The original article was missing a statement regarding a shared first authorship. The authors Julia M. Geissler and Timo D. Vloet contributed equally to the manuscript.

Multimodal treatment of children with ADHD often includes parent–child training (PCT). However, due to the high heritability, parents of children with ADHD are frequently also affected by the disorder, which is likely to constitute a significant barrier to successful treatment of the child. This secondary analysis of our randomized controlled multicentre AIMAC trial (ADHD in mothers and children) investigates whether children’s outcomes following parent–child training in combination with maternal ADHD treatment depend on maternal symptom improvement. In a first step focusing on treatment of maternal ADHD, 144 mothers of mother–child dyads were randomized to multimodal ADHD treatment (group psychotherapy plus methylphenidate) or clinical management (mainly supportive counselling). After 12 weeks (T2), a 12-week PCT program (T2–T3) for all mother–child dyads was added to treat children’s ADHD. Maternal symptomatology (CAARS-O:L; SCL-90-R) and children’s externalizing symptoms (ADHD-ODD Scale, SDQ) were repeatedly assessed (T1 = baseline, T2, T3). Effects of changes in maternal symptomatology (T1–T2) on the change in children’s symptom scores (T1–T3) were analysed using a general linear model, controlling for baseline scores, study centre, and maternal treatment group. 125 mother–child dyads were analysed. Mothers showed significant improvements in ADHD symptoms and overall psychopathology [CAARS-O:L ADHD index: mean − 3.54, SE 0.74 p < 0.0001; SCL-90-R Global Severity (GS): mean − 11.03, SE 3.90, p = 0.0056]. Although children’s externalizing symptoms improved significantly (ADHD-ODD Scale: mean − 4.46, SE 0.58, p < 0.0001), maternal improvement had no effect on children’s outcomes after Bonferroni–Holm correction for multiple testing. The findings do not support our hypothesis that children’s outcomes following PCT for ADHD depend on maternal symptom improvements.

The efficacy of parent-child training (PCT) regarding child symptoms may be reduced if the mother has attention-deficit/hyperactivity disorder (ADHD). The AIMAC study (ADHD in Mothers and Children) aimed to compensate for the deteriorating effect of parental psychopathology by treating the mother (Step 1) before the beginning of PCT (Step 2). This secondary analysis was particularly concerned with the additional effect of the Step 2 PCT on child symptoms after the Step 1 treatment.

OBJECTIVEWe examined predictors and moderators of treatment outcome in mothers and children diagnosed with ADHD in a large multicentre RCT.METHODIn total, 144 mother-child dyads with ADHD were randomly assigned to either a maternal ADHD treatment (group psychotherapy and open methylphenidate medication, TG) or to a control treatment (individual counselling without psycho- or pharmacotherapy, CG). After maternal ADHD treatment, parent-child training (PCT) for all mother-child dyads was added. The final analysis set was based on 123 dyads with completed primary outcome assessments (TG: n = 67, CG: n = 56). The primary outcome was the change in each child's externalizing symptoms. Multiple linear regression analyses were performed.RESULTSThe severity of the child's externalizing problem behaviour in the family at baseline predicted more externalizing symptoms in the child after PCT, independent of maternal treatment. When mothers had a comorbid depression, TG children showed more externalizing symptoms after PCT than CG children of depressive mothers. No differences between the treatment arms were seen in the mothers without comorbid depression.CONCLUSIONSSeverely impaired mothers with ADHD and depressive disorder are likely to need additional disorder-specific treatment for their comorbid psychiatric disorders to effectively transfer the contents of the PCT to the home situation (CCTISRCTN73911400).

