Serotonin Syndrome in Children and Adolescents Exposed to Selective Serotonin Reuptake Inhibitors - A Review of Literature.

OBJECTIVE: The use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents is increasing in Canada and internationally. While SSRIs are known for their generally well tolerated side effect profile, serotonin syndrome can arise as a severe complication. The objective of this study is to review literature on SSRI-related serotonin syndrome in the pediatric population. METHODS: An extensive review of literature on "serotonin syndrome" is conducted using PubMed from inception to March 2019, focusing on subjects zero to 18 years of age. Descriptive statistics are used for data analysis. RESULTS: The search yielded N=337 references and N=18 studies are included, all of which are case reports. The cases encompass ethnically diverse subjects ranging from 4 to 18 years of age, diagnosed with serotonin syndrome after exposure to SSRI agents. Most common presenting symptoms are confusion, agitation, tachycardia, hypertension, hyperreflexia, rigidity, and tremor. Serotonin syndrome manifested from SSRI monotherapy (7/18; 3 after first dose), when SSRI was combined with another serotonergic agent (6/18), or after an overdose (5/18). Risk factors include high starting doses and co-prescription. Changing multiple medications at the same time adds to diagnostic challenges. CONCLUSIONS: Serotonin syndrome is a severe adverse drug reaction associated with SSRI, and can be associated with diverse presentations in the pediatrics population and diagnostic challenges. Clinicians are recommended to be vigilant in the monitoring and recognition of serotonin syndrome.

OBJECTIF: L'utilisation des inhibiteurs sélectifs du recaptage de la sérotonine (ISRS) chez les enfants et les adolescents est en croissance au Canada et sur la scène internationale. Bien que les ISRS soient connus pour leur profil d'effets secondaires généralement bien toléré, le syndrome sérotoninergique peut survenir comme complication grave. La présente étude a pour objectif d'examiner la littérature sur le syndrome sérotoninergique lié aux ISRS dans la population pédiatrique. MÉTHODES: Une vaste revue de la littérature sur le « syndrome sérotoninergique ¼ est menée à l'aide de PubMed du début à mars 2019, portant sur les sujets de 0 à 18 ans. Des statistiques descriptives servent à l'analyse des données. RÉSULTATS: La recherche a donné N = 337 références et N = 18 études sont incluses qui sont toutes des études de cas. Les cas comprennent des sujets de différentes ethnies qui ont de 4 à 18 ans, et ont reçu un diagnostic de syndrome sérotoninergique après une exposition à des ISRS. Les symptômes communs les plus présentés sont la confusion, l'agitation, la tachycardie, l'hypertension, l'hyperréflexie, la rigidité et le tremblement. Le syndrome sérotoninergique se manifestait après la monothérapie d'ISRS, (7/18; 3 après la première dose), quand les ISRS étaient combinés avec un autre agent sérotoninergique (6/18), ou après une surdose (5/18). Les facteurs de risque comprennent des doses de départ élevées et la co-prescription. Changer de multiples médicaments à la fois ajoute aux difficultés diagnostiques. CONCLUSIONS: Le syndrome sérotoninergique est une réaction indésirable grave à un médicament associé aux ISRS, et peut être associé à diverses présentations dans la population pédiatrique et à des difficultés diagnostiques. On recommande aux cliniciens d'être vigilants pour surveiller et reconnaître le syndrome sérotoninergique.

Stimulant Withdrawal in a Child with Autism Spectrum Disorder and ADHD - A Case Report.

OBJECTIVE: To consider whether the concepts of tolerance and withdrawal to stimulant medications apply to a preadolescent female, affected by autism spectrum disorder (ASD) and treated for associated attention-deficit/hyperactivity disorder (ADHD). METHODS: We describe the case history and review scientific English language literature pertaining to acute withdrawal effects associated with methylphenidate and amphetamine derivatives in children. RESULTS: An 11-year-old female with ASD and ADHD referred to our clinic experienced vomiting, headaches, and light sensitivity following abrupt discontinuation of methylphenidate; she subsequently presented with migraines and marked malaise immediately after a dose reduction in lisdexamfetamine. Evidence supports the notion that ADHD symptoms in children with ASD can be effectively treated with methylphenidate; however, beneficial effects are less robust relative to children with a primary ADHD diagnosis. Children affected by ASD are also more susceptible to adverse effects. Literature on withdrawal from stimulants in children is limited to case studies; in contrast, in the adult population more information is available, especially in adults with substance abuse disorders. Adults experiencing stimulant withdrawal often experience depression, fatigue, changes in appetite, and insomnia or hypersomnia. CONCLUSIONS: We argue that tolerance to stimulants was conceivably developing in this young female, and consequently discontinuation of methylphenidate and dose reduction of lisdexamfetamine resulted in withdrawal symptoms. Children with ASD are more sensitive to stimulant medications and we wonder whether this extends to an increased sensitivity to developing tolerance to stimulant medication. Clinicians ought to be vigilant about the emergence of symptomology suggestive of withdrawal phenomena following stimulant discontinuation.

