The Impact of Methylphenidate on Pubertal Maturation and Bone Age in ADHD Children and Adolescents: Results from the ADHD Drugs Use Chronic Effects (ADDUCE) Project.

OBJECTIVE: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. METHOD: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. RESULTS: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. CONCLUSION: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study.

OBJECTIVE: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. METHODS: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). RESULTS: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. CONCLUSION: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

The Association between Nonsuicidal Self-Injury and Perfectionism in Adolescence: The Role of Mental Disorders.

Previous evidence has drawn attention to the fact that maladaptive perfectionism is a risk factor for engagement in nonsuicidal self-injury (NSSI). Until now, few studies have examined this topic, especially among community adolescents. The aim of this study was to explore the relationship between perfectionism dimensions and NSSI functions to examine the potential mediating effect of mental disorders. Altogether, 146 Hungarian community adolescents (ages 13-18 years) were involved. All participants completed the Hungarian adaptation of the Inventory of Statements about Self-Injury (ISAS), the Frost Multidimensional Perfectionism Scale (FMPS), and the Mini International Neuropsychiatric Interview Kid. To analyse the interrelationships among NSSI, perfectionism, and mental disorders, we conducted regression and network analysis. Of the 146 adolescents, 90 (61.64%, girls: 71.11%) engaged in NSSI. The Concern over Mistakes and Doubts about Action scales of the FMPS significantly and positively predicted both NSSI intrapersonal and interpersonal motivation, with comparable effect sizes, and this association was fully mediated by anxiety disorders. There was a significant direct negative relationship between the FMPS Organisation dimension and both main NSSI functions. This study draws attention to an increasing trend and the extremely high NSSI prevalence rate among community adolescents. Adolescents with perfectionistic concerns are at heightened risk for anxiety disorders, which can increase their vulnerability to NSSI engagement.

Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study.

BACKGROUND: Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. METHODS: We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6-17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex). FINDINGS: Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7-11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference -0·07 (95% CI -0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. INTERPRETATION: Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring. FUNDING: EU Seventh Framework Programme.

[Coronavirus Pandemic - #STAYHOME: How Are You Holding Up? Questions And Tips For 11-18-Year-Olds To Make It Better].

PURPOSE: Adolescents have to cope with several challenges and restrictions due to the COVID-19 pandemic, with many of those incongruent with the typical developmental tasks of adolescent age. Some adolescents might be particularly vulnerable in this situation, including those who are deprived of psychological, social or health care services and/or are exposed to abuse or neglect in their home environment. The aims of the current international multicentre follow-up study are to: 1. collect data on the mental health and quality of life of adolescents during and after the pandemic; 2. improve their mental health by providing an online prevention program that addresses their actual needs; 3. accelerate the development of culturally adapted prevention programs by involving an international team, and 4. to contribute to adequate preparation for any potentially occurring, similar situationin the future. METHODS: Participants aged 11-18 years and their parents/caregivers from diff erent parts of Europe and non-European countries are recruited online. Data are collected regularly in a follow-up study by means of structured self-administered online questionnaires on adolescents' mental health, quality of life and current attitudes and needs. The baseline data collection was in March 2020 at first restrictions of the COVID pandemic in Europe. It is followed up several times (at the beginning weekly, later monthly, bi-monthly, three-monthly) to study changes in mental health, quality of life and attitudes of children and adolescents during the coronavirus disease pandemic. Data were collected by means of structured questionnaires (see below). The time frame of the study is set to one year from study start, March 2021. The last data collection was done in December 2020. The prevention program is developed and provided based on continuously analysed incoming data. CONCLUSIONS: Prevention based on the results of the study is expected to contribute to maintaining adolescents' mental health, improve their quality of life, increase their and their environment's cooperation with the necessary restrictions during the pandemic, and to make reintegration easier once the restrictions are over. Furthermore, the study has the potential to inform on the wellbeing of children and adolescents in extreme situations in general, thus contribute to future preventive measures and policymaking. Implications and Contribution: The proposed international online follow-up study is expected to provide scientifi c evidence for 1. possible changes in the mental health and quality of life of adolescents during and after a pandemic situation, 2. the eff ectiveness of a culturally adapted prevention program developed to address challenges associated with these changes.