BACKGROUND:This is the first randomized controlled multicenter trial to evaluate the effect of two treatments of maternal attention-deficit hyperactivity disorder (ADHD) on response to parent-child training targeting children's external psychopathology.METHODS:Mother-child dyads (n = 144; ADHD according to DSM-IV; children: 73.5% males, mean age 9.4 years) from five specialized university outpatient units in Germany were centrally randomized to multimodal maternal ADHD treatment [group psychotherapy plus open methylphenidate medication; treatment group (TG): n = 77] or to clinical management [supportive counseling without psychotherapy or psychopharmacotherapy; control group (CG): n = 67]. After 12 weeks, the maternal ADHD treatment was supplemented by individual parent-child training for all dyads. The primary outcome was a change in the children's externalizing symptom scores (investigator blinded to the treatment assignment) from baseline to the end of the parent-child training 6 months later. Maintenance therapy continued for another 6 months. An intention-to-treat analysis was performed within a linear regression model, controlling for baseline and center after multiple imputations of missing values.RESULTS:Exactly, 206 dyads were assessed for eligibility, 144 were randomized, and 143 were analyzed (TG: n = 77; CG: n = 66). After 6 months, no significant between-group differences were found in change scores for children's externalizing symptoms (adjusted mean TG-mean CG=1.1, 95% confidence interval -0.5-2.7; p = .1854), although maternal psychopathology improved more in the TG. Children's externalizing symptom scores improved from a mean of 14.8 at baseline to 11.4 (TG) and 10.3 (CG) after 6 months and to 10.8 (TG) and 10.1 (CG) after 1 year. No severe harms related to study treatments were found, but adverse events were more frequent in TG mothers than in CG mothers.CONCLUSIONS:The response in children's externalizing psychopathology did not differ between maternal treatment groups. However, multimodal treatment was associated with more improvement in maternal ADHD. Child and maternal treatment gains were stable (CCT-ISRCTN73911400).

ADHD seriously impacts family functioning, even the more in families with simultaneous parental and child ADHD. The aim of the study was to examine asso- ciations between family impact of child ADHD and child, mother and family characteristics in multiplex families with children and mothers both affected by ADHD. One hundred and forty-four mother-child pairs were assessed (children: mean age 9.4 ± 1.7 years, 73.6 % male). Family impact of child ADHD was rated by mothers using the Family Impact Questionnaire (FIQ). Multiple linear regression analyses were performed with child and mater- nal psychopathology and basic family characteristics such as employment, partnership status and number of children as predictors and FIQ subscores as criteria. Rates of vari- ance explained by family variables were 49 % for negative feelings towards the child, 37 % for impact on partnership, 31 % for impact on social life and 27 % for impact on finances (p .001, respectively). Pearson correlations with family impact were especially strong for child externaliz- ing symptoms, maternal ADHD and co-morbid symptoms of the mother. The strongest independent predictor was oppositional defiant child behaviour. In ADHD multiplex families, mothers' perception of the impact of an ADHD child on its family can be explained to a substantial degree by child psychopathology, maternal psychopathology and basic family characteristics. Although a cross-sectional design does not allow for causal interpretations, the

ADHD seriously impacts family functioning, even the more in families with simultaneous parental and child ADHD. The aim of the study was to examine associations between family impact of child ADHD and child, mother and family characteristics in multiplex families with children and mothers both affected by ADHD. One hundred and forty-four mother–child pairs were assessed (children: mean age 9.4 ± 1.7 years, 73.6 % male). Family impact of child ADHD was rated by mothers using the Family Impact Questionnaire (FIQ). Multiple linear regression analyses were performed with child and maternal psychopathology and basic family characteristics such as employment, partnership status and number of children as predictors and FIQ subscores as criteria. Rates of variance explained by family variables were 49 % for negative feelings towards the child, 37 % for impact on partnership, 31 % for impact on social life and 27 % for impact on finances (p < .001, respectively). Pearson correlations with family impact were especially strong for child externalizing symptoms, maternal ADHD and co-morbid symptoms of the mother. The strongest independent predictor was oppositional defiant child behaviour. In ADHD multiplex families, mothers’ perception of the impact of an ADHD child on its family can be explained to a substantial degree by child psychopathology, maternal psychopathology and basic family characteristics. Although a cross-sectional design does not allow for causal interpretations, the findings of this study offer important targets for the treatment of ADHD in a family context pointing to the need for assessing and treating parental mental health and co-morbid symptoms besides ADHD core symptoms.

