Psychiatric comorbidity in patients with pediatric bipolar disorder - A systematic review.

BACKGROUND: A growing body of evidence suggests that pediatric bipolar disorder (PBD) frequently co-occurs with comorbid psychiatric disorders that may impact functioning. OBJECTIVE: To review existing literature on the prevalence of psychiatric comorbidity and general functioning in patients with a primary diagnosis of PBD. METHODS: We performed a systematic literature search on the PubMed, Embase and PsycInfo databases on November 16th, 2022. We included original papers on patients ≤18 years with primary PBD and any comorbid psychiatric disorder, diagnosed according to a validated diagnostic tool. Risk of bias of the individual studies was assessed using the STROBE checklist. We calculated weighted means to assess the comorbidity prevalence. The review complied with PRISMA statement guidelines. RESULTS: Twenty studies with a total study population of 2722 patients with PBD were included (mean age = 12.2 years). We found an overall high prevalence of comorbidity in patients with PBD. The most common comorbidities were attention-deficit-hyperactivity disorder (ADHD) (60%) and oppositional defiant disorder (ODD) (47%). Anxiety disorders, obsessive-compulsive disorder, conduct disorder, tic disorders and substance-related disorders affected between 13.2% and 29% of patients, while one in 10 had comorbid mental retardation or autism spectrum disorder (ASD). The prevalence of comorbid disorders was lower in studies that assessed the current prevalence in patients in full or partial remission. General functioning was overall not specifically decreased in patients with comorbidity. CONCLUSIONS: Comorbidity across a broad range of disorders was high in children diagnosed with PBD, especially regarding ADHD, ASD, behavioral and anxiety disorders including OCD. Future original studies should assess current prevalence of comorbidities in patients with PBD who are in remission to obtain more reliable estimates of psychiatric comorbidity in this patient group. The review highlights the clinical and scientific importance of comorbidity in PBD.

An observational study of emotion regulation in children with Tourette syndrome.

BACKGROUND: Explosive outbursts occur in 25%-70% of children with Tourette syndrome (TS) and may cause more distress than the tics themselves. Previous studies have indicated that a comorbid diagnosis of attention-deficit/hyperactivity disorder (ADHD) is associated with emotional dysregulation in TS; however, this relationship has almost exclusively been studied using parent-reported questionnaires. METHODS: We examined emotion regulation (ER) with an observational measure in 150 medication-naïve children aged 7-12 allocated to four groups: Forty-nine children with TS, 23 children with ADHD, 16 children with TS + ADHD, and 62 typically developing controls. We assessed participants' ER ability, as well as parent-child interactions in the context of a complex puzzle task, and coded the observed behavior with the Tangram Emotion Coding Manual (TEC-M). We examined group differences in ER, as well as associations between ER and severity of symptoms pertaining to TS and ADHD. RESULTS: Children with TS did not differ from controls in their ER ability. However, children with ADHD and TS + ADHD had more problems with ER than those with TS only and controls. Finally, parents of children with ADHD displayed more tension during the experimental task. ER ability was not associated with tic severity nor premonitory urges; however, better ER ability was associated with less severe symptoms of ADHD. CONCLUSIONS: This study is the first to evaluate ER with an observational, clinician-rated measure in a controlled social setting in children with TS. Our findings support earlier questionnaire-based studies by showing impaired ER in children with TS + ADHD, but not in children with TS without comorbidity. These findings inform our understanding of the phenomenology of emotional dysregulation in TS and the role of comorbid disorders.

Inflammatory and oxidative stress biomarkers in children and adolescents with bipolar disorder - A systematic review and meta-analysis.

