Clarity and applicability of adverse drug reaction-related monitoring instructions in clinical practice guidelines for children and adolescents treated with antipsychotic drugs: a review of six clinical practice guidelines.

OBJECTIVES: Monitoring instructions related to adverse drug reactions (ADRs) are not always clearly described in clinical practice guidelines (CPGs) and not always easily applicable in daily clinical practice. The aim of this study was to assess the clarity of presentation and the applicability of ADR-related monitoring instructions in CPGs for children and adolescents treated with antipsychotic drugs. SETTING: Guidelines from different countries were selected, and monitoring instructions for 13 ADR-related parameters were assessed. PRIMARY AND SECONDARY OUTCOME MEASURES: To assess the clarity and the applicability of the sections concerning monitoring instructions in each CPG, the Appraisal of Guidelines for Research and Evaluation instrument was used. To assess the clarity and the applicability of the monitoring instructions for each ADR-related parameter, the Systematic Information for Monitoring score was used. RESULTS: Six CPGs were included. Overall, the presentation of the monitoring instructions in the different CPGs was clear; three CPGs scored >75%. All CPGs scored lower on applicability, as, for example, the barriers and facilitators were poorly described. The number of ADR-related parameters included in the CPGs varied between 8 and 13. Why and what to monitor was always described for each parameter. When to start monitoring was also often described (90.2%), but when to stop monitoring was less frequently described (37.4%). CONCLUSIONS: The CPGs differed on the parameters that needed to be monitored. Overall, the monitoring instructions were clearly presented, but improvement in their applicability is required. By improving the monitoring instructions, CPGs can provide better guidance on monitoring ADRs in daily clinical practice.

Monitoring of Adverse Drug Reaction-Related Parameters in Children, Youth, and Young Adults Prescribed Antipsychotic Drugs by General Practitioners.

Objective: The aim of the study was to assess monitoring of adverse drug reaction (ADR)-related parameters in children, youth, and young adults treated with second-generation antipsychotic drugs (SGAs) prescribed by general practitioners (GPs). Methods: This retrospective follow-up study included children, youth, and young adults aged 0 - 24 years, who had an initial prescription of an SGA recorded in the Clinical Practice Research Datalink between 2000 and 2017, and who were prescribed an SGA more than once for a duration of at least 6 months. It included an assessment of which ADR-related physical parameters (weight, height, body-mass index, waist circumference, pulse, blood pressure, and heart examination) and laboratory parameters (glucose, HbA1c, lipids, and prolactin) were monitored in children, youth, and young adults at least once every 6-month period, stratified by sex, age categories, and calendar years. Results: In total, 7006 patients were included and the mean duration of follow-up was 1.6 years. Monitoring frequencies of all parameters were below 25%. Blood pressure and weight were monitored in 23.6% and 23.4%, respectively, of all children, youth, and young adults during the first half year; waist circumference was monitored in 0.2%. Females were monitored more often than males, some differences between age categories were observed, and monitoring frequencies increased after 2000, but did not exceed 35% in any year. Conclusion: Monitoring frequencies of ADR-related parameters in children, youth, and young adults treated with SGAs prescribed by a GP were low. Monitoring in primary care should be improved to enable a better evaluation of the benefit-risk balance during antipsychotic drug therapy.

Monitoring of Adverse Drug Reaction-Related Parameters in Children and Adolescents Treated With Antipsychotic Drugs in Psychiatric Outpatient Clinics.

