Development of the GABAergic system from birth to adolescence

The neurotransmitter GABA (γ-aminobutyric acid), acting via inotropic GABA(A) and metabotropic GABA(B) receptors, plays an essential role in a variety of distinct neuronal processes, including regulation of neuronal excitability, determination of temporal aspects of spike trains, control of the size and propagation of neuronal assemblies, generation of oscillatory activity, and neuronal plasticity. Although the developmental switch between excitatory and inhibitory GABA(A) receptor-mediated responses is widely appreciated, the fact that the postnatal maturation of the GABAergic system lasts until late adolescence is not so persuasively promoted. This review summarizes recent knowledge of the maturation of various aspects of the GABAergic systems, like functional expression of GABA synthesizing/degrading enzymes and transporters, density of GABAergic synapses, GABAergic projection patterns, GABA receptor subunit composition, and properties of GABAergic interneurons, with an emphasis on the late developmental alterations. In addition, some aspects of the development of mental capabilities during adolescence and their relation the delayed maturation of the GABAergic system are presented.     

Stability and prediction of schizophrenia from adolescence to adulthood

Stability of schizophrenia diagnosis from adolescence to adulthood, antecedents of schizophrenia, and differences in developmental and behavioural histories between subjects with early onset schizophrenia (EOS) and with adult onset schizophrenia (AOS) were investigated in 145 adult subjects diagnosed with mental disorders in adolescence and re-diagnosed on the basis of medical records according to DSM-IV.A very high diagnostic stability schizophrenia was demonstrated at the 28-year follow-up.Several factors, including neurological adversities, delayed language development, low IQ, and congenital functional disability, differentiated significantly between schizophrenic subjects and non-schizophrenic subjects.Histories of concussion, physical abuse, parental divorce, and unstable familial context differentiated significantly between EOS and AOS subjects.Our findings support earlier evidence of schizophrenia being a chronic disorder with high diagnostic stability, and confirm the importance of neurological adversities, delayed language development, and low IQ as factors predictive of schizophrenia.Exploration of four case histories of AOS subjects delineates "pre-schizophrenic warning cluster" where combination of neurological adversities, temperamental problems, antisocial behaviour, preference for solitary play, and unstable family system constitute main factors.     

Neurobehavioral deficits at adolescence in children at risk for schizophrenia: The Jerusalem Infant Development Study.

BACKGROUND: The Jerusalem Infant Development Study is a prospective investigation comparing offspring of schizophrenic parents with offspring of parents who have no mental disorder or have nonschizophrenic mental disorders. During infancy and school age, a subgroup of offspring of schizophrenic parents showed global neurobehavioral deficits that were hypothesized to be indicators of vulnerability to schizophrenia. The purposes of the present investigation were to determine if neurobehavioral deficits were present in the offspring of schizophrenics at adolescence, to examine their stability over time, and to explore their relation to concurrent mental adjustment. METHODS: Sixty-five Israeli adolescents were assessed on a battery of neurologic and neuropsychological assessments. They were also administered psychiatric interviews from which best-estimate DSM-III-R diagnoses and scores of global adjustment were derived. RESULTS: Adolescents with poor neurobehavioral functioning were identified from composites of motor and cognitive-attentional variables. A disproportionate number of offspring of schizophrenic parents (42%; 10/24), and especially male offspring of schizophrenic parents (73%; 8/11), showed poor neurobehavioral functioning relative to offspring of nonschizophrenic parents (22%; 9/41). Adolescent offspring of schizophrenics with poor neurobehavioral functioning had been poorly functioning at earlier ages and had poor psychiatric adjustment at adolescence. All 4 offspring of schizophrenics receiving schizophrenia spectrum diagnoses by adolescence showed a pattern of poor neurobehavioral functioning across developmental periods. CONCLUSIONS: Results are consistent with the hypothesis that individuals at genetic risk for schizophrenia may display lifelong neurobehavioral signs that are indicators of vulnerability to schizophrenia and that are associated with psychiatric adjustment generally and schizophrenic spectrum disorder specifically.     

Developmental changes in functional brain networks from birth through adolescence

Investigation of the brain connectome using functional magnetic resonance imaging (fMRI) and measures derived from graph theory analysis has emerged as a new approach to study brain development, cognitive function, and neurophysiological disorders. Here we use graph theory analysis to examine the influence of age, sex, and neurocognitive measures on developmental changes to the global and regional topology of functional brain networks derived from fMRI data recorded in 189 healthy subjects from the age of 0–18 years during rest. We observed that Global Efficiency and Rich‐Club coefficient increased with age and Local Efficiency and Small‐Worldness decreased with age, while Modularity at the global level showed an inverted U‐shaped trajectory during development. Marginally significant differences were observed in Local Efficiency, Small‐Worldness, and Modularity at a global level between boys and girls throughout development. We also examine the effects of neurocognitive measures in boys and girls globally and locally. Our results provide new insight to understand brain maturation of functional brain connectome and its relation to cognitive development from birth through adolescence.     

