adult research, and no previous study has focused exclusively on an adolescent population. We evaluated adaptations of these therapies for adolescent inpatients with psychosis (CBTpA and FIpA), delivered as an adjunct to inpatient standard care (SC). SUBJECTS AND METHODS Thirty adolescent inpatients with psychotic symptoms on admission were sequentially allocated to receive CBTpA+SC (n=10); FIpA+SC (n=10) or SC alone (n=10). Psychotic symptoms and functioning were measured at admission and discharge. RESULTS Group comparisons did not reach conventional significance, but effect sizes in this pilot study showed a promising impact of CBTpA compared to SC alone, in reducing symptoms (ES: d=0.6), with smaller effect sizes for functioning (d=0.2) and for FIpA (symptoms, d=0.1 and functioning, d=0.4). There was no advantage of either additional treatment in reducing length of stay, but self-report satisfaction ratings were higher for both psychological therapies. DISCUSSION AND CONCLUSIONS The study is the first to focus on an exclusively adolescent population, using appropriately adapted therapy protocols. Findings suggest that the interventions are feasible, acceptable and helpful for adolescents with psychosis. Larger randomised controlled trials are now needed.

P03-111 - Does antipsychotic medication affect white matter in schizophrenia and bipolar disorder? a review of diffusion tensor imaging literature

Introduction White matter (WM) abnormalities are considered integral to the pathophysiology of Schizophrenia (SZ) and Bipolar Disorder (BD), but there is ongoing uncertainty about the contribution of medication to these findings. Objectives Diffusion Tensor Imaging (DTI) is a neuroimaging technique that provides quantitative indices of the structural and orientational characteristics of WM. These indices include mean diffusivity (MD), which is a directionally averaged measure of the apparent diffusion coefficient, and fractional anisotropy (FA), which summarizes the orientational dependence of diffusivity. We wanted to determine if these indices are affected by antipsychotic medication. Aims Our aim was to examine the available literature in order to differentiate antipsychotic effects from disorder-specific WM abnormalities on DTI measures. Methods We conducted a systematic qualitative review of the DTI literature in Bipolar Disorder (BD) and Schizophrenia (SZ), between 1998 and 2010 and included only studies where the relationship between DTI measures and antipsychotic medication was explicitly examined and reported. Results We identified 40 studies in SZ and 8 in BD. All studies were cross-sectional and involved relatively small patient samples. 32 studies (80%) did not find any relationship between antipsychotic medication (dose, cumulative exposure) and FA or MD. Conclusions Current evidence does not indicate a major impact of antipsychotic treatment on DTI indices of WM integrity. However, the lack of longitudinal, within-subject designs is a major gap in the current literature.

The role of ethnicity and diagnosis in rates of adolescent psychiatric admission and compulsory detention: a longitudinal case-note study

Objectives To explore whether ethnic variations in psychiatric admission and detention reported for adults also apply to adolescents and to establish the influence of diagnosis. Design A longitudinal, case-note study over a 10-year period. Setting An adolescent inpatient psychiatric unit in London. Participants All adolescents admitted to the unit. Main outcome measures Rates of admission and detention under the Mental Health Act, according to catchment area population. Results Young Black people were nearly six times more likely than the White group to be admitted with psychosis but showed no increase in admission for non-psychotic conditions. Young people in the Other group were over three times more likely to be admitted with psychosis but showed only a modest increase in admission with non-psychotic conditions. Young Asians were over twice as likely to be admitted with psychosis but were only one-third as likely to be admitted with non-psychotic conditions. Young people with psychosis in the Black and Other groups were around three times more likely to have been detained, but there were no significant differences for non-psychotic conditions. Conclusions Significant ethnic variation was found in the rates of admission and detention for adolescents. However, diagnosis was also an important consideration and must be taken into account when examining for evidence of ethnic bias in the use of mental health services by young people. Further investigation is required to establish whether adolescent care pathways are providing a safe and appropriate level of inpatient care for all ethnic groups.