Aim: To assess the frequency of monitoring of adverse drug reaction (ADR) related parameters in children and adolescents treated with antipsychotic drugs in psychiatric outpatient clinics and the considerations when monitoring was not performed. Methods: This retrospective follow-up study included 100 randomly selected outpatients aged ≤18 years who had a first prescription of an antipsychotic drug recorded in the electronic medical records of psychiatric outpatient clinics between 2014 and 2017. They were followed for up to 3 years. This study assessed the frequency of monitoring for physical parameters (weight, height, body mass index, waist circumference, pulse, blood pressure, and an electrocardiogram) and laboratory parameters (glucose, lipids, and prolactin) before the first prescription of an antipsychotic drug as well as during its use. Monitoring frequencies were stratified by the patient characteristics (sex, age, cardiovascular risk factors, and use of other psychotropic drugs), and by location of antipsychotic drug initiation (psychiatric outpatient clinic or elsewhere). Additionally, this study assessed the considerations mentioned in the medical records for not monitoring ADR-related parameters. Results: Overall, physical parameters were monitored more frequently (weight: 85.9% during the first half-year) than laboratory parameters (glucose and cholesterol: both 23.5%). There were no significant differences in monitoring at least one physical as well as in monitoring at least one laboratory parameter during the baseline period and during the total follow-up of antipsychotic drug treatment between the patient characteristics. In total, 3% of the children and adolescents were never monitored for any physical parameter, and 54% were never monitored for any laboratory parameter. For a minority of the children (14.8%) who were never monitored for laboratory parameters, considerations were recorded in their medical records, including refusal by the child or parents and monitoring performed by the general practitioner or elsewhere. Conclusion: Monitoring frequencies of ADR-related parameters in children and adolescents treated with antipsychotic drugs in psychiatric outpatient clinics varied and especially monitoring of laboratory parameters was infrequent. Considerations why monitoring was not performed were rarely recorded. The optimal method of monitoring and documentation thereof should become clear to optimize the benefit-risk balance of antipsychotic drug treatment for each child.

Which Child Will Benefit From a Behavioral Intervention for ADHD? A Pilot Study to Predict Intervention Efficacy From Individual Reward Sensitivity.

Objective: This article aims to assess whether individual differences in reward sensitivity can be used to predict which children with attention-deficit/hyperactivity disorder (ADHD) will benefit most from behavioral interventions that include reinforcement. Methods: A 12-week behavioral intervention was offered to 21 children with ADHD and their parents. Reward sensitivity was assessed prior to the intervention using a combination of psychological and physiological measures. ADHD symptoms were assessed pre- and posttreatment using the Strengths and Weaknesses of ADHD and Normal behavior (SWAN) rating scale. Results: Lower scores on one of the questionnaire scales were associated with greater pre/posttreatment differences in ADHD symptoms. Conclusion: We found that pre/posttreatment change was associated with one measure of parent-rated reward sensitivity. Children with low impulsive negative behavior toward gaining reward improved most during treatment. This result suggests that aspects of reward-related behaviors in ADHD may be useful to predict the effectiveness of treatment.

Reported Adverse Drug Reactions in Children and Adolescents Treated with Antipsychotics.

OBJECTIVES: To characterize reported adverse drug reactions (ADRs) in children and adolescents treated with antipsychotics and determine differences in relative reporting frequency between genders, age classes, and reporter types. METHODS: Individual case safety reports of children ages 1 - 17 years in whom an antipsychotic drug was the suspected or interacting drug from the worldwide database, VigiBase, from 1968 until March 2017, were included. Reported ADRs were categorized based on the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries and clinical reasoning. Proportional reporting ratios (PRRs) and 95% confidence intervals (95% CIs) were calculated for genders, age classes, and reporter types. RESULTS: In total, 45,201 reported ADRs were included. The most frequently reported were ADRs related to extrapyramidal syndrome (14.7%), breast disorders or blood prolactin level changes (4.7%), and cardiac arrhythmias (4.6%). Differences in relative reporting frequencies were observed between age classes and reporter types, and less prominent between genders. For example, ADRs related to hyperglycemia/new-onset diabetes mellitus were less frequently reported in children ages 1 - 5 than in children ages 12 - 17 (PRR: 0.4, 95% CI: 0.2 - 0.5). ADRs related to cardiac arrhythmias were less frequently reported by consumers compared with health care professionals (PRR: 0.5, 95% CI: 0.5 - 0.6), whereas ADRs related to a change in weight/body mass index were more frequently reported by consumers (PRR: 3.2, 95% CI: 2.9 - 3.5). CONCLUSION: A wide spectrum of ADRs were reported in children treated with antipsychotics. The relative differences in reporting frequency between age classes and reporter types can be of help to tailor information about possible ADRs and to monitor for ADRs.

