Understanding patient characteristics and medication prescriptions in children with mental health and neurodevelopmental disorders referred to a sleep clinic-A quality improvement/quality assurance analysis.

Introduction: Motivated by challenges faced in outpatient sleep services for mental health and neurodevelopmental disorders (MHNDD) during the COVID-19 clinical shutdown, a pan-Canadian/international working group of clinicians and social scientists developed a concept for capturing challenging sleep and wake behaviours already at the referral stage in the community setting. Methods: In a quality improvement/quality assurance (QIQA) project, a visual logic model was the framework for identifying the multiple causes and possible interventions for sleep disturbances. Intake forms informed clinicians about situational experiences, goals/concerns, in addition to the questions from the Sleep Disturbances Scale for Children (SDSC), the ADHD Rating Scale-IV and medication history. Descriptive statistics were used to describe the sample. Results: 66% of the pilot study patients (n = 41) scored in the SDSC red domains (highest scoring) with highest sub-scores for insomnia (falling asleep 73%; staying asleep: 51%) and daytime somnolence (27%). A total of 90% of patients were taking at least one medication; 59% sleep initiation/sleep medications, 41% in combination with further non-stimulant medications, 9% with stimulants, 27% with antidepressants and 18% with antipsychotics. Polypharmacy was observed in 62% of all patients and in 73% of the ones medicated for sleep disturbances. Qualitative information supported individualisation of assessments. Conclusion: Our intake process enabled a comprehensive understanding of patients' sleep and wake profiles prior to assessment, at the referral stage. The high prevalence of insomnia in patients, combined with polypharmacy, requires special attention in the triaging process at the community level.

Sleep as an outcome measure in ADHD randomized controlled trials: A scoping review.

Sleep disturbances are highly prevalent among children with ADHD. Yet, diagnostic and treatment regimens are primarily focused on daytime symptomatology. The goals of this scoping review are to 1) identify interventional ADHD RCTs that have used sleep as an outcome measure, 2) describe and assess the validity of tools utilized to measure sleep-specific outcomes. 40/71 RCTs used sleep as a primary outcome. Actigraphy (n = 18) and sleep log/diary (n = 16) were the most common tools to measure sleep, followed by Children's Sleep Habits Questionnaire (n = 13), and polysomnography (n = 10). Sleep was a secondary outcome in 31 RCTs. Polysomnography and actigraphy used a heterogeneous spectrum of sleep-related variables and technical algorithms, respectively. 19/23 sleep questionnaires were validated covering a spectrum of sleep-related domains. Despite the intrinsic nature of sleep disturbances in ADHD, the number of RCTs measuring sleep-specific outcomes is limited and tools to measure outcomes are not standardized. Given the potential adverse effects of ADHD medications on sleep, sleep should be included as a core outcome measure in future clinical trials.

Celecoxib versus placebo as an adjunct to treatment-as-usual in children and youth with obsessive-compulsive disorder: protocol for a single-site randomised quadruple-blind phase II study.

BACKGROUND: Cyclooxygenase (COX) enzymes oxidise arachidonic acid to prostaglandins, which modulate neuronal function and inflammation in the central nervous system. Consensus guidelines suggest non-steroidal anti-inflammatory drugs as a possible adjunctive approach in adults with obsessive-compulsive disorder (OCD) and in children with acute-onset OCD subtypes. However, there is limited evidence to support this approach. The primary objective of this study is to determine the efficacy of the COX-2-selective inhibitor celecoxib as an adjunct to treatment-as-usual in children and youth with moderate-to-severe OCD. The safety of this intervention including adverse events will also be systematically assessed. METHODS: The Adjunctive CElecoxib in childhood-onset OCD (ACE-OCD) study is a single-centre randomised, quadruple-blind, placebo-controlled superiority trial with two parallel groups: celecoxib 100 mg twice daily and placebo. Treatments will be added to participants' routine clinical care, which will not change over the course of the study. Target recruitment is 80 participants ages 7-18 with no recent treatment changes. The primary outcome is OCD severity after 12 weeks of treatment, measured by clinician-administered Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Secondary outcomes include CY-BOCS score after 6 weeks; difference in the proportion of participants achieving a clinically meaningful response or remission; mean clinical global impression of severity and improvement after 6 and 12 weeks; and proportion of participants reporting adverse events possibly or probably related to the study intervention. The primary analyses, carried out according to intention-to-treat principles, will compare the celecoxib to placebo group on each outcome of interest, adjusting for baseline scores using analysis of covariance or logistic regression. Participants will be offered a 12-week open-label celecoxib extension and will be invited to participate in an ancillary study for biomarker analyses. ETHICS AND DISSEMINATION: This protocol has been approved by the University of British Columbia Children's and Women's Research Ethics Board and has received a No Objection Letter from Health Canada. The findings will be disseminated in peer-reviewed journals and presentations to multiple stakeholders including patients, parents and healthcare providers. TRIAL REGISTRATION NUMBER: NCT04673578.

