Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed. Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. Interpretation: As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

Maternal psychopathology and early child temperament predict young children's salivary cortisol 3 years later.

Neuroendocrine dysfunction is hypothesized to be an early emerging vulnerability marker for depression. We tested whether the main and interactive effects of maternal psychopathology and early child temperamental vulnerability for depression assessed at age three predicted offspring's basal cortisol function at age 6 years. 228 (122 males) children participated in the baseline and follow-up assessments. At age three, maternal lifetime psychopathology was assessed with a diagnostic clinical interview, and child temperamental positive affectivity (PA) and negative affectivity (NA) were assessed using laboratory observations. At age six, children's waking and evening cortisol were assessed on 2 days. Maternal lifetime anxiety predicted offspring's higher morning cortisol at age six. Child temperamental NA at age three predicted higher evening cortisol at age six. There was a significant interaction between maternal lifetime depression and child temperamental PA at age three in predicting offspring's morning cortisol at age six. For the offspring of mothers with lifetime depression, higher PA at age 3 predicted lower morning cortisol at age 6. These findings highlight the importance of examining the main and interactive effects of maternal psychopathology and early child temperamental vulnerability in predicting the development of offspring's stress physiology. Findings hold significance in identifying etiological mechanisms of risk and delineating the complex developmental pathways to psychopathology.

Temperamental emotionality in preschool-aged children and depressive disorders in parents: associations in a large community sample.

Researchers and clinicians have long hypothesized that there are temperamental vulnerabilities to depressive disorders. Despite the fact that individual differences in temperament should be evident in early childhood, most studies have focused on older youth and adults. We hypothesized that if early childhood temperament is a risk factor for depressive disorders, it should be associated with better established risk markers, such parental depression. Hence, we examined the associations of laboratory-assessed positive emotionality (PE), negative emotionality (NE), and behavioral inhibition (BI) with semistructured interview-based diagnoses of parental depressive disorders in a community sample of 536 3-year old children. Children with higher levels of NE and BI had higher probabilities of having a depressed parent. However, both main effects were qualified by interactions with child PE. At high and moderate (but not low) levels of child PE, greater NE and BI were associated with higher rates of parental depression. Conversely, at low (but not high and moderate) levels of child NE, low PE was associated with higher rates of parental depression. Child temperament was not associated with parental anxiety and substance use disorders. These findings indicate that laboratory-assessed temperament in young children is associated with parental depressive disorders; however, the relations are complex, and it is important to consider interactions between temperament dimensions rather than focusing exclusively on main effects.