Nicolas Bodeau

Pre-, peri- and neonatal risk factors for autism.

Objective. To identify pre‐, peri‐ and neonatal risk factors for pervasive developmental disorders (PDD). Methods. We searched the Medline database through March 2011 for relevant case–control and population‐based studies on pre‐, peri‐ and neonatal hazards related to PDD, including autism. We identified 85 studies for this review. Data were extracted systematically and organized according to risk factors related to family history, pregnancy, gestational age, delivery, birth milestones and the neonates condition at birth. Results. During the prenatal period, risk factors for PDD were advanced maternal or paternal ages, being firstborn vs. third or later, maternal prenatal medication use and mothers status as foreign born. During the perinatal and neonatal periods, the risk factors for PDD were preterm birth, breech presentation, planned cesarean section, low Apgar scores, hyperbilirubinemia, birth defect and a birthweight small for gestational age. The influence of maternal pre‐eclampsia, diabetes, vomiting, infections and stress during pregnancy requires further study in order to determine risk for PDD. Discussion. Despite evidence for the association of some pre‐, peri‐ and neonatal risk factors associated with PDD, it remains unclear whether these risks are causal or play a secondary role in shaping clinical expression in individuals with genetic vulnerability. A plausible hypothsesis is that improvements in obstetric and neonatal management have led to an increased rate of survivors with pre‐existing brain damage. Given the variety of risk factors, we propose that future studies should investigate combinations of multiple factors, rather than focusing on a single factor.

Adverse effects of second-generation antipsychotics in children and adolescents: a Bayesian meta-analysis.

Abstract In adults, second-generation antipsychotics (SGAs) have a low frequency of extrapyramidal syndrome (EPS) and a moderate frequency of metabolic adverse effects. Here we aimed to assess short-term adverse effects of SGAs in children and adolescents. We searched for relevant studies in MEDLINE and EMBASE (1996–2010), Food and Drug Administration and European Medicines Agency clinical trial registries, and reference lists of review articles. We found 41 were short-term (3–12 weeks) controlled studies that evaluated SGA adverse effects in youths. Using Bayesian meta-analysis, we analyzed odds ratios (ORs) or mean average effects. Numbers of arms (subjects) in the 41 trials were aripiprazole, 10 (n = 671); olanzapine, 14 (n = 413); quetiapine, 10 (n = 446); risperidone, 25 (n = 1040); ziprasidone, 4 (n = 228); clozapine, 5 (n = 79); and placebo/untreated, 23 (n = 1138), totaling 93 arms (4015 patients). Clozapine was assessed only for weight gain and somnolence. Compared with placebo, significant treatment-related increases were observed for weight gain with olanzapine (mean ± SD = 3.99 ± 0.42 kg; 95% credible interval, 3.17–4.84 kg), clozapine (2.38 ± 1.13 kg; 95% credible interval, 0.19–4.62 kg), risperidone (2.02 ± 0.32 kg; 95% credible interval, 1.39–2.66 kg), quetiapine (1.74 ± 0.38 kg; 95% credible interval, 0.99–2.5 kg), and aripiprazole (0.89 ± 0.32 kg; 95% credible interval, 0.26–1.51 kg); glucose levels with risperidone (3.7 ± 1.36 mg/dL; 95% credible interval, 1.08–6.42 mg/dL) and olanzapine (2.09 ± 1.08 mg/dL; 95% credible interval, 0.13–4.32 mg/dL); cholesterol levels with quetiapine (10.77 ± 2.14 mg/dL; 95% credible interval, 6.6–14.95 mg/dL) and olanzapine (4.46 ± 1.65 mg/dL; 95% credible interval, 1.24–7.73 mg/dL); triglyceride levels with olanzapine (20.18 ± 5.26 mg/dL; 95% credible interval, 9.85–30.53 mg/dL) and quetiapine (19.5 ± 3.92 mg/dL; 95% credible interval, 11.84–27.17 mg/dL); hyperprolactinemia with risperidone (OR, 38.63; 95% credible interval, 8.62–125.6), olanzapine (OR, 15.6; 95% credible interval, 4.39–41.1), and ziprasidone (OR, 9.35; 95% credible interval, 1.24–37.03); and EPS with ziprasidone (OR, 20.56; 95% credible interval, 3.53–68.94), olanzapine (OR, 6.36; 95% credible interval, 2.43–13.84), aripiprazole (OR, 3.79; 95% credible interval, 2.17–6.17), and risperidone (OR, 3.71; 95% credible interval, 2.18–6.02). All SGAs increased the risk of somnolence/sedation. We conclude that short-term metabolic effects and EPS are frequent in children treated with SGAs. Second-generation antipsychotics have distinct profiles of secondary effects, which should be considered in making treatment decisions.