Long term methylphenidate exposure and growth in children and adolescents with ADHD. A systematic review and meta-analysis.

BACKGROUND: Methylphenidate (MPH) is an efficacious treatment for ADHD but concerns have been raised about potential adverse effects of extended treatment on growth. OBJECTIVES: To systematically review the literature, up to December 2018, conducting a meta-analysis of association of long-term (> six months) MPH exposure with height, weight and timing of puberty. RESULTS: Eighteen studies (ADHD n = 4868) were included in the meta-analysis. MPH was associated with consistent statistically significant pre-post difference for both height (SMD = 0.27, 95% CI 0.16-0.38, p < 0.0001) and weight (SMD = 0.33, 95% CI 0.22-0.44, p < 0.0001) Z scores, with prominent impact on weight during the first 12 months and on height within the first 24-30 months. No significant effects of dose, formulation, age and drug-naïve condition as clinical moderators were found. Data on timing of puberty are currently limited. CONCLUSIONS: Long-term treatment with MPH can result in reduction in height and weight. However, effect sizes are small with possible minimal clinical impact. Long-term prospective studies may help to clarify the underlying biological drivers and specific mediators and moderators.

Long-Term Suicide Risk of Children and Adolescents With Attention Deficit and Hyperactivity Disorder-A Systematic Review.

Background: Attention deficit and hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood. Recently, several studies showed the high suicide risk of patients with ADHD; however, most of these studies had a cross-sectional design. Aims: The aim of the current research is to complete a systematic review of published studies which investigate the suicide risk of ADHD patients with longitudinal design. Methods: The systematic search was made on OVID Medline, PsychInfo, PubMed, Scopus, and Web of Science. The search terms were (ADHD OR attention deficit hyperactivity disorder) AND (suicide OR suicidal OR suicidality) AND (follow-up OR longitudinal study OR prospective study). The inclusion criteria were as follows: written in English; the participants were under 18 years at baseline; longitudinal, prospective studies; ADHD population at baseline and at follow-up; and suicide behavior as a primary outcome. The exclusion criteria were as follows: the study did not contain empirical data and reviews/meta-analyses and studies which aimed to investigate the drug treatment efficacy of ADHD. Results: After the screening process, 18 papers were included in the systematic review. Ten articles were altogether published in the last 5 years. The range of follow-up periods varied between 2 and 17 years. Several different assessment tools were used to investigate the symptoms and/or the diagnosis of ADHD and the suicidal risk. Nine studies enrolled children aged under 12 at baseline, and three studies used birth cohort data, where there was no strict age-based inclusion criteria. A total of 17 studies found a positive association between ADHD diagnosis at baseline and the presence of suicidal behavior and/or attempts at the follow-up visits. Limitations: The main limitation of this review is the methodological heterogeneity of the selected studies. A further limitation is the relatively low number of studies that examined a population with balanced gender ratios. Additionally, only one study published data about the treatment of ADHD. Finally, though we carefully chose the keywords, we still may be missing some relevant papers on this topic. Conclusions: In spite of the methodological diversity of the included studies, the results of the current systematic review highlight the importance of screening suicidality in the long term in patients with ADHD. Therefore, further studies that compare the suicidal risk of treated and untreated groups of ADHD patients in the long term are needed.

Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence.

Methylphenidate (MPH), the most common medication for children with Attention Deficit/Hyperactivity Disorder (ADHD) in many countries, is often prescribed for long periods of time. Any long-term psychotropic treatment in childhood raises concerns about possible adverse neurological and psychiatric outcomes. We aimed to map current evidence regarding neurological and psychiatric outcomes, adverse or beneficial, of long-term MPH (> 1 year) treatment in ADHD. We coded studies using a "traffic light" system: Green: safe/favours MPH; Amber: warrants caution; Red: not safe/not well-tolerated. Un-categorisable study findings were coded as "Unclear". Although some evidence suggests an elevated risk of psychosis and tics, case reports describe remission on discontinuation. Several studies suggest that long-term MPH may reduce depression and suicide in ADHD. Evidence suggests caution in specific groups including pre-school children, those with tics, and adolescents at risk for substance misuse. We identified a need for more studies that make use of large longitudinal databases, focus on specific neuropsychiatric outcomes, and compare outcomes from long-term MPH treatment with outcomes following shorter or no pharmacological intervention.