Psychiatric Manifestations in Patients with Biopterin Defects.

Psychiatric manifestations in patients with tetrahydrobiopterin (BH4) defects are common, and may occur even with treatment of the underlying disorder. The neurobiological background of these conditions has been linked to abnormalities of neurotransmitters, such as dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid. Here, we review the psychiatric profile of all patients with BH4 defects followed in the pediatric and adult metabolic clinics at our center. Three patients with autosomal recessive (AR) guanosine triphosphate cyclohydrolase (GTPCH) deficiency and three patients with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency were reviewed.All patients had behavioral disturbances and two had significant psychiatric comorbidities. These included attention deficit/hyperactivity disorder, anxiety, depression, aggression, or oppositional defiant disorder. One patient with PTPS deficiency had a severe psychiatric presentation, requiring inpatient admission and temporary placement into foster care for intensive behavioral therapy. Another with AR GTPCH deficiency was diagnosed with aggressive behavioral dysregulation requiring intensive psychiatric treatment. Management of the psychiatric manifestations of BH4 defects can be challenging, due to lack of information and studies of interactions between psychiatric medications on the deficient neurotransmitters and their receptors in these conditions. Further studies are needed to establish safety and efficacy of these treatments.

Retrospective Review of Fluvoxamine-Clomipramine Combination Therapy in Obsessive-Compulsive Disorder in Children and Adolescents.

OBJECTIVES: To inform dosing and describe the pharmacokinetic interaction, efficacy and safety of fluvoxamine-clomipramine combination therapy for treatment-resistant pediatric obsessive-compulsive disorder (OCD). METHODS: A retrospective chart review of OCD-affected patients at a tertiary care children's hospital between January 2010 and August 2017 was conducted. Those included were 18 years of age or younger at initiation of fluvoxamine-clomipramine combination therapy and had at least one set of serum concentration values capturing clomipramine and desmethylclomipramine levels. RESULTS: Six adolescents met study inclusion criteria. Fluvoxamine adequately inhibited clomipramine metabolism to desmethylclomipramine in a dose-dependent manner. Fluvoxamine-clomipramine combination therapy was generally well tolerated with no serious or life-threatening adverse effects reported. CONCLUSION: Fluvoxamine-clomipramine combination therapy permits use of lower clomipramine doses than typically used as clomipramine monotherapy and appears to be a safe alternative for pediatric OCD patients failing sequential selective serotonin reuptake inhibitor monotherapy trials. Inter-patient variability and saturable kinetics support therapeutic drug monitoring of serum clomipramine and desmethylclomipramine concentrations to optimize therapy. A proposed algorithm that aligns with current OCD treatment guidelines is described. Further study is needed to evaluate efficacy of this approach.

OBJECTIFS: Préciser la posologie et décrire l'interaction pharmacocinétique, l'efficacité et l'innocuité de la thérapie combinée fluvoxamine-clomipramine pour le trouble obsessionnel-compulsif (TOC) pédiatrique réfractaire au traitement. MÉTHODES: Une revue de dossiers rétrospective de patients souffrant du TOC à un hôpital pour enfants de soins tertiaires entre janvier 2010 et août 2017 a été menée. Les patients inclus avaient 18 ans ou moins lors de l'initiation de la thérapie combinée fluvoxamine-clomipramine et avaient au moins une série de valeurs de concentration sérique pour le captage des taux de clomipramine et de desméthylclomipramine. RÉSULTATS: Six adolescents satisfaisaient aux critères d'inclusion de l'étude. La fluvoxamine inhibait adéquatement le métabolisme de la clomipramine pour la desméthylclomipramine de manière dose-dépendante. La thérapie combinée fluvoxamine-clomipramine était généralement bien tolérée sans effets indésirables sérieux ou dangereux déclarés. CONCLUSION: La thérapie combinée fluvoxamine-clomipramine permet d'utiliser des doses plus faibles de clomipramine que celles habituellement utilisées en monothérapie de clomipramine et semble être une solution de rechange sûre pour les patients du TOC pédiatrique qui ne répondent pas aux essais de monothérapie d'inhibiteurs sélectifs séquentiels de recaptage de la sérotonine. La variabilité inter-patients et la cinétique saturable soutiennent le contrôle des médicaments thérapeutiques et des concentrations sériques de clomipramine et de desméthylclomipramine afin d'optimiser la thérapie. Un algorithme proposé qui correspond aux lignes directrices du traitement du TOC est décrit. Il faut d'autres études pour évaluer l'efficacité de cette approche.