Evidence suggests a role for low-grade inflammation and oxidative stress in the pathophysiology of bipolar disorder. We conducted a systematic review and meta-analysis of peripheral markers of inflammation and oxidative stress in children and adolescents under 20 years of age with bipolar disorder. We searched PubMed, Embase and psycINFO and performed random effects meta-analysis calculating standardized mean differences (SMD) of marker levels between patients with bipolar disorder and healthy control individuals. Ten studies comprising a total of 418 patients with bipolar disorder and 3017 healthy control individuals were included. The levels of C-Reactive Protein were higher in patients with bipolar disorder compared with healthy individuals (SMD 0.53; 95 %CI: 0.33-0.74; I2 = 0 %). For other biomarkers there were no statistically significant differences between groups. Findings were limited by a low number of studies and participants and methodological issues in the included studies. More and larger studies using rigorous methodology are needed to establish the role of inflammation and oxidative stress in children and adolescents with bipolar disorder.

Fine Motor Skills in Children with Tourette Syndrome and their Unaffected First-degree Siblings.

Background: The exact etiology of Tourette Syndrome (TS) remains unclear, making the search for impaired neuropsychological functions possibly connected to the underlying cause of TS as important as it is challenging. One neuropsychological domain of interest is fine motor skills. Method: This study compared fine motor skill performance on the Purdue Pegboard Task (PPT) in 18 children with TS, 24 unaffected first-degree siblings and 20 controls. A set of screening questionnaires was administered to determine comorbid psychiatric illness. Results: Children with TS, their siblings and controls did not differ significantly in fine motor skills as measured with the PPT. Performance on the PPT was not correlated with tic severity; however, we found an inverse correlation with severity of attention-deficit/hyperactivity disorder (ADHD) symptoms, as assessed by parent reported ADHD symptoms. Children with TS were found to have significantly higher parent reported ADHD symptoms compared to controls, yet only two out of the 18 participants had been diagnosed with ADHD. Conclusion: This study suggests that fine motor skill impairment in children with TS may be more strongly correlated with comorbid ADHD than to TS and tics.

Inhibitory Control in Children with Tourette Syndrome Is Impaired in Everyday Life but Intact during a Stop Signal Task.

Tourette Syndrome (TS) has previously been associated with deficits in inhibitory control (IC). However, studies on IC in individuals with TS have produced conflicting results. In the present study, we investigated IC, comparing the Stop Signal Reaction Time (SSRT) measure with parent and teacher ratings of daily life IC in 169 children aged 8-12 (60 with TS, 60 typically developing controls, 27 with attention-deficit/hyperactivity disorder (ADHD), and 22 with TS + ADHD). We further investigated associations of IC with TS and ADHD symptom severity. Children with TS showed intact SSRT performance, but impairments in daily life IC, as reported by parents and teachers. For the latter, we observed a staircase distribution of groups, with the healthy controls presenting with the best IC, followed by TS, TS + ADHD, and finally ADHD. Dimensional analyses indicated a strong association between ADHD severity and both measures of IC. Our results indicate that children with TS are not impaired in a laboratory-based measure of IC, although some difficulties were evident from measures of everyday behaviour, which may in part be due to parents and teachers interpreting tics as disinhibited behaviour. Comorbid ADHD or the severity of subthreshold ADHD symptomatology appeared to account for IC deficits.

Male Circumcision Complications - A Systematic Review, Meta-Analysis and Meta-Regression.

OBJECTIVE: To determine the risk of complications requiring treatment following male circumcision by health-care professionals and to explore the impact of participant characteristics, type of circumcision and study design. METHODS: We identified studies through systematic searches in online databases (MEDLINE, EMBASE and CENTRAL) and hand searches. We performed random-effects meta-analysis to determine risk of circumcision complications and mixed-effects metaregression analyses to explore the impact of participant characteristics, type of circumcision and study design. Methods were prespecified in a registered protocol (Prospero CRD42020116770) and according to PRISMA guidelines. RESULTS: We included 351 studies with 4.042.988 participants. Overall complication risk was 3.84% (95% confidence interval 3.35-4.37). Our meta-analysis revealed that therapeutic circumcisions were associated with a 2-fold increase in complications as compared to nontherapeutic (7.47% and 3.34%, respectively). Adhesions, meatal stenosis and infections were the most frequent complication subgroups to therapeutic circumcisions. Bleeding, device removals and infections occurred more frequently in nontherapeutic circumcisions. Additionally, adjusted metaregression analyses revealed that children above 2 years, South American continent, older publication year and smaller study populations increased complication risk. Type of circumcision method, provider and setting were not associated with complication risk. Sensitivity analyses including only better-quality studies reporting indication, age at circumcision, treatment for complications, full-text articles, and adequate follow-up clinically for a minimum of one month or through databases confirmed our main findings while accounting better for heterogeneity. CONCLUSION: Circumcision complications occur in about 4 per hundred circumcisions. Higher risks of complications were determined by therapeutic circumcisions and by childhood age when compared to infant. Future studies should assess therapeutic and childhood circumcisions separately.