Attachment theory and clinical implications for at-risk children

Recent research describes attachment behavior as a resilient and complex biosocial, interactional phenomenon. The attachment bond is considered to be more plastic than originally conceived, and the role of mothers per se is less critical than responsive, stable caretaking. These recent findings are reviewed and a series of implications for clinical interventions with at-risk children are offered.     

The patterns of schizophrenia in adolescence

Summary A survey is presented of the patterns of schizophrenia seen in adolescent girls. A preliminary study of 50 cases indicates that there are three types based on differences in pre-psychotic development. Each group has special features in diagnosis, prognosis, and treatment.From the psychiatric division of Bellevue Hospital, New York, N.Y.     

N-acetylcysteine as a potentially useful medication to prevent conversion to schizophrenia in at-risk individuals

Schizophrenia is a chronic and often severe psychotic disorder. Its causes include imbalances in mediators involved in neuroplasticity, apoptosis, cell resilience and dendritic arborization. Among these mediators, oxidative species are particularly relevant for the pathophysiology of the disease, and this is the rationale for experimental use of antioxidant medications, such as N-acetylcysteine (NAC). Onset of schizophrenia is usually preceded by a period of subtle and unspecific symptoms, the prodrome, in which preventive interventions could delay or even stop the progression to full-blown psychosis. In this article, we propose that NAC could be a useful medication to prevent evolution of schizophrenia in individuals at risk for psychosis.     

Development of emotional autonomy from adolescence to young adulthood in Spain

The main objective of this study was to learn whether emotional autonomy is truly part of a developmental stage for Spanish adolescents and young adults or if it is an indicator of difficult family relationships. Using a longitudinal design, a sample of ninety young people was followed for ten years, from their initial adolescence until their first years of adulthood. At four observation points, the participants completed various questionnaires to evaluate their emotional autonomy, the cohesion in their family relationships and their life satisfaction. There were no gender differences in the development of emotional autonomy. Family cohesion and life satisfaction showed significant negative associations with emotional autonomy and these associations became more pronounced as participants moved from adolescence into adulthood. Based on our results, emotional autonomy from parents does not seem to be a developmental stage taking place during adolescence, but rather, an indicator of difficult family relationships.     

The development of schizophrenia in late adolescence

Adolescence is an unusual psychologic time. A recent psychodevelopmental approach to psychosis attempted to show how psychotic signs might arise from typical features of adolescence; for example, delusions appear to reflect common adolescent themes of attachment and autonomy. This psychodevelopmental approach emphasizes how normal adolescents grow out of a natural egocentricity and idealism through learning about others; this theory converges with more recent neurologic theories. (Such neurologic theories agree that mentalizing-for others abilities are a crucial mechanism whereby the suspected neurologic problems of psychosis translate into the symptoms.) A psychodevelopmental account implies a therapeutic priority would be reattaching psychosis sufferers with their peer group, perhaps through work placement schemes. It also recommends cognitive work directing self-consciousness into understanding other people. Psychodevelopmental approaches offer a useful theoretic background for psychologic interventions with young “at risk” people.     

Seasonality of birth in schizophrenia

Summary The seasonality of birth in 142 schizophrenics from Barcelona (Spain) has been studied, showing a pattern similar to that described by other authors, with a maximum in winter. If sample is compared with the local general population there are significant differences, but these disappear when the comparison is made with a control population properly stratified by age, sex, place of birth, place of residence and social status. The same results are obtained using statistical methods suggested by other authors. The seasonality pattern usually obtained in schizophrenia could be due to a selective stratification of the ill population based on variables that might or might not be related to illness.     

Development and predictors of mental ill-health and wellbeing from childhood to adolescence

Purpose

The aim is to investigate the (1) longitudinal development in mental ill-health and wellbeing from ages 11 to 14, (2) predictors of changes in mental health outcomes, and (3) sex and reporter differences.

Method

Data are taken from 9553 participants in the Millennium Cohort Study, with both mental ill-health (parent- and self-report) and wellbeing outcomes of the cohort members measured at ages 11 and 14. A range of childhood socio-demographic, human capital, family and wider environment risk and protective factors are investigated.

Results

Wellbeing has weak stability and mental ill-health has moderate stability between ages 11 and 14 and large sex differences emerge in all the mental health outcomes investigated, with girls experiencing lower wellbeing and greater symptoms of mental illness at age 14. Raw associations between outcomes, and differences in their predictors, indicate varying patterns emerging for parent- and self-reported mental ill-health, with parent-reported symptoms in childhood a poor predictor of both self-reported wellbeing and depressive symptoms in adolescence. Investigating the emergent sex differences in prevalences highlights childhood risk and protective factors at this age that are more salient in females, including family income, school connectedness, cognitive ability, whereas peer relationships and bullying were equally relevant for mental health development in both males and females.