Retrospective Review of Clozapine Use in Children and Adolescents.

OBJECTIVE: Literature describing use of clozapine by children and adolescents is limited. The primary study objective was to assess the patterns of clozapine use in an inpatient child and adolescent population. METHODS: A retrospective review of child and adolescent inpatients receiving clozapine at a Canadian children's hospital from January 2000 through December 2014 was conducted. Interdisciplinary comprehensive data collection was conducted by experienced clinicians. Baseline population characteristics and psychiatric illness risk factors were captured. Illness symptoms and severity were assessed retrospectively using validated measures including the Brief Psychiatric Rating Scale (BPRS), Children's Global Assessment Scale (CGAS) and Clinical Global Impressions (CGI) scales. Estimated clozapine dosing requirements for each patient to achieve a serum level associated with response was calculated. Clozapine-related adverse events were captured. RESULTS: Twenty-eight inpatients (64% female) receiving clozapine during the study period were identified. Mean age at clozapine initiation was 15.8 years. Twenty-three patients (82%) were taking clozapine at discharge, and of these, 22 patients (96%) experienced at least minimal improvement in BPRS and CGAS scores. Patients took a mean of 33.1 days from clozapine start to reach their maximum clozapine dosage, a mean maximum of 57% of their estimated clozapine dose requirement. Mean length of stay following clozapine initiation was 60.7 days. We observed a high rate of benign hematological adverse events, but no episodes of severe neutropenia. The majority of patients were of ethnicity associated with high risk for metabolic adverse events. CONCLUSION: Most hospitalized, treatment-refractory children requiring clozapine clinically improve despite experiencing high, but largely manageable, adverse event rates.

OBJECTIF: La littérature décrivant l'utilisation de la clozapine par les enfants et les adolescents est limitée. Le premier objectif de l'étude était d'évaluer les modèles de l'utilisation de la clozapine dans une population hospitalisée d'enfants et d'adolescents. MÉTHODES: Une revue rétrospective d'enfants et d'adolescents hospitalisés recevant de la clozapine dans un hôpital canadien pour enfants de janvier 2000 à décembre 2014 a été menée. Une collection de données interdisciplinaires détaillées a été menée par des cliniciens d'expérience. Les caractéristiques de la population au départ et les facteurs de risque de maladie psychiatrique ont été captés. Les symptômes et la gravité de la maladie ont été évalués rétrospectivement à l'aide de mesures validées notamment l'échelle abrégée d'évaluation psychiatrique (BPRS), l'échelle d'évaluation globale des enfants (CGAS) et les échelles d'évaluation clinique (CGI) Les besoins de dosage estimés de clozapine pour que chaque patient obtienne un niveau sérique associé à la réponse ont été calculés. Les effets indésirables liés à la clozapine ont été captés. RÉSULTATS: Vingt-huit patients hospitalisés (64% de sexe féminin) recevant de la clozapine durant la période de l'étude ont été identifiés. L'âge moyen lors de l'initiation de la clozapine était de 15,8 ans. Vingt-trois patients (82%) prenaient de la clozapine au congé, et sur ceux-là, 22 patients (96%) connaissaient au moins un minimum d'amélioration aux scores de BPRS et CGAS. Les patients ont pris une moyenne de 33,1 jours à partir du début de la clozapine pour apprendre à connaître leur dosage maximum de clozapine, un maximum moyen de 57% de leur besoin estimé, de dose de clozapine. La durée de séjour moyenne suivant l'initiation de clozapine était de 60,7 jours. Nous avons observé un taux élevé d'effets indésirables d'hématologie bénigne mais aucun épisode de neutropénie grave. La majorité des patients étaient d'une ethnicité associée à un risque élevé d'événements métaboliques indésirables. CONCLUSION: La plupart des enfants réfractaires au traitement hospitalisés nécessitant de la clozapine s'améliorent cliniquement même s'ils connaissent des effets indésirables élevés mais largement traitables.

Management of Acute Agitation and Aggression in Children and Adolescents with Pro Re Nata Oral Immediate Release Antipsychotics in the Pediatric Emergency Department.