Monitoring of Metabolic, Cardiac, and Endocrine Indicators in Youth Treated With Antipsychotics as Reported by Health Care Professionals.

BACKGROUND: It is unclear how youth treated with antipsychotics are monitored. The purpose of this study was to assess monitoring of metabolic, cardiac, and endocrine indicators in youth (<18 years old) treated with antipsychotics as reported by health care professionals in the Netherlands. METHODS: A questionnaire was designed to collect information from health care professionals regarding the monitoring of youth treated with antipsychotics. Data were collected at a national conference. FINDINGS AND RESULTS: Fifty-nine health care professionals completed the questionnaire, of which 53 (89.8%) were child and adolescent psychiatrists (approximately 20% of all child and adolescent psychiatrists in the Netherlands). More than 80% of respondents reported monitoring physical indicators-weight, height, body mass index, heart rate, and blood pressure-and over 50% reported monitoring laboratory indicators-lipid profile, blood glucose, and prolactin level. Most of the respondents reported monitoring physical indicators more than twice per year and laboratory indicators once per year. Almost all respondents (56/59, 94.9%) reported monitoring according to a clinical guideline or protocol. Only 1 respondent reported monitoring the indicators completely according to the clinical guideline. Respondents mentioned that facilitating factors for monitoring, such as access to electrocardiogram facilities, were insufficiently available. CONCLUSIONS: Although all health care professionals reported monitoring metabolic, cardiac, and endocrine indicators in youth treated with antipsychotics, great variability exists in reported monitoring practices. Factors contributing to this variability must be assessed to optimize the benefit-risk ratio for the individual patient.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

Effectiveness of the Incredible Years Parenting Program for Families with Socioeconomically Disadvantaged and Ethnic Minority Backgrounds.

Families with socioeconomically disadvantaged and ethnic minority backgrounds are often hard to reach for the prevention and treatment of disruptive child behavior problems. We examined whether the Incredible Years parenting intervention can successfully reach and benefit families with socioeconomic disadvantaged and ethnic minority backgrounds in the Netherlands. One hundred fifty-four families from a wide range of socioeconomic and ethnic backgrounds were recruited in an outpatient clinic for child and adolescent psychiatry and in elementary schools serving deprived neighborhoods. Families were randomly assigned to the BASIC Incredible Years parenting intervention or a waiting list control condition. Children were 3-8 years old (M = 5.59, SD = 1.35; 62% boys, 66% ethnic minorities) and 65% of the children met Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) criteria for oppositional defiant disorder, conduct disorder, and/or attention-deficit hyperactivity disorder. Incredible Years reduced parent-reported disruptive child behavior and teacher-reported hyperactive and inattentive child behavior and increased parent-reported use of praise and incentives and reduced harsh and inconsistent discipline. Incredible Years did not affect parent-reported hyperactive and inattentive child behavior; teacher-reported child conduct problems; and parent-reported use of appropriate discipline techniques, clear expectations, physical punishment, and parenting stress. Of importance, the effectiveness of Incredible Years did not differ across families with different socioeconomic and ethnic backgrounds. Effects were maintained at 3-month follow-up. This study shows that socioeconomically disadvantaged and ethnic minority families in disadvantaged neighborhoods can be engaged in and benefit from parenting interventions to reduce disruptive child behavior.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder.

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD.

Differences in ADHD medication usage patterns in children and adolescents from different cultural backgrounds in the Netherlands.