Background Metabolic control and dietary management of patients with phenylketonuria (PKU) are based on single blood samples obtained at variable intervals. Sampling conditions are often not well-specified and intermittent variation of phenylalanine concentrations between two measurements remains unknown. We determined phenylalanine and tyrosine concentrations in blood over 24 hours. Additionally, the impact of food intake and physical exercise on phenylalanine and tyrosine concentrations was examined. Subcutaneous microdialysis was evaluated as a tool for monitoring phenylalanine and tyrosine concentrations in PKU patients. Methods Phenylalanine and tyrosine concentrations of eight adult patients with PKU were determined at 60 minute intervals in serum, dried blood and subcutaneous microdialysate and additionally every 30 minutes postprandially in subcutaneous microdialysate. During the study period of 24 hours individually tailored meals with defined phenylalanine and tyrosine contents were served at fixed times and 20 min bicycle-ergometry was performed. Results Serum phenylalanine concentrations showed only minor variations while tyrosine concentrations varied significantly more over the 24-hour period. Food intake within the patients’ individual diet had no consistent effect on the mean phenylalanine concentration but the tyrosine concentration increased up to 300% individually. Mean phenylalanine concentration remained stable after short-term bicycle-exercise whereas mean tyrosine concentration declined significantly. Phenylalanine and tyrosine concentrations in dried blood were significantly lower than serum concentrations. No close correlation has been found between serum and microdialysis fluid for phenylalanine and tyrosine concentrations. Conclusions Slight diurnal variation of phenylalanine concentrations in serum implicates that a single blood sample does reliably reflect the metabolic control in this group of adult patients . Phenylalanine concentrations determined by subcutaneous microdialysis do not correlate with the patients’ phenylalanine concentrations in serum/blood.

Increased intra-subject variability of reaction times (ISV-RT) is one of the most consistent findings in attention-deficit/ hyperactivity disorder (ADHD).Although the nature of this phenomenon is still unclear, it has been hypothesised to reflect interference from the Default Mode Network (DMN).So far, ISV-RT has been operationally defined either as a frequency spectrum of the underlying RT time series, or as a measure of dispersion of the RT scores distribution.Here, we use a novel RT analysis framework to link these hitherto unconnected facets of ISV-RT by determining the sensitivity of different measures of RT dispersion to the frequency content of the underlying RT time series.N=27 patients with ADHD and N=26 healthy controls performed several visual N-back tasks.Different measures of RT dispersion were repeatedly modelled after individual frequency bands of the underlying RT time series had been either extracted or suppressed using frequency-domain filtering.We found that the intra-subject standard deviation of RT preserves the "1/f noise" characteristic typical of human RT data.Furthermore and most importantly, we found that the ex-Gaussian parameter τ is rather exclusively sensitive to frequencies below 0.025 Hz in the underlying RT time series and that the particularly slow RTs, which nourish τ, occur regularly as part of an quasi-periodic, ultra-slow RT fluctuation.Overall, our results are compatible with the idea that ISV-RT is modulated by an endogenous, slowly fluctuating process that may reflect DMN interference.

Parental ADHD may be a significant barrier to a successful treatment for the child's ADHD. The objective of our randomized controlled trial was to evaluate whether the treatment for maternal ADHD improves the efficacy of a behavioural parent training for children's ADHD. Patient enrolment and a description of the full analysis set (FAS) of mother-child pairs with non-missing baseline data are presented. One hundred and forty-four mother-child pairs were randomized to two treatments for maternal ADHD: cognitive behavioural group psychotherapy plus open methylphenidate treatment or control treatment (supportive counselling). After 3 months of treatment for maternal ADHD, mother-child pairs participated in a behavioural parent-child training. Assessment for eligibility included standardized instruments. After pre-screening out of 444 mother-child pairs, 206 were evaluated for trial participation and 144 were randomized. The FAS was built up by 143 dyads (children: mean age 9.4 years, 73 % males; mothers: mean age: 38.3 years). Fifty-two per cent of the children and 66 % of the mothers had combined ADHD subtype. Current axis-I co-morbidity rates were 48 % in children and 31 % in mothers. Maternal axis-II co-morbidity was 20.1 %. Fifty-seven per cent of the mothers lived together with the father of the index-child, and 29 % were single mothers. Sixty-two per cent had part-time or full-time employment. There was a selection bias excluding mothers with lack of time and effort for participation and mothers affected by coexisting mental and physical illness. Nevertheless, for our trial we were able to collect a sample comparable to routine psychiatric outpatient settings (registration: CCT-ISRCTN73911400, funding: BMBF-01GV0605).