Reappraisal is an effective emotion regulation strategy in children with Tourette syndrome and ADHD.

BACKGROUND AND OBJECTIVES: Difficulties in emotion regulation (ER) have been associated with several psychiatric disorders, emphasizing a need for a greater understanding of the concept and its associations with disruptive behavior. We aimed to study the ER strategy of cognitive reappraisal with an experimental test to increase our knowledge of emotional processes in child psychopathology. METHODS: In the present study, we examined emotional reactivity and cognitive reappraisal with a computer task in 160 medication-naïve children aged 8-12 comprising four groups: Fifty-eight children with Tourette syndrome (TS), 26 children with attention-deficit/hyperactivity disorder (ADHD), 19 children with TS and ADHD, and 57 typically developing controls. RESULTS: The use of cognitive reappraisal reduced negative affect across all participants and the ability to reappraise was positively correlated with age, whereas reactivity was not. Overall, groups did not differ in reactivity or regulation success. Looking at specific differences within groups, however, only the ADHD group did not significantly decrease negative affect when reappraising. Finally, the use of strategies considered to be efficacious was correlated with regulation success, whereas the use of a less adaptive strategy related to suppression was associated with reactivity, but not regulation of emotions. LIMITATIONS: The study was limited by small, clinical contrast groups and a lack of blinding to diagnostic status in the coding of verbal strategies employed during the task. CONCLUSIONS: Cognitive reappraisal appears to be a beneficial ER strategy for children regardless of diagnostic status. Our findings indicate that children can learn and employ an adaptive ER strategy when instructed in the technique, even in the presence of attention problems, which is highly relevant to therapeutic approaches to dysregulated behavior.

A superior ability to suppress fast inappropriate responses in children with Tourette syndrome is further improved by prospect of reward.

In children with Tourette syndrome (TS), tics are often attributed to deficient self-control by health-care professionals, parents, and peers. In this behavioural study, we examined response inhibition in TS using a modified Simon task which probes the ability to solve the response conflict between a new non-spatial rule and a highly-overlearned spatial stimulus-response mapping rule. We applied a distributional analysis to the behavioural data, which grouped the trials according to the individual distribution of reaction times in four time bins. Distributional analyses enabled us to probe the children's ability to control fast, impulsive, responses, which corresponded to the trials in the fastest time bin. Additionally, we tested whether the ability to suppress inappropriate action tendencies can be improved further by the prospect of a reward. Forty-one clinically well-characterized medication-naïve children with TS, 20 children with attention-deficit/hyperactivity disorder (ADHD), and 43 typically developing children performed a Simon task during alternating epochs with and without a prospect of reward. We applied repeated measures ANCOVAs to estimate how the prospect of reward modulated reaction times and response accuracy, while taking into account the distribution of the reaction times across trials. We found between-group differences in accuracy when subjects responded relatively fast. The TS group responded more accurately than typically developing control children when resolving the response conflict introduced by the Simon task. The opposite pattern was found in children with ADHD. Prospect of reward improved accuracy rates in all groups. Although the Tourette group performed with superior accuracy in the fast trials, it was still possible for them to benefit from prospect of reward in fast trials. The findings corroborate the notion that children with TS have an enhanced capacity to inhibit fast inappropriate response tendencies. This ability can be improved further by offering a prospect of reward which might be useful during non-pharmacological therapeutic interventions.

