Retinal function anomalies in young offspring at genetic risk of schizophrenia and mood disorder: The meaning for the illness pathophysiology.

BACKGROUND: Visual defects are documented in psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder. One of the most consistent alterations in patients is a change in cone and rod electroretinographic (ERG) responses. We previously showed a reduced rod b-wave amplitude in a small sample of young offspring born to an affected parent. A confirmation of the patients ERG anomalies in young offspring at high genetic risk would offer a new approach to the neurodevelopmental investigation of the illness. We thus investigated cone and rod responses in a larger sample of young healthy high-risk offspring. METHODS: The ERG was recorded in 99 offspring of patients having DMS-IV schizophrenia, bipolar or major depressive disorder (mean age 16.03; SD 6.14) and in 223 healthy controls balanced for sex and age. The a- and b-wave latency and amplitude of cones and rods were recorded. RESULTS: Cone b-wave latency was increased in offspring (ES = 0.31; P = 0.006) whereas rod b-wave amplitude was decreased (ES = -0.37; P = 0.001) and rod latency was increased (ES = 0.35; P = 0.002). CONCLUSIONS: The ERG rod and cone abnormal response previously reported in adult patients having schizophrenia, bipolar disorder or major depressive disorder are detectable in genetically high-risk offspring as early as in childhood and adolescence. Moreover, a gradient of effect sizes among offspring and the three adult diagnoses was found in the cone response. This suggests that ERG waveform as a risk endophenotype might become part of the definition of a "childhood risk syndrome".

The Electroretinogram May Differentiate Schizophrenia From Bipolar Disorder.

BACKGROUND: The retina is recognized as an approachable part of the brain owing to their common embryonic origin. The electroretinogram (ERG) has proved to be a valuable tool to investigate psychiatric disorders. We therefore investigated its accuracy as a tool to differentiate schizophrenia (SZ) from bipolar disorder (BP) even after balancing patients for their main antipsychotic medication. METHODS: ERG cone and rod luminance response functions were recorded in 150 patients with SZ and 151 patients with BP and compared with 200 control subjects. We created a subgroup of subjects-45 with SZ and 45 with BP-balanced for their main antipsychotic medication. RESULTS: A reduced cone a-wave amplitude and a prolonged b-wave latency were observed in both disorders, whereas a reduced cone b-wave amplitude was present in SZ only. Reduced mixed rod-cone a- and b-wave amplitudes were observed in both disorders. Patients with SZ were distinguishable from control subjects with 0.91 accuracy, 77% sensitivity, and 91% specificity with similar numbers for patients with BP (0.89, 76%, and 88%, respectively). Patients with SZ and patients with BP could be differentiated with an accuracy of 0.86 (whole sample) and 0.83 (subsamples of 45 patients with 80% sensitivity and 82% specificity). Antipsychotic dosages were not correlated with ERG parameters. CONCLUSIONS: The ERG waveform parameters used in this study provided a very accurate distinction between the two disorders when using a logistic regression model. This supports the ERG as a tool that could aid the clinician in the differential diagnosis of SZ and BP in stabilized medicated patients.

Cognitive structure from childhood to adulthood in kindreds densely affected by schizophrenia and bipolar disorder.

The developmental aspects of cognitive structures from childhood until adulthood and across different levels of risk for psychopathology have been little studied. The aim of the current study was to explore the cognitive factorial structure in subsamples from highly familial and densely affected kindreds of schizophrenia and bipolar disorder - i.e. affected adult members, non-affected adult members and high-risk youth. The same neuropsychological battery was administered in a sample of 480 participants: schizophrenia and bipolar patients (n=51), young high-risk offspring (n=61), non-affected adult relatives of patients (n=96), and controls (n=272). Exploratory Factorial Analysis was performed in the control sample and yielded a 5-factor solution: verbal comprehension, processing speed/working memory, visual learning and memory, verbal learning and memory, reasoning and problem solving. Confirmatory factor analysis indicated that the hierarchical 5-factor solution was well suited for the young high-risk offspring, the non-affected adult relatives of patient and the patients. A hierarchical model with a "g" factor was a good fit for all subsamples. These results suggest that cognitive impairments may aggregate in highly familial individuals.

Childhood abuse and neglect may induce deficits in cognitive precursors of psychosis in high-risk children.