Conclusion

Low–moderate stability of mental health outcomes stresses the importance of the transition period for mental health, highlighting an intervention window at these ages for prevention. Socio-economic status is associated with mental health development in females but not in males at this age, highlighting a sex-specific vulnerability of deprivation associated with poorer mental health in adolescent females.

     

Neurocognitive performances in participants of at-risk mental state for schizophrenia and in first-episode patients

As suggested by the neurodevelopmental model, neurocognitive disturbances are core features of schizophrenia spectrum disorders. The aim of the present study was to explore the neurocognitive performance of symptomatically defined high-risk participants as well as first-episode patients on tests of verbal memory, executive functioning, working memory, and attention. The sample consisted of 54 participants at risk for schizophrenia and 37 patients with a first episode of psychosis. The high-risk group exhibited a similar cognitive performance profile to that of the first-episode participants when compared with normative data. The neurocognitive functioning of both patient groups were within standard average range at most of the cognitive domains. Moreover the intellectual functioning of both groups was within higher average level, while decreased "hit rates" could be observed within both subtests "Figures" and "Symbols" of the Continuous Performance Test-Identical Pairs Version (CPT-IP) in the group of first-episode patients. Direct comparison between the clinical groups did show increasing impairments of these parameters in first-episode patients compared to high-risk participants. Results suggest that high-risk participants do perform at average neurocognitive performance levels at all tested domains compared with normative data. Compared to norm values first-episode patients showed decreased attention abilities.     

Risk factor clustering for psychopathology in socially at-risk Spanish children

BACKGROUND: Data based on general population studies of exposure-to-risk factors is not adequate to describe the mental health of children living in the most extreme "high-risk" environments. METHODS: Data were collected in a longitudinal prospective study of two cohorts of 9 and 13 year-old socially at-risk children. Cluster analysis was used to classify youths based on the reports about potential areas of risk. The psychopathological structure of empirical clusters was compared through cross-sectional and longitudinal epidemiological indexes and through multiple regression and multivariate analysis of variance. RESULTS: Cluster analysis provided eight binary high-low risk classifications. Exposure to risk was highly prevalent. In preadolescence, broken family, parenting style and contextual profiles were the highest risk factors for psychopathology. In adolescence, they were psychological variables, verbal comprehension, pre-peri-postnatal history, physical health and family characteristics. Cumulative risk followed a linear trend for psychopathology and functional impairment. The child's perception of low marital discord and good school achievement were protective factors. CONCLUSIONS: Extreme socially at-risk populations have specific profiles of risk that can be identified through a person-centered approach and may be amenable to selective preventive interventions.     

Late adolescence and young adulthood -- their etiopathogenetic significance for schizophrenia

The significant upsurge of schizophrenic illness manifestations during adolescence and young adulthood is a core finding of epidemiological research in schizophrenia. The reasons are probably manifold, so far, however, not well understood. From the perspective of neurobiological maturation, processes of neuronal reorganisation in cortical and subcortical structures are hot topics. Aberrant forms of pruning, sprouting and myelinization may play a major role in the pathogenesis of a schizophrenic breakdown. The consequences for the pathophysiology of schizophrenia have to be considered. Models of neuroplasticity during adolescence can be connected with models of a neurodevelopmental vulnerability and models of neurotoxicity within an integrated aproach in order to better understand premorbid adjustment, onset, and course of schizophrenic illness. From the perspective of psychosocial development, prominent developmental tasks have to be considered, which form a major challenge to all adolescents, bearing, however, special risks for some adolescents. Patterns of psychosocial adaptation found during this developmental period must be considered in their long-term consequences. Neurobiological reorganisation and psychosocial transformation are both sides of one developmental process during adolescence and young adulthood.     

Reduction of auditory event-related P300 amplitude in subjects with at-risk mental state for schizophrenia

Neurophysiological methods allow the examination of cognitive-cortical functioning in patients with schizophrenia in its prodromal states. As revealed by previous studies, event-related potential components such as auditory evoked P300 associated with cognitive processes, such as attention and orientation, are known to be reduced in amplitude in acute and chronic as well as in medicated and unmedicated patients. It is, however, unclear whether a P300 amplitude reduction occurs before the schizophrenic psychosis is fully manifested. We studied patients in the prodromal phase of the schizophrenic disorder (i.e. subjects with an at-risk mental state showing attenuated psychotic symptoms or brief limited intermittent symptoms) as well as first-episode patients and chronic patients with schizophrenia and compared these groups to healthy subjects. The event-related P300 was recorded during an auditory oddball paradigm. Groups differed significantly from each other in the P300 amplitude at Pz (F(3/149)=2.532, p=0.02). Post-hoc tests revealed significantly lower P300 amplitudes of non-medicated prodromal (p=.03), first-episode (p=.01) and chronic patients (p=.001) compared to the healthy controls. The study revealed that there are neurophysiological changes as the reduction in P300 amplitudes begins early in schizophrenia at the prodromal phase, i.e. before a manifestation of full-blown psychosis, and that these changes seem to have a progressive course from prodromal to chronic state of schizophrenia as assumed in this cross-sectional study.