PURPOSE: Differences in incidence and prevalence of ADHD medication use between ethnic groups have been reported. Goal of this study was to determine whether there are also differences in usage patterns of ADHD medication among native Dutch children and adolescents and those with a Moroccan, Turkish and Surinam cultural background in the Netherlands between 1999 and 2010. METHODS: In a cohort of ADHD patients <19 years (N = 817) incident use and discontinuation of ADHD medication were measured for ethnicity and adjusted for age, gender and socio-economic status. RESULTS: A significant higher proportion of ADHD-diagnosed patients from Moroccan (32 %) and Turkish (42 %) cultural background never used ADHD medication compared to Dutch natives (21 %). One-fifth of native Dutch and Turkish patients already used ADHD medication before the ADHD diagnosis date. Discontinuation of ADHD medication within 5 years was significantly higher in Moroccan [HR 2.4 (95 % CI 1.8-3.1)] and Turkish [HR 1.7 (95 % CI 1.1-2.6)] patients. A sensitivity analysis with a zip code-matched comparison between Dutch natives and non-natives showed similar results, suggesting this effect is probably not explained by socio-economic status (SES). CONCLUSION: Differences are found in prescribing and use of ADHD medication between patients with a different cultural background. Native Dutch and Turkish patients start more frequently with ADHD medication before the ADHD diagnose date, which can be an indication of differences in either referral patterns and/or access to care. A higher percentage of patients with a Moroccan and Turkish cultural background never start using ADHD medication at all and discontinuation rate is higher compared to Dutch natives and Surinamese.

Association between ADHD drug use and injuries among children and adolescents.

To study the association between attention deficit hyperactivity disorder (ADHD) drug use and the incidence of hospitalization due to injuries. A random sample of 150,000 persons (0-18 years) was obtained from the Dutch PHARMO record linkage system. An ADHD medication cohort as well as an up to six age/sex/index date sampled control cohort with no history of ADHD drug use was formed. Differences in incidence of hospitalization due to injuries were stratified for age and sex and compared prior, during and after exposure on ADHD drugs. The overall incidence of hospital admissions for injuries was two times higher in the ADHD medication cohort [incidence rate ratios (IRR) 2.2 (95 % CI 1.6-2.9)]. The incidence rate for injuries during exposure to ADHD drugs was lower in the exposed period compared to the period prior to ADHD drug use, although the difference was not statistically significant [IRR 0.68 (95 % CI 0.29-1.60)]. The relative risk for injuries was almost five times higher in the ADHD medication cohort among those who concomitantly used other psychotropics [IRR 4.8 (95 % CI 1.4-16.9)]. Risk for injuries was highest in 12-18 years olds. Children and adolescents using ADHD medication showed a twofold risk for hospital admissions for injuries. ADHD drug use might diminish the increased injury risk, but still overall risk is higher than in age/sex sampled children and adolescents without treatment with ADHD drugs. Use of ADHD and concomitant psychotropics increases the risk for injuries compared to only ADHD drug use.

Trends in incidence and characteristics of children, adolescents, and adults initiating immediate- or extended-release methylphenidate or atomoxetine in the Netherlands during 2001-2006.

BACKGROUND: Previous Dutch studies showed increasing psychostimulant use, especially methylphenidate immediate-release (MPH-IR), between 1995 and 2003. In 2003 the extended-release (ER) formulation of MPH and in 2005 atomoxetine (ATX) were introduced in The Netherlands, which increased treatment options. OBJECTIVE: The aim of this study was to describe the change in incidence of attention-deficit/hyperactivity disorder (ADHD) drugs and the prescription profiles of patients younger than 45 years starting treatment with these medicines between 2001 and 2006. METHODS: Data were obtained from Dutch community pharmacies as collected by the Foundation for Pharmaceutical Statistics, covering 97% of all dispenses for prescription medicines to outpatients in The Netherlands. RESULTS: The overall incidence of ADHD drugs use increased 6.5-fold from 2001 to 2006 in men as well as in women. The absolute incidence was highest among 6- to 11-year-old boys. The percentage of first-time MPH-IR users decreased from 98.3% in 2001 to 75.9% in 2006. Likewise, MPH-ER use increased from 0% in 2001 to 18.9% in 2006, and ATX use increased from 0% in 2001 to 3.9% in 2006. The new nonstimulant drug ATX was prescribed more often to adults if they had been previously treated with selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, or antipsychotics. Youngsters <17 years initiated on ATX were often previously treated with antipsychotics or clonidine/guanfacine. CONCLUSION: These findings demonstrate an increase in incidence in use of ADHD drugs between 2001 and 2006 in The Netherlands. The major proportion of all treated patients comprised boys, 6-11 years old; most of them were treated with MPH-IR. In a few years time, the use of extended-release drugs as part of all ADHD drug prescriptions increased considerably, despite the lack of full reimbursement of these extended-release drugs. Psychostimulants and atomoxetine in children, adolescents, and adults are probably used to address different treatment needs.