OBJECTIF: Examiner si les concepts de tolérance et de sevrage des médicaments stimulants s'appliquent à une pré-adolescente souffrant d'un trouble du spectre de l'autisme (TSA) et traitée pour un trouble de déficit de l'attention avec hyperactivité (TDAH) associé. MÉTHODES: Nous décrivons les antécédents du cas et examinons la littérature scientifique en anglais relative aux effets de sevrage associés au méthylphénidate et aux dérivés d'amphétamine chez les enfants. RÉSULTATS: Une fillette de 11 ans souffrant de TSA et de TDAH envoyée à notre clinique éprouvait des vomissements, des maux de tête et une sensibilité à la lumière par suite d'une cessation abrupte de méthylphénidate; elle a ensuite présenté des migraines et un malaise marqué immédiatement après la réduction d'une dose de lisdexamfétamine. Les données probantes soutiennent la notion que les symptômes du TDAH chez les enfants souffrant du TSA peuvent être efficacement traités par méthylphénidate; cependant, les effets bénéfiques sont moins intenses chez les enfants dont le diagnostic primaire est le TDAH. Les enfants souffrant du TSA sont également plus susceptibles aux effets indésirables. La littérature sur le sevrage des stimulants chez les enfants se limite aux études de cas; par contre, il y a plus d'information dans la population adulte, spécialement chez les adultes souffrant de troubles d'abus de substances. Les adultes vivant un sevrage de stimulant présentent souvent dépression, fatigue, changements d'appétit, et insomnie ou hypersomnie. CONCLUSIONS: Nous alléguons que la tolérance aux stimulants se développait probablement chez cette jeune fille et que par conséquent, la cessation de méthylphénidate et la réduction de la dose de lisdexamfétamine ont entraîné des symptômes de sevrage. Les enfants souffrant de TSA sont plus sensibles aux médicaments stimulants et nous nous demandons si cela s'étend à une sensibilité accrue au développement d'une tolérance aux médicaments stimulants. Les cliniciens doivent être vigilants devant l'apparition d'une symptomatologie suggestive d'un phénomène de sevrage suivant la cessation d'un stimulant.

Combined Modality Intervention for ADHD With Comorbid Reading Disorders: A Proof of Concept Study.

To evaluate the relative efficacy of two reading programs with and without adjunctive stimulant medication for children with attention-deficit/hyperactivity disorder and comorbid reading disorder (ADHD+RD). Sixty-five children (7-11 years in age) were assigned randomly to one of three intensive remedial academic programs (phonologically or strategy-based reading instruction, or general academic strategy and social skills training) in combination with either immediate-release methylphenidate or placebo. Multiple-blind procedures were used for medication/placebo, given twice daily. Children received 35 hours of instruction in 10 weeks, taught by a trained teacher in a separate school classroom, in small matched groups of 2 to 3. Children's behavior and reading abilities were assessed before and after intervention. Stimulant medication produced expected beneficial effects on hyperactive/impulsive behavioral symptoms (reported by classroom teachers) but none on reading. Children receiving a reading program showed greater gains than controls on multiple standardized measures of reading and related skills (regardless of medication status). Small sample sizes precluded interpretation of possible potentiating effects of stimulant medication on reading skills taught in particular reading programs. Intensive reading instruction, regardless of treatment with stimulant medication, may be efficacious in improving reading problems in children with ADHD+RD and warrants further investigation in a large-scale study.

Depression Screening and Health Outcomes in Children and Adolescents: A Systematic Review.

OBJECTIVE: Depression screening among children and adolescents is controversial. In 2009, the United States Preventive Services Task Force first recommended routine depression screening for adolescents, and this recommendation was reiterated in 2016. However, no randomized controlled trials (RCTs) of screening were identified in the original 2009 systematic review or in an updated review through February 2015. The objective of this systematic review was to provide a current evaluation to determine whether there is evidence from RCTs that depression screening in childhood and adolescence improves depression outcomes. METHOD: Data sources included the MEDLINE, MEDLINE In-Process, EMBASE, PsycINFO, Cochrane CENTRAL and LILACS databases searched February 2, 2017. Eligible studies had to be RCTs that compared depression outcomes between children or adolescents aged 6 to 18 years who underwent depression screening and those who did not. RESULTS: Of 552 unique title/abstracts, none received full-text review. No RCTs that investigated the effects of screening on depression outcomes in children or adolescents were identified. CONCLUSIONS: There is no direct RCT evidence that supports depression screening among children and adolescents. Groups that consider recommending screening should carefully consider potential harms, as well as the use of scarce health resources, that would occur with the implementation of screening programs.

