Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial.

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7-18 years; 24.6% males) was treated with fluoxetine (10-40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208-328 ng/mL (transdiagnostically) and 201.5-306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose-serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.

Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder.

BACKGROUND: Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. METHOD: This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7-18 years) within the prospective multicenter "TDM-VIGIL" project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. RESULTS: A strong linear positive dose-serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. CONCLUSIONS: This TDM-flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug-drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry.

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice.

INTRODUCTION: Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. METHODS: Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. RESULTS: 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4-10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). CONCLUSION: Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings.

Psychiatric Comorbidities in 1p36 Deletion Syndrome and Their Treatment-A Case Report.

1p36 deletion syndrome represents the most common terminal deletion observed in humans. Major clinical findings comprise developmental delay/intellectual disability, poor or absent expressive language, congenital central muscular hypotonia, brain anomalies, brachydactyly/camptodactyly, short feet, and characteristic facial features like straight eyebrows, deep-set eyes, and midface hypoplasia. So far, there is very limited knowledge about comorbid psychiatric disorders and their effective treatment in this special population. To fill this gap, this case report presents an initially four-year-old girl with 1p36.33-1p36.32 deletion, moderate intellectual disability, insomnia, oppositional-defiant disorder and attention deficit/hyperactivity disorder covering a period of time of about 1.5 years comprising initial psychological/psychiatric assessment, subsequent day clinic/outpatient treatment (amongst others including off-label use of melatonin and methylphenidate as well as parent-child interaction therapy) and follow-up assessment. Follow-up results indicated good efficacy of melatonin and methylphenidate medication without any adverse effects. Multidisciplinarity in diagnosis and treatment are mandatory to meet needs of patients with complex genetic disorders like 1p36 deletion syndrome. Off-label use of melatonin (for insomnia) and methylphenidate (for attention deficit/hyperactivity disorder) should be considered in young children with 1p36 deletion syndrome if behavioral interventions are not sufficient.

Psychological Adjustment of Children and Adolescents with 22q11.2 Deletion Syndrome and Their Mothers' Stress and Coping-A Longitudinal Study.

At present, there is a lack of longitudinal studies on the psychological adjustment of both children and adolescents with 22q11.2 deletion syndrome (22q11.2DS) and their primary caregivers. To fill this gap, we performed a four-year follow-up study. Mothers filled out the Child Behavior Checklist 4-18, the Social Orientation of Parents with Handicapped Children questionnaire to assess maternal stress and coping strategies, and the Freiburger Personality Inventory-Revised-subscales strain and life satisfaction. Fifty-five subjects with 22q11.2DS (26 males and 29 females; age: M = 10.79 years, SD = 3.56 years) and their biological mothers (age: M = 40.84 years, SD = 4.68 years) were included in this study. Significantly higher levels of behavior problems than in the general population and an increase in these problems, especially internalizing ones, over time could be found. In contrast, maternal stress did not change significantly over time, but mothers demonstrated increased levels of strain and reduced life satisfaction at T2. Thus, careful monitoring as well as early and adequate interventions, if indicated, should be offered to families with a child with 22q11.2DS, not only for somatic complaints but also for problems with psychological adjustment.

Psychiatric Disorders and Distal 21q Deletion-A Case Report.

Partial deletion of chromosome 21q is a very rare genetic condition with highly variable phenotypic features including heart defects, high or cleft palate, brain malformations (e.g., cerebral atrophy), developmental delay and intellectual disability. So far, there is very limited knowledge about psychiatric disorders and their effective treatment in this special population. To fill this gap, the authors present the case of an initially five-year-old girl with distal deletion (del21q22.2) and comorbid oppositional defiant disorder (main psychiatric diagnosis) covering a period of time of almost four years comprising initial psychological/psychiatric assessment, subsequent treatment with Parent-Child Interaction Therapy (PCIT), and follow-up assessments. Post-intervention results including a 19-month follow-up indicated good overall efficacy of PCIT and high parental satisfaction with the treatment. This case report makes a substantial contribution to enhancing knowledge on psychiatric comorbidity and its effective treatment in patients with terminal 21q deletion. Moreover, it emphasizes the necessity of multidisciplinarity in diagnosis and treatment due to the variety of anomalies associated with 21q deletion. Regular screenings for psychiatric disorders and (if indicated) thorough psychological and psychiatric assessment seem to be reasonable in most affected children, as children with developmental delays are at increased risk of developing psychiatric disorders. As demonstrated with this case report, PCIT seems to be a good choice to effectively reduce disruptive behaviors in young children with partial deletion of chromosome 21q.

Parents' Perception of Their 2⁻10-Year-Old Children's Contribution to The Dyadic Parent-Child Relationship in Terms of Positive and Negative Behaviors.