Effects of long-term methylphenidate use on growth and blood pressure: results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS).

BACKGROUND: Concerns have been raised over the safety of methylphenidate (MPH), with regard to adverse effects on growth and blood pressure. Our study investigates whether, and to what extent, methylphenidate use in boys with ADHD is associated with having low body mass index (BMI), having low height, and increased systolic and diastolic blood pressure. METHODS: Data used for this study stem from the German KiGGS dataset. Three different groups of boys aged 6-15 years were included in the analysis: ADHD patients who used MPH for less than 12 months; ADHD patients who used MPH for 12 months or more; and ADHD patients without current MPH treatment. Each of these three groups was compared to a non-ADHD control group regarding low weight (BMI ≤ 3rd percentile), low height (≤3rd percentile) and raised systolic and diastolic blood pressure. For growth outcomes, boys were categorized according to age (< 11 years/≥11 years, to account for pubertal maturation). Multivariable logistic regression was conducted to test for associations. RESULTS: 4244 boys were included in the study; MPH < 12 months: n = 65 (n = 36 < 11 years), MPH ≥ 12 months: n = 53 (n = 22 < 11 years), ADHD controls: n = 320 (n = 132 < 11 years), non-ADHD controls: n = 3806 (n = 2003 < 11 years). Pre-pubertal boys with MPH use less than 12 months and pubertal/postpubertal boys with MPH use of 12 months or greater were significantly more likely to have a BMI ≤ 3rd percentile compared to non-ADHD controls. Boys from the ADHD control group were significantly less likely to have a raised systolic blood pressure compared to non-ADHD controls. Beyond that, no significant between group differences were observed for any other growth and BP parameter. CONCLUSION: The analyses of the KiGGS dataset showed that MPH use in boys with ADHD is associated with low BMI. However, this effect was only observed in certain groups. Furthermore, our analysis was unable to confirm that MPH use is also associated with low height (≤3rd percentile) and changes in blood pressure.

Plate Alone Versus Plate and Lag Screw for Lapidus Arthrodesis: A Biomechanical Comparison of Compression.

Background. Arthrodesis of the first tarsal metatarsal joint can be accomplished in many ways. The compressive force attained between various constructs remains unclear. This study compares compression achieved through a locking/compression Lapidus plate both with and without the addition of a lag screw. Methods: A dorsal medial Lapidus/locking compression plate (Total Compression Plate System, OrthoPro, Salt Lake City, UT, now Wright Medical) was applied to one cadaveric limb, while the same plate with the addition of a 4.0-mm cannulated lag screw was applied to the contralateral limb for a total of 5 matched pairs of cadaveric specimens. Compressive force was recorded over time and compared between the constructs using a compression sensor (8" FlexiForce Resistive Force Sensor, Phidgets Inc, Calgary, Alberta, Canada). Results: Compression was maintained for 45.4 minutes in the plate only construct, and 317 minutes with the addition of the lag screw (P = .010). The mean time to 50% peak compression for the plate only construct was 4.90 minutes compared with 15.11 minutes for plate with lag screw construct (P = .012). Conclusion: The addition of a lag screw is recommended for extending the length of compression and possibly reducing nonweightbearing time and the risk of nonunion. Levels of Evidence: Level V.

Association of Risk of Suicide Attempts With Methylphenidate Treatment.

