Marinos Kyriakopoulos

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.

A Diffusion Tensor Imaging Study of White Matter in Early-Onset Schizophrenia

BACKGROUND Voxel-based analysis of diffusion tensor magnetic resonance imaging (DTI) data was used to examine white matter integrity in adolescents with early-onset schizophrenia (EOS), defined as schizophrenia beginning before the 18th birthday. METHODS Nineteen patients with EOS, aged 13 to 19, were compared with 20 healthy volunteers matched for age, gender, and parental socioeconomic status. Diffusion tensor magnetic resonance imaging data were acquired on a GE Signa NVi 1.5 Tesla system (General Electric, Milwaukee, Wisconsin). Maps of fractional anisotropy (FA) were registered into standard space, and group differences were examined using a nonparametric statistical approach. RESULTS In comparison with healthy participants, EOS patients had significantly lower FA in the white matter of the parietal association cortex bilaterally and in the left middle cerebellar penduncle. No areas with significantly higher FA in patients were identified. CONCLUSIONS Parietal and cerebellar white matter abnormalities may contribute to the emergence of psychotic symptoms in adolescence.

Recent diffusion tensor imaging findings in early stages of schizophrenia

Purpose of review Several lines of evidence suggest that the normal integration of cerebral function may be compromised in schizophrenia. Abnormalities in white matter tracts, which connect brain regions into functional networks, may be directly relevant to its pathophysiology. Diffusion tensor imaging (DTI) has increasingly been used to study white matter abnormalities in schizophrenia; in this review, we will discuss recent DTI findings focusing on the early stages of the disorder. Recent findings Deficits in white matter integrity as inferred by DTI appear to be present in the early stages of schizophrenia, even in neuroleptic-naive patients, and may be the result of interaction between illness-related processes and normal development. The pattern of identified abnormalities is not totally consistent across all studies, with frontotemporal, frontoparietal and temporooccipital connections as well as projection fibers and cerebellar white matter being among the affected tracts. Summary Recent DTI findings further support the hypothesis of structural dysconnectivity in schizophrenia. The presence of white matter abnormalities early in the course of the illness is suggestive of these being related to the emergence of the disorder.

Effect of age at onset of schizophrenia on white matter abnormalities

BACKGROUND The pattern of brain morphological changes at the early stages of schizophrenia may depend on the age at onset of illness; in children and adolescents with schizophrenia, grey matter deficits are seen in the parietal lobe whereas in individuals with adult onset these are more widespread. AIMS To examine whether white matter is similarly affected. METHOD Diffusion tensor imaging was used to compare fractional anisotropy measures in individuals with adolescent-onset (n = 17) and adult-onset schizophrenia (n = 17) with those in age- and gender-matched controls. RESULTS Compared with their respective controls, individuals with adolescent-onset schizophrenia showed fractional anisotropy decrease in parietal regions; individuals with adult onset showed additional fractional anisotropy reductions in frontal, temporal and cerebellar regions. A differential effect of age at onset (adolescent v. adult) was noted bilaterally in medial prefrontal white matter. CONCLUSIONS White matter abnormalities in frontal regions in schizophrenia may depend on developmental stage at the time of illness onset.

Pathophysiology of early onset schizophrenia

Early onset schizophrenia (with onset before adulthood) represents a rarer and possibly more severe form of the disorder which has received particular attention in the last two decades. Current evidence strongly suggest continuity with adult onset schizophrenia, with phenomenological, cognitive, genetic and neuroimaging data pointing towards similar neurobiological correlates and clinical deficits but worse long term outcome. Future research in early onset cases is likely to increase further our insight into the neurodevelopmental origins of schizophrenia and the complex gene-environment interactions affecting its emergence.

Adolescents with suicidal and nonsuicidal self-harm: Clinical characteristics and response to therapeutic assessment

Self-harm is one of the best predictors of death by suicide, but few studies directly compare adolescents with suicidal versus nonsuicidal self-harm. Seventy adolescents presenting with self-harm (71% young women, ages 12-18 years) who participated in a randomized controlled trial were divided into suicidal and nonsuicidal self-harm categories using the Columbia Classification Algorithm of Suicide Assessment. Adolescents with suicidal self-harm were more likely than those with nonsuicidal self-harm to be young women, 22/23 (96%) versus 34/47 (72%), odds ratio (OR) = 8.33, 95% confidence interval (CI) [1.03, 50.0]; had a later age of onset of self-harm, 15.4 years vs. 13.8 years, mean difference = 1.6, 95% CI [.8, 2.43]; and used self-poisoning more often, 18/23 (78%) versus 11/47 (23%), OR = 3.43, 95% CI [2.00, 5.89]. Only those with nonsuicidal self-harm had an improvement on Childrens Global Assessment Scale score following a brief therapeutic intervention, mean difference = 8.20, 95% CI [.97, 15.42]. However, there was no interaction between treatment and suicidality. There are important differences between adolescents presenting with suicidal and nonsuicidal self-harm. Suicidal self-harm in adolescence may be associated with a less favorable response to therapeutic assessment.

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.

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.

Antipsychotics use in children and adolescents: An on-going challenge in clinical practice

Antipsychotic medications (APs) are a well-established pharmacological treatment in adults with serious mental health problems. However, many adult mental health disorders have their origins and onset in childhood or adolescence. The understanding that neuropsychiatric conditions of childhood are in part biologically determined, led to an increase in the number of clinical trials supporting evidence on the efficacy of antipsychotic agents as first-line treatment for childhood psychotic disorders and therapeutic augmentation of nonpsychotic conditions. In recent years the use of antipsychotics in children and adolescents for neurodevelopmental, behavioural and psychiatric disorders has significantly increased while the age of prescription has decreased. These trends have not been matched by advances in the understanding of APs’ safety profile in this group of patients. It is therefore crucial that current and future practice is informed by up-to-date synthesis of the evidence and clinical guidelines about the use and monitoring of these treatments in paediatric populations, since the effectiveness of early therapeutic interventions in children can affect positively the long-term outcome.