Less discontinuation of ADHD drug use since the availability of long-acting ADHD medication in children, adolescents and adults under the age of 45 years in the Netherlands.

Treatment options for ADHD in the Netherlands have increased with the introduction of the extended-release formulations of methylphenidate (MPH ER, Concerta(®)) in 2003 and atomoxetine (ATX, Strattera(®)) in 2005, but data on the effect on drug usage patterns are scarce. The objective of the present study was to describe changes in the patterns of ADHD medication use and determinants thereof among children, adolescents and adults (<45 years) starting ADHD medication since the introduction of MPH ER and ATX. Data were obtained from Dutch community pharmacies as collected by the Foundation for Pharmaceutical Statistics, covering 97% of all dispenses for prescription medicines to outpatients in the Netherlands. Usage patterns (continuation, discontinuation, switching and addition) of ADHD drugs were evaluated at 3, 6 and 12 months after initiation for three separate time cohorts (patients starting ADHD medication in Jan-Dec 2002, Jan 2003-June 2004, respectively July 2004-Dec 2005). It was found that between 2002 and 2006, most ADHD drug users were initiated on methylphenidate IR. Discontinuation of any ADHD drug treatment decreased over time partly in favour of switching and addition. Discontinuation at 3 months decreased from around 33% to around 25%, at 6 months from less than 50% to almost 35%, and at 12 months from just fewer than 60% to less than 45%. Discontinuation was higher among females and in adults >18 years. After the introduction of MPH ER and ATX (time cohort III), 16.5% of the incident ADHD drug users switched their medication and almost 9% added an ADHD drug to the prior ADHD drug. In conclusion, discontinuation of incident ADHD drug use is high after 3, 6 and 12 months. During the study period, the incidence of discontinuation decreased because of the availability of extended-release methylphenidate and atomoxetine.

Current issues around the pharmacotherapy of ADHD in children and adults.

BACKGROUND: New drugs and new formulations enter the growing market for ADHD medication. The growing awareness of possible persistence of ADHD impairment beyond childhood and adolescence resulting in increased pharmacotherapy of ADHD in adults, is also a good reason for making an inventory of the what is generally known about pharmacotherapy in ADHD. AIM: To discuss current issues in the possible pharmacotherapy treatment of ADHD in children, adolescents and adults with respect to the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used. METHODS: A search of the literature with an emphasis on the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used in pharmacotherapy. RESULTS: According to the guidelines, the treatment of ADHD in children consists of psychosocial interventions in combination with pharmacotherapy when needed. Stimulants are the first-choice drugs in the pharmacological treatment of ADHD in children despite a number of well known and frequently reported side effects like sleep disorders and loss of appetite. With regard to the treatment of adults, stimulant treatment was recommended as the first-choice pharmacotherapy in the single guideline available. Both in children and adults, there appears to be an additional though limited role for the nonadrenergic drug atomoxetine. The increase of ADHD medication use, in children, adolescents and in adults, can not only be interpreted as a sign of overdiagnosis of ADHD. Despite the frequent use of stimulants, there is still a lack of clarity on the effects of long-term use on growth and nutritional status of children. Cardiovascular effects of both stimulants and atomoxetine are rare but can be severe. The literature suggests that atomoxetine may be associated with suicidal ideation in children. CONCLUSION: Although pharmacotherapy is increasing common in the treatment of ADHD in both children and adults, there are still a lot of questions about side effects and how best to counter them. This suggests an important role for close monitoring of children and adults treated with stimulants or atomoxetine.