Depression During Pregnancy: Is the Developmental Impact Earlier in Boys? A Prospective Case-Control Study

OBJECTIVE Animal studies have shown sex differences in the impact of prenatal maternal stress on the offspring. The aim of this prospective case-control study was to assess the effect of prenatal depression on newborn and 1-year-old infant characteristics as related to gender, controlling for confounding variables. METHOD We screened 205 pregnant women from April 2004 to November 2006 for depressive symptoms. Inclusion in the prenatal depression group (n = 34) was based on meeting DSM-IV criteria for major depressive episode. We excluded postnatal depression from the control group (n = 79) by routine screening at 2 and 6 months. Newborn and 1-year-old infant characteristics were evaluated with the Neonatal Behavioral Assessment Scale (NBAS) and the Infant-Toddler Social and Emotional Assessment, respectively. RESULTS Despite our use of numerous exclusion criteria (eg, at-risk pregnancy, preterm delivery), prenatal depression highly correlated with anxiety and stress scores. Male newborns of mothers with prenatal depression had lower scores than controls on the motor skills and regulation of states NBAS clusters (P = .03 and P = .026, respectively). At 1 year, infants of prenatally depressed mothers presented higher scores on generalized anxiety (P = .002), particularly in males (P = .009); activity/impulsivity (P = .042); and sleep problems (P = .023) than controls. CONCLUSIONS As in animal studies, depression during pregnancy may affect infant development in a way that is related to gender. Early gender differences observed to be associated with depression, stress, and anxiety during pregnancy may be a key to understanding the higher prevalence in males of child psychiatric disorders.

Prenatal Ultrasound Screening: False Positive Soft Markers May Alter Maternal Representations and Mother-Infant Interaction

Background In up to 5% of pregnancies, ultrasound screening detects a “soft marker” (SM) that places the foetus at risk for a severe abnormality. In most cases, prenatal diagnostic work-up rules out a severe defect. We aimed to study the effects of false positive SM on maternal emotional status, maternal representations of the infant, and mother-infant interaction. Methodology and Principal Findings Utilizing an extreme-case prospective case control design, we selected from a group of 244 women undergoing ultrasound, 19 pregnant women whose foetus had a positive SM screening and a reassuring diagnostic work up, and 19 controls without SM matched for age and education. In the third trimester of pregnancy, within one week after delivery, and 2 months postpartum, we assessed anxiety, depression, and maternal representations. Mother-infant interactions were videotaped during feeding within one week after delivery and again at 2 months postpartum and coded blindly using the Coding Interactive Behavior (CIB) scales. Anxiety and depression scores were significantly higher at all assessment points in the SM group. Maternal representations were also different between SM and control groups at all study time. Perturbations to early mother-infant interactions were observed in the SM group. These dyads showed greater dysregulation, lower maternal sensitivity, higher maternal intrusive behaviour and higher infant avoidance. Multivariate analysis showed that maternal representation and depression at third trimester predicted mother-infant interaction. Conclusion False positive ultrasound screenings for SM are not benign and negatively affect the developing maternal-infant attachment. Medical efforts should be directed to minimize as much as possible such false diagnoses, and to limit their psychological adverse consequences.

Psychiatric and cognitive phenotype of childhood myotonic dystrophy type 1

Aim  To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1).

Are child and adolescent responses to placebo higher in major depression than in anxiety disorders? A systematic review of placebo-controlled trials.

Background In a previous report, we hypothesized that responses to placebo were high in child and adolescent depression because of specific psychopathological factors associated with youth major depression. The purpose of this study was to compare the placebo response rates in pharmacological trials for major depressive disorder (MDD), obsessive compulsive disorder (OCD) and other anxiety disorders (AD-non-OCD). Methodology and Principal Findings We reviewed the literature relevant to the use of psychotropic medication in children and adolescents with internalized disorders, restricting our review to double-blind studies including a placebo arm. Placebo response rates were pooled and compared according to diagnosis (MDD vs. OCD vs. AD-non-OCD), age (adolescent vs. child), and date of publication. From 1972 to 2007, we found 23 trials that evaluated the efficacy of psychotropic medication (mainly non-tricyclic antidepressants) involving youth with MDD, 7 pertaining to youth with OCD, and 10 pertaining to youth with other anxiety disorders (N = 2533 patients in placebo arms). As hypothesized, the placebo response rate was significantly higher in studies on MDD, than in those examining OCD and AD-non-OCD (49.6% [range: 17–90%] vs. 31% [range: 4–41%] vs. 39.6% [range: 9–53], respectively, ANOVA F = 7.1, p = 0.002). Children showed a higher stable placebo response within all three diagnoses than adolescents, though this difference was not significant. Finally, no significant effects were found with respect to the year of publication. Conclusion MDD in children and adolescents appears to be more responsive to placebo than other internalized conditions, which highlights differential psychopathology.

Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement

During adolescence, some individuals with autism spectrum disorder (ASD) engage in severe challenging behaviors, such as aggression, self-injury, disruption, agitation and tantrums. We aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD admitted to a dedicated neurobehavioral unit. We included retrospectively in 2008 and 2009 29 adolescents and young adults with ASD hospitalized for severe challenging behaviors and proposed a guideline (Perisse et al., 2010) that we applied prospectively for 29 patients recruited for the same indications between 2010 and 2012. In total, 58 patients were admitted (n=70 hospitalizations, mean age=15.66 (±4.07) years, 76% male). We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), comorbid organic conditions, etiologic diagnosis of the episode, and treatments. We explored predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge. All but 2 patients exhibited severe autistic symptoms and intellectual disability (ID), and two-thirds had no functional verbal language. During the inpatient stay (mean=84.3 (±94.9) days), patients doubled on average their GAFS scores (mean=17.66 (±9.05) at admission vs. mean=31.4 (±9.48) at discharge). Most common etiologies for acute behavioral crises were organic causes [n=20 (28%), including epilepsy: n=10 (14%) and painful medical conditions: n=10 (14%)], environmental causes [n=17 (25%) including lack of treatment: n=11 (16%) and adjustment disorder: n=6 (9%)], and non-ASD psychiatric condition [n=33 (48%) including catatonia: n=5 (7%), major depressive episode: n=6 (9%), bipolar disorder: n=4 (6%), schizophrenia: n=6 (9%), other/unknown diagnosis: n=12 (17%)]. We found no influence of age, gender, socio-economic status, migration, level of ID, or history of seizure on improvement of GAFS score at discharge. Severity of autism at admission was the only negative predictor (p<.001). Painful medical conditions (p=.04), non-ASD psychiatric diagnoses (p=.001), prior usage of specialized ASD care programs (p=.004), functional language (p=.007), as well as a higher number of challenging behaviors upon admission (p=.001) were associated with higher GAFS scores at discharge. Clinical severity at admission, based on the number of challenging behaviors (r=.35, p=.003) and GAFS score (r=-.32, p=.008) was correlated with a longer inpatient stay. Longer hospitalization was however correlated (r=.27, p=.03) with higher GAFS score at discharge even after adjustment for confounding factors. Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach.

Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk

BackgroundAutism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families.MethodsWe extracted from the Autism Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with relevant medical data (n = 664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven’s Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS).ResultsThe prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4).ConclusionsEpilepsy in multiplex autism may define a different subgroup in terms of clinical characteristics and genetic risk.

Children and adolescents with severe mental illness need vitamin d supplementation regardless of disease or treatment

BACKGROUND To protect against osteoporosis, keeping the vitamin D blood level (25[OH]D; VDBL) above 30 ng/mL is recommended. It is established that regular intake of vitamin D, calcium intake, and physical exercise contribute to maximizing bone mineral mass during childhood and adolescence. Recent articles suggest that patients with schizophrenia treated with antipsychotics have low VDBL and may have a higher risk of hip fractures in their later years than the general population. OBJECTIVES To evaluate whether adolescent psychiatric inpatient VDBL is lower than the 30-ng/mL optimal threshold and to document low-VDBL risk factors. METHOD We determined the VDBL of all consecutive inpatients from three adolescents units in 2009 (N = 136). Univariate analyses explored the influence on VDBL of (1) well-documented risk factors (e.g., age, gender, ethnic origin, body mass index, or season) and (2) suspected risk factors (e.g., disease type or antipsychotic treatment). RESULTS All but six patients had a VDBL <30 ng/mL (mean [ ± SD]: 15.9 [ ± 8.4] ng/mL). VDBL was significantly lower for all patients during the first quarter of the year compared to the other three (all p < 0.01). VDBL was also lower for blacks/North Africans 12.8 (±7.0) than for Caucasians/Europeans 17.2 (±8.5): t = 2.62, p = 0.009. We found no differences between patients regarding disease category (K = 3.75, p = 0.154) or antipsychotic treatment (t = 0.127, df = 124, p = 0.89). CONCLUSION VDBL in an adolescent population with severe mental illness is lower than current recommendations of optimal level for bone health regardless of treatment or disease type. Because adolescence is a period of bone construction and could represent a critical window of opportunity for maximizing bone mass, especially among patients with severe mental illness, we recommend vitamin D supplementation.

A Multidimensional Approach to the Study of Emotion Recognition in Autism Spectrum Disorders

Although deficits in emotion recognition have been widely reported in autism spectrum disorder (ASD), experiments have been restricted to either facial or vocal expressions. Here, we explored multimodal emotion processing in children with ASD (N = 19) and with typical development (TD, N = 19), considering uni (faces and voices) and multimodal (faces/voices simultaneously) stimuli and developmental comorbidities (neuro-visual, language and motor impairments). Compared to TD controls, children with ASD had rather high and heterogeneous emotion recognition scores but showed also several significant differences: lower emotion recognition scores for visual stimuli, for neutral emotion, and a greater number of saccades during visual task. Multivariate analyses showed that: (1) the difficulties they experienced with visual stimuli were partially alleviated with multimodal stimuli. (2) Developmental age was significantly associated with emotion recognition in TD children, whereas it was the case only for the multimodal task in children with ASD. (3) Language impairments tended to be associated with emotion recognition scores of ASD children in the auditory modality. Conversely, in the visual or bimodal (visuo-auditory) tasks, the impact of developmental coordination disorder or neuro-visual impairments was not found. We conclude that impaired emotion processing constitutes a dimension to explore in the field of ASD, as research has the potential to define more homogeneous subgroups and tailored interventions. However, it is clear that developmental age, the nature of the stimuli, and other developmental comorbidities must also be taken into account when studying this dimension.