Parent-child relationship is developed and changed through reciprocal interactions between a child and his/her parent, and these interactions can strongly influence the child's development across domains (e.g., emotional, physical, and intellectual). However, little is known about the parental perception of the child's contribution to the dyadic parent-child relationship in terms of positive and negative behaviors. We therefore aimed to develop and validate an economical parent-report instrument to assess these important aspects. The validation study included 1642 mothers (Mage = 37.1) and 1068 fathers (Mage = 40.4) of 1712 children aged 2⁻10 years (Mage = 6.6) who completed the new instrument, the Child Relationship Behavior Inventory (CRBI). Statistical results indicated that the CRBI is a reliable and valid measure. Mothers reported more positive child behaviors towards them, whereas fathers perceived fewer problems with problematic relationship behavior than mothers. In their parents' perception, girls showed more positive and less problematic relationship behaviors than boys. The frequency of problematic child relationship behavior significantly decreased with increasing child age while positive relationship behavior did not show any correlation with the child's age. To assess both positive and negative child relationship behaviors could be helpful to better understand the relevance of these different aspects for the development of the parent-child relationship.

Non-Fatal Intoxication with a High Dose of Citalopram in a Suicidal 14-Year-Old Girl.

The use of selective serotonin reuptake inhibitors (SSRIs) like citalopram in the clinical treatment of depressive symptoms in children and adolescents has become increasingly common, although application is mostly off-label. The increasing number of prescriptions is not only due to their good efficacy, but also due to their good tolerability and the comparatively low risk in cases of intoxication. However, there is discussion about the cardiac safety of overdose ingestion of citalopram. Here, we report in detail on an adolescent with depressive symptoms who used 800 mg of citalopram in order to attempt suicide. In contrast to other case reports in adults, our patient showed only mild neurological symptoms and no cardiac toxicity or symptoms of a serotonin syndrome, despite a high citalopram blood concentration measured about two hours following ingestion of citalopram (633 ng/ml; therapeutic reference range for adults 50-110 ng/ml).

Disruptive Behaviors across Different Disorders: Evaluation of a Clinical Sample Using the Eyberg Child Behavior Inventory.

OBJECTIVE: The study reports the prevalence of disruptive behaviors in a help-seeking sample of young children across a diverse range of clinical diagnoses (based on ICD-10). METHOD: The Eyberg Child Behavior Inventory (ECBI), a parent rating scale of disruptive behaviors, was completed on 310 children (2-11 years) at three child and adolescent psychiatry clinics in three German states (Bavaria, Hesse, Lower Saxony); the majority of children were outpatients. RESULTS: Mean intensity scores of disruptive behaviors differed significantly by diagnostic group, with the lowest ratings within a community sample, and increasingly higher scores in children with a diagnosis from the internalizing spectrum, those with pervasive developmental disorders, and finally, those with externalizing disorders (e. g. hyperkinetic disorder, conduct disorders). Seventy percent of the clinical sample, compared to only 17 % of the community sample, exceeded the normative cut-off score of 111, indicating that disruptive behaviors are common in young German children seeking help for different mental health problems. CONCLUSIONS: These findings support the Research Domain Criteria approach by showing that disruptive behaviors cross our current diagnostic labels and may need to be assessed and conceptualized in treatment planning, even in children without a primary diagnosis from the externalizing spectrum.

Psychological adjustment of young subjects with Möbius sequence and their primary caregivers' strain and life satisfaction: First longitudinal data.

AIMS/METHODS: At present, there is no information about the course of psychological adjustment in young subjects with Möbius sequence (MS) and their parents' strain and life satisfaction. To fill this gap, we performed a four-year follow-up study. Parents were anonymously asked to fill out the Child Behavior Checklist 4-18 [CBCL/ 4-18] or the Young Adult Behavior Checklist 18-30 [YABCL/ 18-30] and the Freiburger Personality Inventory-Revised [FPI-R], subscales strain and life satisfaction. RESULTS: 12 males and 14 females (mean: 15.20 years, standard deviation: 3.48 years) could be included in the follow-up (response rate: 83.9%).Compared to the general population, subjects with MS showed significantly higher scores on almost all CBCL scales (exception: externalizing problems) at T1 and T2. At both study times, parental strain and life satisfaction were not significantly different from findings in the general population. No significant longitudinal changes could be found for CBLC scales, parental strain and life satisfaction. CONCLUSIONS: Problems with psychological adjustment seem to be frequent among younger subjects with MS. Therefore, careful monitoring as well as early and adequate interventions, if indicated, are crucial for subjects with MS, not only with regard to somatic complaints but also to aspects of adjustment.

Clinical Usefulness of Aripiprazole Treatment in a Girl with Prader-Willi Syndrome and Psychosis.