The Puzzle of Emotion Regulation: Development and Evaluation of the Tangram Emotion Coding Manual for Children.

The ability to regulate one's emotions is crucial to engaging successfully in social contexts. Difficulties in emotion regulation are seen in multiple psychiatric disorders, prompting an increased interest in the concept. Suitable methods for assessing emotion regulation, however, are lacking. In this study, we investigated the interrater and intrarater reliability, construct validity, and content validity of a new observational method for evaluating children's emotion regulation abilities (a complex puzzle task) in a sample of 62 children without psychiatric disorders and 23 children with attention-deficit/hyperactivity disorder (ADHD) aged 7-12, using intra-class correlation coefficients for the reliability analyses and Spearman's rank-order correlations for analyses of convergent and discriminant validity. A panel of experts examined the content validity of the test, and Mann-Whitney U-tests were used to investigate the ability of the test to differentiate the non-clinical group from the ADHD group. Results showed a high level of interrater and intrarater reliability of the test. There was mixed evidence for convergent and discriminant validity as expected due to the novelty and experimental nature of the test, making it difficult to compare with questionnaire-based measures. Content validity analysis was satisfactory, and the group comparison showed that the test differentiated the groups on the primary outcome measure. Overall, the measure demonstrated high feasibility and satisfactory psychometric properties. The generic nature of the test makes it suitable for use across psychiatric disorders and age groups with potential relevance in both research and clinical settings.

Chronic restraint stress in rats causes sustained increase in urinary corticosterone excretion without affecting cerebral or systemic oxidatively generated DNA/RNA damage.

Increased oxidatively generated damage to nucleic acids (DNA/RNA) may be a common mechanism underlying accelerated aging in psychological stress states and mental disorders. In the present study, we measured the urinary excretion of corticosterone and markers of systemic oxidative stress on nucleic acids, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively, in rats subjected to chronic restraint stress. To reliably collect 24h urine samples, the full 3-week restraint stress paradigm was performed in metabolism cages. We further determined frontal cortex and hippocampal levels of oxidatively generated nuclear DNA damage, as measured by oxoguanine DNA glycosylase and formamidopyrimidine DNA glycosylase sensitive sites detected by the comet assay, as well as the expression of genes involved in DNA repair (Ogg1 and Nudt1) and inflammation (Ccl2 and Tnf). The metabolism cage housing in itself did not significantly influence a range of biological stress markers. In the restraint stress group, there was a sustained 2.5 fold increase in 24h corticosterone excretion from day 2 after stress initiation. However, neither whole-body nor cerebral measures of nucleic acid damage from oxidation were affected by stress. In contrast, cerebral DNA repair enzymes exhibited a general trend towards an induction, which was significant for hippocampal Nudt1. The results and their implications for stress sensitivity and resilience are discussed.

Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala.

Although affective disorders have high prevalence, morbidity and mortality, we do not fully understand disease etiopathology, nor have we determined the exact mechanisms by which treatment works. Recent research indicates that intracellular calcium ion dysfunction might be involved. Here we use the chronic restraint stress model of affective disorder (6 h restraint per day for 21 days) in combination with electroconvulsive stimulations to examine the effects of stress and an effective antidepressive treatment modality on L-type voltage gated calcium channel subunit mRNA expression patterns in the brain. We find that stress tended to upregulate Ca(v)1.2 and Ca(v)1.3 channels in a brain region specific manner, while ECS tended to normalise this effect. This was more pronounced for Ca(v)1.2 channels, where stress clearly increased expression in both the basolateral amygdala, dentate gyrus and CA3, while stress only upregulated Ca(v)1.3 channel expression significantly in the dentate gyrus. ECS effects on Ca(v)1.2 channel expression were generally specific to stressed animals. Our findings are consistent with and extent previous studies on the involvement of intracellular calcium ion dysfunction in affective disorders. Selective modulation of neuronal L-type voltage gated calcium channels appears to be a promising target for the development of novel antidepressive treatment modalities.