Background: Acute agitation in the pediatric emergency department (ED) has the potential to escalate into aggression and result in harm. Rapid and effective management may be warranted. Use of pro re nata (prn) oral immediate-release (IR) quetiapine, haloperidol, loxapine, and chlorpromazine has been observed in the pediatric ED at Surrey Memorial Hospital to manage this condition; however, evidence for oral prn antipsychotic use is limited in the pediatric population. Objectives: The primary objective is to characterize the dose of prn oral IR quetiapine used to manage acute agitation or aggression in a pediatric ED. Secondary objectives include characterizing the dose of prn oral IR haloperidol, loxapine, and chlorpromazine; and describing the 1-hour response rate, admission rate, length of stay (LOS), and adverse drug effects. Method: The medical records of pediatric patients who received at least one prn oral dose of IR quetiapine, haloperidol, loxapine, or chlorpromazine for acute agitation and aggression, without regard to the etiology of symptom presentation, between January 1, 2012 and December 31, 2016, were analyzed retrospectively. Results: Sixty-nine patients met the inclusion criteria. The mean dose of quetiapine was 32 mg/dose (0.54 mg/kg per dose); and the response rate was 53%. The mean haloperidol, loxapine, and chlorpromazine doses were 4 mg (0.07 mg/kg per dose), 13 mg (0.19 mg/kg per dose), and 29 mg/dose (0.53 mg/kg per dose) respectively; and the response rates were 36%, 30%, and 50%, respectively. Between 19% and 60% of patients were admitted, majority to the psychiatry ward. The median LOS in the ED was between 5 and 18 hours for nonadmitted patients. Extrapyramidal side effects (EPS) were reported with first-generation antipsychotics (FGA), but not with quetiapine. Conclusion: Quetiapine appears to be a viable agent for managing acute agitation and aggression in the pediatric ED with low rates of EPS. Further studies are encouraged to compare the effectiveness of quetiapine with FGA. A Clinical Trial Registration number is not applicable for this study.

Lifesaving Electroconvulsive Therapy for a Child With Autism Spectrum Disorder, Severe Self-Injurious Behavior, and Neuroleptic Malignant Syndrome.

We present a case of a preteen with autism spectrum disorder and severe self-injurious behavior who developed neuroleptic malignant syndrome on antipsychotics and required urgent electroconvulsive therapy and continued maintenance electroconvulsive therapy for ongoing clinical stability.

Stimulant 'rapid metabolizers': wrong label, real phenomena.

This is a review of the empirical literature regarding what has been described anecdotally as patients who are 'rapid metabolizers' of stimulant medication. The authors propose that this is a misnomer used to describe two types of atypical pharmacokinetic patterns of response: high-dose responders, short-duration responders and two types of atypical pharmacodynamics patterns of response: patients who develop either acute or chronic tolerance. The authors propose that use of more precise terminology should facilitate both patient education and research to better understand the physiology and clinical management of atypical response patterns to stimulant treatment. Presently, the understanding of the pharmacokinetics and pharmacodynamics of psychostimulants is still quite limited. Further scientific research is needed to understand unusual patterns of pharmacological response seen in the clinic. Careful identification and precise description of these patterns would facilitate understanding the pharmacokinetics and pharmacodynamics of stimulants impacts the atypical response patterns seen in the clinic.

Therapeutic drug levels of second generation antipsychotics in youth: a systematic review.

OBJECTIVE: In children and adolescents, the prevalence rate of mental illness is claimed to be as high as 10-20%. Effective pharmacological treatments are available for use in children, adolescents, and adults; however, most of what is known about the effects of these treatments has been confirmed in clinical studies involving adults only. Second generation antipsychotic drugs (SGAs) are the most common class of antipsychotic medication used in pediatric populations, and these drugs are increasingly being used for disorders other than psychosis. Many SGAs are routinely used in pediatric care, and the vast majority of use in this population is off label. Children, adolescents, and adults differ in age, weight, height, and metabolism, which may lead to pharmacokinetic differences in how drugs ultimately affect target tissues. The aim of this review is to summarize and evaluate the literature that investigated blood plasma levels of SGAs in youth. METHODS: Plasma levels were assessed in relation to their administered dose, indication, and therapeutic range (if known). Studies were limited to those evaluating oral administration only. A systematic electronic database search for peer-reviewed articles published between 2000 and 2013 was conducted. Twenty-one articles were included in the review. Additional articles for discussion were also included throughout the article. RESULTS: The only SGA that may require routine therapeutic drug monitoring (TDM) in youth given the current body of research is clozapine. Highly variable results were seen in studies of aripiprazole, olanzapine, and risperidone, indicating that more research is needed on plasma levels with these drugs. Quetiapine maintained a similar profile to that found in adults, with no dosage adjustments or indications of TDM. CONCLUSION: TDM may be indicated in any circumstance in which cytochrome P450 inhibitors or inducers are coprescribed. Further research is required for establishing a sounder safety profile for SGA use in the pediatric population.