Prader-Willi syndrome (PWS) is a quite rare multi-systemic genetic disorder strongly associated with psychiatric illness in adults, especially psychosis. This report presents a 16-year-old female with PWS and symptoms of brief psychotic disorder with a complete resolution of symptoms under aripiprazole medication. However, an exacerbation occurred after aripiprazole reduction. Apart from a weight gain of about 2 kg over the course of two years, no adverse effects could be found. This first report on the use of aripiprazole in a subject with PWS and psychosis suggests that aripiprazole might be a promising treatment approach in this distinct group of patients.

Tailoring Parent-Child Interaction Therapy (PCIT) for Older Children: A Case Study.

Parent-Child Interaction Therapy (PCIT) is an evidence-based intervention designed for families of 2- to 6-year-old children with disruptive behavior disorders. This article illustrates the application of PCIT in a 10-year-old boy with attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). Both parents and the patient attended PCIT sessions. The course of therapy included minor changes to the PCIT protocol. After 13 PCIT sessions, the patient displayed disruptive behaviors within normal limits, and 12 months later he no longer met diagnostic criteria for ODD. Results remained stable at a 17-month follow-up assessment. This case study suggests that the use of PCIT in families of children with ODD markedly older than the recommended age range might be a promising approach for improving family functioning and reducing behavior problems. Further research with larger samples of older children with ODD is needed to replicate and elaborate the findings of this case study.

Dimensional Latent Structure of Early Disruptive Behavior Disorders: A Taxometric Analysis in Preschoolers.

Although disruptive behavior disorders (DBDs) are used as a distinct categorical diagnosis in clinical practice, they have repeatedly been described as having a dimensional structure in taxometric analyses. In the current study the authors analyzed the latent status of disruptive behaviors (DB) in a large sample (N = 2,808) of German preschool children (2-6 years old, mean age 53.7 months, SD = 13.5, 48.4% girls). The Eyberg Child Behavior Inventory (ECBI) as well as the Strengths and Difficulties Questionnaire (SDQ) were used to compile indicators of the DB core dimensions (Temper Loss, Aggression, Noncompliance, and Low Concern for others). Three widely used taxometric methods (a) MAXEIG, (b) MAMBAC, and (c) L-Mode were applied. Simulation data were created to evaluate the Comparison Curve Fit Index values (CCFIs), which were below 0.45, supporting a dimensional solution. Hence, in the current study the latent structure of DB in preschoolers encompassed differences in degree rather than kind. Researchers and practitioners should be mindful of the dimensional latent status of DB in theory building, assessment, classification, and labeling.

[Neuropsychiatric aspects of Prader-Willi syndrome ­ a review]. / Neuropsychiatrische Aspekte bei Prader-Willi-Syndrom ­ eine Übersicht.

Prader-Willi Syndrome (PWS) is caused by the absence of paternal expression of imprinted genes in the region at 15q11­q13. With an estimated birth incidence of 1/15 000 ­ 1/30 000, PWS is one of the more frequent genetic syndromes among humans. Typical physical features include neonatal hypotonia and feeding problems, hypogonadism, hyperphagia in later childhood with consecutive obesity, and short stature. Most people with PWS show a mild to moderate intellectual disability. Furthermore, lability of mood, temper tantrums, skin-picking, and compulsive behaviors are quite typical for subjects with PWS. Psychotic disorders have also been found to be quite common in adulthood. This manuscript reviews current knowledge about the etiology, physical features, developmental aspects, behavioral phenotype, and psychiatric disorders that occur as well as existing psychopharmacological and psychotherapeutic interventions.

[Parent-child interaction therapy (PCIT)]. / Parent-Child Interaction Therapy.

Parent-child interaction therapy (PCIT), a manualized evidence-based intervention, was originally developed to treat disruptive behavior problems in children aged 2­6 years. It is also considered to be an evidence-based intervention for physical abuse among children. Moreover, PCIT has proved to be effective for attention deficit hyperactivity disorder, autism spectrum disorder, separation anxiety disorder, and depression. Thus, it could become the first evidence-based, transdiagnostic intervention method for 2­6-year-old children. PCIT is based on attachment theory as well as learning theory, combining aspects of play therapy and behavior therapy. It consists of two treatment phases: child-directed interaction (CDI) and parent-directed interaction (PDI). In both phases parents are taught special skills. When interacting with their child parents practice these skills and are live coached by the therapist. CDI aims at improving the parent-child relationship and is the basis for PDI. In CDI, parents learn to follow their child's lead as long as the child shows appropriate behavior. In PDI, parents practice effectively taking the lead wherever necessary. On average, it takes about 15­20 sessions to complete PCIT, which can be terminated as soon as the parents demonstrate a mastery of the skills, when child disruptive behavior has been reduced to clearly normal levels, and when the parents have become confident in managing child behavior on their own.

Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder.

Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins-as crucial moderators of neuroplasticity-impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = -2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65; df = 2.43; p < 0.05); neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961; df = 2.41; p < 0.05, η (2) = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes.

Self-perception of children and adolescents with Möbius sequence.

Möbius sequence is a rare congenital disorder usually defined as a combination of facial weakness with impairment of ocular abduction. Some studies suggest that psychosocial and psychiatric problems might be increased among affected persons. So far, there have been no studies on the self-perception of children and adolescents with the sequence. Seventeen participants with Möbius sequence (9 male, 8 female) aged 9-15 (mean: 11.59) years were studied. None of the probands was mentally retarded or had a diagnosis of autism spectrum disorder. Participants filled out well standardized German questionnaires on depression (Depressionsinventar für Kinder und Jugendliche [DIKJ]), anxiety (Angstfragebogen für Schüler [AFS]) and personality aspects (Persönlichkeitsfragebogen für Kinder von 9-14 Jahren [PFK 9-14]). Additionally, their primary caregivers were asked to complete a special questionnaire to compile the probands' personal, somatic and psychosocial history as well as the German version of the Strengths and Difficulties Questionnaire, Parent Form [SDQ-Deu]. According to the participants' self-perception only one girl scored clinical (t-score ≥ 63) for manifest anxiety [AFS] and depression [DIKJ] (5.9% vs. 10% in the general population). Moreover, the whole sample reported significantly lower test anxiety (p=0.000) and manifest anxiety (p=0.005) [AFS] whereas general anxiety as a personality aspect [PFK 9-14] did not differ from the normative sample. Compared to normative data, subjects expressed significantly less depression (p=0.023) and impulsivity (p=0.042). One out of 17 subjects was rated abnormal for total problems on the SDQ-Deu (5.9% vs. 10% of the normative sample), five participants scored abnormal for social problems (29.4%) and three for emotional problems (17.6%). Social problems correlated significantly with the probands' age (rho=0.707; p=0.002). As Möbius patients have severe difficulties with facial expression of feelings, and others might therefore falsely recognize them as serious or even depressed, the subjects' self-perception is crucial for assessment and diagnosis, especially if it differs considerably from that of the primary caregivers.

Moebius sequence and autism spectrum disorders--less frequently associated than formerly thought.

Moebius sequence is a rare congenital disorder usually defined as a combination of facial weakness with impairment of ocular abduction. It is questionable, whether there is a strong association of the sequence with autism spectrum disorders (ASDs) as suggested in some earlier case reports and studies. Twenty-two participants with Möbius sequence aged 6-16 years followed a request of the German Moebius foundation to participate in a nationwide study. All patients had a physical examination and intelligence testing. Primary caregivers were asked to complete two screening measures of ASD (Behaviour and Communication Questionnaire, VSK; Marburger Asperger's Syndrome Rating Scale, MBAS). For those who reached the cut-off for ASD and/or showed behavioural aspects indicative of ASDs during IQ testing and/or physical examination, well standardized diagnostic instruments (Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and Kinder-DIPS) were administered. Minimal diagnostic criteria for Möbius sequence were congenital facial weakness (uni- or bilateral) and impairment of ocular abduction (uni- or bilateral). Three boys (one of them mentally retarded) out of 22 participants (12 males and 10 females) were found suspicious of ASD by screening, but none of them fulfilled diagnostic criteria of ASD on a clinical consensus conference. Therefore, ASDs seem to be not as frequent as reported in previous studies on patients with Möbius sequence.

Reduced NoGo-anteriorisation during continuous performance test in deletion syndrome 22q11.2.

Deletion syndrome 22q11.2 (DS22q11.2) is a high-risk factor for psychiatric disorders. Alterations in brain morphology and function including the anterior cingulate cortex (ACC) are suggested to underlie the increased psychiatric disposition. We assessed response-inhibition in patients with DS22q11.2 (n=13) and healthy controls (n=13) matched for age, sex, and handedness by means of a Go-NoGo-Task during recording of a multi-channel electroencephalography (EEG). Analysis of event-related potentials (P300) resulted in an aberrant topographical pattern and NoGo-anteriorisation (NGA) as a parameter of medial prefrontal function was significantly reduced in patients with DS22q11.2 compared to controls. Differences in IQ between groups did not account for the findings. Source localization analysis (LORETA) revealed diminished left temporal brain activation during the Go-condition, but no altered ACC activation in DS22q11 during the NoGo-condition. Despite recent reports of structural alterations of the ACC in DS22q11.2 our findings suggest that response-inhibition mediated by the ACC is not impaired in DS22q11.2.