Importance: Patients with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk of attempting suicide. Stimulants, such as methylphenidate hydrochloride, are the most common treatment for ADHD, but the association between their therapeutic use and suicide is unclear. Objective: To investigate the association between methylphenidate and the risk of suicide attempts. Design, Setting, and Participants: A population-based, electronic medical records database from the Hong Kong Clinical Data Analysis & Reporting System was used to identify 25 629 individuals aged 6 to 25 years who were treated with methylphenidate between January 1, 2001, and December 31, 2015. Those who had attempted suicide were included in the analysis. A self-controlled case series design was used to control for time-invariant characteristics of the patients. Main Outcomes and Measures: Relative incidence of suicide attempt during periods when patients were exposed to methylphenidate compared with nonexposed periods. Results: Among 25 629 patients with methylphenidate prescriptions, 154 had their first recorded suicide attempt within the study period; of these individuals, 111 (72.1%) were male; mean (SD) age at baseline was 7.15 (2.19) years. The overall incidence of suicide attempts during methylphenidate treatment was 9.27 per 10 000 patient-years. An increased risk of suicide attempts was detected during the 90-day period before methylphenidate was initiated, with an incidence rate ratio (IRR) of 6.55 (95% CI, 3.37-12.72). The IRR remained elevated during the first 90 days of treatment (IRR, 3.91; 95% CI, 1.62-9.42) before returning to baseline levels during ongoing treatment (IRR, 1.35; 95% CI, 0.77-2.38). When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of suicide attempts was not elevated (IRR, 0.78; 95% CI, 0.26-2.35). Conclusions and Relevance: The incidence of suicide attempts was higher in the period immediately before the start of methylphenidate treatment. The risk remained elevated immediately after the start of methylphenidate treatment and returned to baseline levels during continuation of methylphenidate treatment. The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment. Therefore, this study's results do not support a causal association between methylphenidate treatment and suicide attempts.

Open Reduction Internal Fixation of Posterior Malleolus Fractures and Iatrogenic Injuries: A Cadaveric Study.

Open reduction internal fixation of posterior malleolus fractures from a posterior approach is gaining popularity. One concern that has not been studied is the risk of iatrogenic injury to anatomical structures on the anterior ankle. The purpose of this study is to determine the proximity of these anterior structures with relation to K-wires advanced through the anterior cortex. A total of 10 cadaver ankles were utilized in the study. A posterolateral approach to the ankle was used. K-wires were advanced at varying levels above the articular surface, and then, the proximity of the wires to the following structures was determined: the neurovascular bundle, tibialis anterior (TA), and extensor hallucis longus. Overall, the structure most in danger of being injured was the TA (P < .001). This tendon was injured by 52% of all K-wires. These data suggest that K-wires should be advanced under direct fluoroscopic visualization to minimize the risk of iatrogenic injury. LEVELS OF EVIDENCE: Level IV.

Long-term effects of pubertal stressors on female sexual receptivity and estrogen receptor-α expression in CD-1 female mice.

Exposure to stress during puberty can lead to long-term behavioral alterations. Female mice, of the inbred C57BL/6 strain, have been shown to display lower levels of sexual receptivity in adulthood when exposed to shipping stress or to an immune challenge during puberty. The present study investigated whether this effect can be extended to CD1 outbred mice and examined a possible mechanism through which exposure to stressors could suppress sexual receptivity. The results revealed that CD1 mice injected with lipopolysaccharide (LPS) or exposed to shipping stress at 6 weeks old display lower levels of sexual receptivity in response to estradiol and progesterone in adulthood than control mice. Moreover, mice exposed to shipping stress at 8 weeks old also displayed reduced sexual receptivity, but those injected with LPS at that time showed slightly reduced effects, suggesting that the sensitive pubertal period extends to 8 weeks of age in this strain of mice. The examination of estrogen receptor-α (ER-α) expression revealed that mice exposed to shipping stress during the sensitive period (6 weeks) display lower levels of ER-α expression in the medial preoptic area and the ventromedial nucleus and the arcuate nucleus of the hypothalamus than mice shipped at a younger age. These findings support the prediction that exposure to shipping stress or LPS during puberty decreases behavioral responsiveness to estradiol and progesterone in adulthood in an outbred strain of mice through enduring suppression of ER-α expression in some brain areas involved in the regulation of female sexual behavior.