OBJECTIVESThe primary objective of this study was to demonstrate efficacy of Ritalin(®) LA 20 mg by showing superiority to placebo and noninferiority to Medikinet(®) Retard in a laboratory classroom setting. Secondary objectives included safety/tolerability and further efficacy parameters.METHODSA total of 147 children with attention-deficit/hyperactivity disorder (ADHD) diagnosed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and aged 6-14 (81% males) and known to be methylphenidate (MPH) responders were enrolled in this multicenter, double-blind, randomized, placebo/active-controlled, three-period (7 days each) crossover study. The Swanson, Kotlin, Agler, M-Flynn, and Pelham (SKAMP) scale was used for efficacy ratings. The mean of SKAMP Combined ratings performed at 10:30 a.m., at 12:00 a.m., and at 1:30 p.m. was defined as the primary parameter.RESULTSIn all, 146 patients completed all treatment periods. Intensity and frequency of adverse events were comparable between the two formulations. Ritalin(®) LA demonstrated superiority compared to placebo (p<0.0001). The observed difference in the SKAMP scores between Ritalin(®) LA and Medikinet(®) Retard between the hours 1.5 until 4.5 did not exceed the noninferiority margin (p=0.0003); therefore, the difference is regarded as not clinically relevant. Similar results were obtained for the secondary efficacy variables.CONCLUSIONRitalin(®) LA is an efficacious, well-tolerated treatment option for children aged 6-14 with ADHD.

Several extended-release methylphenidate medications are available for treatment of children with ADHD. Pharmacokinetic investigations suggest that the serum levels of methylphenidate are partially altered when the medication is taken without breakfast. Clinical data comparing different breakfast situations are missing. In this study, different breakfast compositions and their influence on treatment with Ritalin LA are investigated. A total of 150 patients were enrolled in a rater-blinded, randomized crossover trial that compared a minimal breakfast with a standard breakfast in patients under stable treatment with Ritalin LA. Ratings for clinical efficacy were carried out after 1 week by teachers and parents (FBB-ADHS), as well as physicians (CGI). Additionally, a math test was administered to the patients. Of the total patients, 144 finished the trial with a breakfast compliance of 93%. All of the clinical rating scales showed consistently no difference between the two breakfast conditions. Non-inferiority of minimal breakfast versus standard breakfast was shown to be statistically significant (FBB-AHDS(Teacher): 0.97 with minimal breakfast, 1.01 with standard breakfast, P < 0.0001). The clinical efficacy of Ritalin LA is not influenced by breakfast and works independently of food intake.

OBJECTIVES:Catatonic symptoms in children and adolescents have not been well investigated and there are hardly any evaluated recommendations for treatment. The present report deals with the course of disease and the therapy of a severe case of catatonic schizophrenia.METHODS:Reported is the case of a 17-year-old-girl suffering from severe, life-threatening catatonic schizophrenia.RESULTS:Following unsuccessful pre-treatment, medication with clozapine markedly improved the pathology.CONCLUSIONS:Further investigations and case reports about the course of disease and the therapy of the uncommon clinical picture of sever catatonic schizophrenia in children and adolescents are necessary.

Catatonic symptoms in children and adolescents have not been well investigated and there are hardly any evaluated recommendations for treatment. The present report deals with the course of disease and the therapy of a severe case of catatonic schizophrenia. Methods: Reported is the case of a 17-year-old girl suffering from severe, life-threatening catatonic schizophrenia. Results: Following unsuccessful pre-treatment, medication with clozapine markedly improved the pathology. Conclusions: Further investigations and case reports about the course of disease and the therapy of the uncommon clinical picture of severe catatonic schizophrenia in children and adolescents are necessary.

The aim of this study was to evaluate long-term weight gain associated with clozapine, olanzapine, and risperidone treatment and its clinical risk factors in children and adolescents. At four child and adolescent psychiatric departments, the weight and body mass index of initially hospitalized patients (aged 9.0-21.3 years) treated with clozapine (n = 15), olanzapine (n = 8), and risperidone (n = 10) were prospectively monitored for 45 weeks. Clinical risk factors (age, gender, baseline weight, dosage, drug-naivety) were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint. The absolute and percentage average weight gains were significantly higher for the olanzapine group (16.2 +/- 8.8 kg; 30.1 +/- 18.9%) than for the clozapine (9.5 +/- 10.4 kg; 14.8 +/- 15.8%) and the risperidone (7.2 +/- 5.3 kg; 11.5 +/- 6.0%) groups. Olanzapine is associated with extreme long-term weight gain in children and adolescents that, in addition, is much higher than that expected in adults. Clozapine and risperidone are associated with a less marked weight gain in children and adolescents but also much higher than that expected in adults. These differences may affect compliance with medication and health risk.