Focus on Guanfacine Extended-release: A Review of its Use in Child and Adolescent Psychiatry.

OBJECTIVE: To review the basic pharmacology and published literature regarding use of guanfacine extended-release (GXR) for the treatment of attention deficit/hyperactivity disorder in children and adolescents. METHODS: A LITERATURE REVIEW WAS CONDUCTED USING THE SEARCH TERMS: 'guanfacine', with limits set to: Human trials, English Language, and All Child (Age 0-18). Articles pertaining to guanfacine immediate-release or for indications other than attention deficit/hyperactivity disorder (ADHD) were not included for analysis. Additional articles were identified from reference information and poster presentation data. RESULTS: Six prospective, randomized controlled trials (RCT) and four open-label trials (including two long-term safety extension trials) were identified for GXR in the treatment of ADHD. All published RCTs showed superiority over placebo on the primary outcome measure. Subgroup analysis of available RCT data showed no efficacy of GXR at any dose in adolescents. Adverse effects in GXR trials were generally mild to moderate. High rates of early discontinuation were observed in long-term open-label extension trials. CONCLUSION: GXR is an effective option for treatment of ADHD in patients 6-12 years of age as monotherapy, or as adjunctive treatment to psychostimulants.

OBJECTIF: Effectuer une revue de la pharmacologie de base et de la littérature publiée sur l'utilisation de la guanfacine à action prolongée (GXR) pour le traitement du trouble de déficit de l'attention avec hyperactivité (TDAH) chez les enfants et les adolescents. MÉTHODES: Une revue de la littérature a été menée à l'aide des mots clés « guanfacine ¼', et des limites suivantes: essais sur des humains, langue anglaise, et tous les enfants (0­18 ans). Les articles traitant de la guanfacine à action immédiate ou pour indications autres que le TDAH n'ont pas été inclus dans l'analyse. Les articles additionnels ont été repérés dans des bibliographies et les données de présentations par affiches. RÉSULTATS: Six essais randomisés contrôlés (ERC) prospectifs, et quatre essais ouverts (y compris deux essais prolongés d'innocuité à long terme) ont été retenus pour la GXR dans le traitement du TDAH. Tous les ERC publiés montraient la supériorité sur le placebo à la première mesure du résultat. L'analyse par sous-groupe des données d'ERC disponibles n'indiquait aucune efficacité de la GXR à n'importe quelle dose chez les adolescents. Les effets indésirables des essais de la GXR étaient généralement de faibles à modérés. Des taux élevés d'interruption précoce ont été observés dans les essais ouverts prolongés du long terme. CONCLUSION: La GXR est une option efficace de monothérapie pour le traitement du TDAH chez les patients de 6 à 12 ans, ou comme traitement d'appoint des psychostimulants.

Prevalence and patterns of antipsychotic use in youth at the time of admission and discharge from an inpatient psychiatric facility.

The objective of this study was to examine the prevalence and patterns of antipsychotic use in children and adolescents at the time of admission and discharge from a tertiary care inpatient psychiatric facility. This retrospective analysis included all patients 18 years and younger, who were admitted and discharged from a child and adolescent tertiary care inpatient psychiatric facility between May 1, 2008 and December 31, 2009. Data for medications at admission were obtained using a province-wide network that links all pharmacies in British Columbia, Canada to a central set of data systems, whereas data for medications at discharge were obtained using the Department of Pharmacy's (British Columbia Children's Hospital, Vancouver, British Columbia, Canada) inpatient computer database. Apart from antipsychotics, overall drug use included antidepressants, mood stabilizers, benzodiazepines, anticholinergics, stimulants, and sleep medications. Referral and discharge diagnoses were also examined. During the study period, 335 patients were admitted and discharged from the tertiary care inpatient psychiatric facility. Significantly, more patients were prescribed with an antipsychotic at the time of discharge from hospital compared with that of the time when they were admitted to hospital (51.6% vs 30.7%; P < 0.0001). Antidepressants were most often coprescribed with an antipsychotic at admission and discharge (32.0% vs 42.2%, respectively) followed by attention-deficit/hyperactivity disorder medications (22.3% vs 24.9% at admission and discharge, respectively) and anticonvulsants (19.4% vs 19.1% at admission and discharge, respectively). Whether the significant increase in antipsychotic use seen from the time of admission to discharge is solely attributed to clinical worsening or other variables requires further investigation.