BACKGROUND: Millions of children are born to parents affected by major psychoses. Cognitive dysfunctions seen in patients are already detectable in these children. In parallel, childhood maltreatment increases the risk of adult psychoses through unknown mechanisms. We investigated whether high-risk offspring exposed to abuse/neglect displayed more cognitive precursors of adult psychoses in childhood and adolescence than nonexposed offspring. METHODS: We used a stepwise selection strategy from a 25-year follow-up of 48 densely affected kindreds including 1500 adults (405 patients with schizophrenia or bipolar disorder) to select high-risk offspring aged 6-22 years for inclusion in our study. All offspring were assessed for childhood trauma from direct interviews with the offspring, parents and relatives and from the review of lifetime medical records of parents and children and administered a neuropsychological battery including IQ and 4 of the most impaired neuropsychological domains in psychoses. RESULTS: Our study included 66 high-risk offspring. Those who were exposed to abuse/neglect had significantly lower IQ (effect size [ES] = 0.61) than nonexposed offspring and displayed poorer cognitive performance in visual episodic memory (ES = 0.67) and in executive functions of initiation (ES = 1.01). Moreover, exposed offspring presented more combinations of cognitive deficits that were associated with lower Global Assessment of Functioning scores. LIMITATIONS: Exposure to abuse/neglect was not assessed in the control group, thus the study could not test whether the effect of childhood maltreatment occurred only in a high-risk setting and not in the general population. CONCLUSION: In high-risk youths, maltreatment in childhood/adolescence may negatively impact cognitive domains known to be impaired in adults with psychoses, suggesting an early mediating effect in the association between abuse/neglect and adult psychoses. This finding provides a target for future developmental and preventive research.

Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder.

This study introduces a novel way to use the lifetime ratings of symptoms of psychosis, mania and depression in genetic linkage analysis of schizophrenia (SZ) and bipolar disorder (BP). It suggests using a latent class model developed for family data to define more homogeneous symptom subtypes that are influenced by a smaller number of genes that will thus be more easily detectable. In a two-step approach, we proposed: (i) to form homogeneous clusters of subjects based on the symptom dimensions and (ii) to use the information from these homogeneous clusters in linkage analysis. This framework was applied to a unique SZ and BP sample composed of 1278 subjects from 48 large kindreds from the Eastern Quebec population. The results suggest that our strategy has the power to increase linkage signals previously obtained using the diagnosis as phenotype and allows for a better characterization of the linkage signals. This is the case for a linkage signal, which we formerly obtained in chromosome 13q and enhanced using the dimension mania. The analysis also suggests that the methods may detect new linkage signals not previously uncovered by using diagnosis alone, as in chromosomes 2q (delusion), 15q (bizarre behavior), 7p (anhedonia) and 9q (delusion). In the case of the 15q and 2q region, the results coincide with linkage signals detected in other studies. Our results support the view that dissecting phenotypic heterogeneity by modeling symptom dimensions may provide new insights into the genetics of SZ and BP.

Young offspring at genetic risk of adult psychoses: the form of the trajectory of IQ or memory may orient to the right dysfunction at the right time.

OBJECTIVE: Neurocognitive dysfunctions analogous to those of adult patients have been detected in children at risk of schizophrenia and bipolar disorder. This led to the following developmental question: Do IQ and memory impairments exhibit different developmental courses from childhood to young adulthood in terms of stability or fluctuations? METHODS: In a high risk sample, we used a step by step sampling approach to narrow-down the early disease mechanisms. Upstream, we started with a 20-year follow-up of 48 densely affected multigenerational kindreds, including 1500 clinically characterized adult members. We then identified 400 adult members affected by a DSM-IV schizophrenia or bipolar disorder. Downstream, we finally focused on 65 offspring (of an affected parent) aged 7 to 22, who were administered a neuropsychological battery. We then constructed cross-sectional trajectories that were compared to those of controls. RESULTS: The childhood IQ deficit displayed a stability until young adulthood. The delay in visual memory exhibited a non-linear two-stage trajectory: a lagging period during childhood followed by a recuperation period from adolescence until adulthood, as supported by a significant Group x Age Periods interaction. No data suggested deterioration between 7 and 22. CONCLUSION: In these offspring at genetic risk, the developmental trajectory of global IQ impairment may not apply to specific domains of cognition such as episodic memory. Different cognitive dysfunctions would mark different developmental courses. The shape of the trajectories might itself have a meaning and provide empirical leads for targeting the right dysfunction at the right time in future prevention research.