OBJECTIVES The present study analyses the long-term course of disease among patients who underwent inpatient psychotherapeutic treatment in a psychiatric hospital for children and adolescents. METHODS Assessed within the study was a sample of former patients (N = 104) hospitalised in "Haus Vogt" for at least six months from 1983 to 1988. The following instruments were used: Freiburger Strukturiertes Interview (FrStI), World Health Organisation Quality of Life Interview - short version (WHOQOL-BREF), Symptom Checklist of Derogatis - German version (SCL-90-R) and questionnaires for the assessment of the treatment (FBB). RESULTS The quality of life (according to WHOQOL-BREF) of former patients is significantly worse on all relevant scales than that among the general population. The mental health (according to SCL-90-R) of the assessed sample is under average compared to that of the general population. In retrospect, satisfaction with treatment, as investigated by means of the FBB, differed considerably between the former "Haus Vogt" patient sample and a comparative sample from a psychiatric university hospital for children and adolescents. The biggest differences in satisfaction with treatment were found on the scale relationship with the therapist, which was much worse among the sample of former "Haus Vogt" patients than in the control group. CONCLUSIONS The study shows positive long-term results in terms of the school and professional education attained later on. At the same time, the former patients showed persisting psychiatric symptoms and a considerably restricted quality of life.

OBJECTIVE:The aim of this study was to improve and evaluate the practibility of a method for the assessment of drug-associated side effects, and we implemented a clinical drug monitoring for atypical neuroleptics.METHODS:Side effects of initially hospitalized patients treated with clozapine (n = 16), olanzapine (n = 16), and risperidone (n = 19) were prospectively monitored on a weekly basis for the first 3 weeks. In the case of stable medication, measurements of all variables were made every 4 weeks or upon discharge. We used the Dosage Record Treatment Emergent Symptom Scale (DOTES) in a supplemented version to measure the presence and severity of side effects.RESULTS:Drowsiness and decreased motor activity were common, especially in the first 2 weeks. Orthostatic hypotension, increased salivation, constipation, and nasal congestion were seen in more than 30% to 60% of patients treated with clozapine and were less common in adolescents treated with olanzapine and risperidone. Rigidity, tremor, and dystonia were seen in 5% to 15% of patients treated with risperidone and olanzapine. The average weight gain after 6 weeks of treatment with the atypical neuroleptics was significantly higher for the olanzapine group (4.6 +/- 1.9 kg) than for the risperidone (2.8 +/- 1.3 kg) and clozapine (2.5 +/- 2.9 kg) groups.CONCLUSIONS:The authors' supplemented DOTES version is generally applicable to clinical use in mental health centers. The differences among the side effects of these three agents may affect compliance with medication and medical risks of metabolic syndrome, diabetes, and cardiovascular disease. More research on the short- and long-term safety of psychotropic drugs in children and adolescents, using standardized methods, should be considered.

Forty five patients (23 boys and 22 girls) with elective mutism (8.7 +/- 3.6 years old), who were referred to a university department and a child guidance clinic within a 15-year-period, were followed up on average 12 years later. For 41 of them, sufficient information could be obtained at follow-up, and 31 patients could be investigated personally. At follow-up, an interview and a standardized psychopathological examination were carried out as well as two standardized biographic inventories. The main results were: 1) a high load of individual and family psychopathology was characteristic of the patients. The disorder started already at age 3 to 4 and referral age was 8 years on average. 2) In 16 out of 41 patients (39%), a complete remission could be observed. All other patients still revealed some communication problems. 3) The formerly mute patients described themselves as less independent, less motivated with regard to school achievement, less self-confident and less mature and healthy in comparison to a normal reference group. 4) A poor outcome could be best predicted by the variable "mutism within the core family"at the time of referral.