Accuracy of Depression Screening Tools to Detect Major Depression in Children and Adolescents: A Systematic Review.

OBJECTIVE: Depression screening among children and adolescents is controversial, and no clinical trials have evaluated benefits and harms of screening programs. A requirement for effective screening is a screening tool with demonstrated high accuracy. The objective of this systematic review was to evaluate the accuracy of depression screening instruments to detect major depressive disorder (MDD) in children and adolescents. METHOD: Data sources included the MEDLINE, MEDLINE In-Process, EMBASE, PsycINFO, HaPI, and LILACS databases from 2006 to September 30, 2015. Eligible studies compared a depression screening tool to a validated diagnostic interview for MDD and reported accuracy data for children and adolescents aged 6 to 18 years. Risk of bias was assessed with QUADAS-2. RESULTS: We identified 17 studies with data on 20 depression screening tools. Few studies examined the accuracy of the same screening tools. Cut-off scores identified as optimal were inconsistent across studies. Width of 95% confidence intervals (CIs) for sensitivity ranged from 9% to 55% (median 32%), and only 1 study had a lower bound 95% CI ≥80%. For specificity, 95% CI width ranged from 2% to 27% (median 9%), and 3 studies had a lower bound ≥90%. Methodological limitations included small sample sizes, exploratory data analyses to identify optimal cut-offs, and the failure to exclude children and adolescents already diagnosed or treated for depression. CONCLUSIONS: There is insufficient evidence that any depression screening tool and cut-off accurately screens for MDD in children and adolescents. Screening could lead to overdiagnosis and the consumption of scarce health care resources.

Epilepsy, Attention-Deficit/Hyperactivity Disorder and Methylphenidate: Critical Examination of Guiding Evidence.

OBJECTIVE: Attention-Deficit/Hyperactivity Disorder (ADHD) and epilepsy are commonly comorbid; yet in the psychiatric literature, there is a remarkable paucity of guiding evidence regarding the safety and efficacy of treatment using methylphenidate (MPH) in this population. The objective of this review is to critically appraise evidence regarding the treatment of ADHD in the context of seizure disorders in order to better inform management considerations and practices. METHOD: A comprehensive search of the Central, Embase, Medline, and Web of Science databases identified 349 references. After a thorough review, only nine relevant references contributing new information and providing reliable and interpretable data were identified; seven were prospective studies (two double-blind placebo controlled trials, five open-label trials) and two were retrospective reviews. Prospective studies were then reviewed in detail, critically appraised, and interpreted. RESULTS: All studies reported no increase in seizure rates in a majority of participants after exposure to MPH. MPH was effective in treating ADHD symptoms. However, the following major limitations to the studies impede drawing confident conclusions: small sample sizes, lack of uniformity regarding seizure type and severity, seizure-free period pre-stimulant treatment, and low baseline seizure rates. CONCLUSIONS: Given the academic, social, emotional, and functional impact of untreated ADHD, a watchful approach to the use of MPH in children with stable epilepsy who are impaired by ADHD symptoms is justified.

OBJECTIF: Le trouble du déficit d'attention avec hyperactivité (TDAH) et l'épilepsie sont fréquemment comorbides; et pourtant, dans la littérature psychiatrique, il y a une remarquable rareté de données probantes directrices concernant l'innocuité et l'efficacité du traitement par méthylphénidate (MPH) dans cette population. L'objectif de cette revue est d'évaluer de façon critique les données probantes sur le traitement du TDAH dans le contexte des troubles convulsifs afin de mieux éclairer les considérations et pratiques de prise en charge. MÉTHODE: Une recherche exhaustive des bases de données Central, Embase, Medline, et Web of Science a identifié 349 références. Après un examen minutieux, seulement neuf références pertinentes apportant une information nouvelle et offrant des données fiables et interprétables ont été relevées; sept étaient des études prospectives (deux essais à double insu contrôlés contre placebo, cinq essais ouverts) et deux étaient des revues rétrospectives. Les études prospectives ont ensuite été examinées en détail, ont fait l'objet d'une évaluation critique, et ont été interprétées. RÉSULTATS: Toutes les études n'indiquaient aucune hausse des taux de crises d'épilepsie chez une majorité de participants après une exposition au MPH. Le MPH était efficace pour traiter les symptômes du TDAH. Toutefois, les limitations majeures suivantes des études empêchent de tirer des conclusions en toute confiance : petites tailles d'échantillons, absence d'uniformité à propos du type et de la gravité des crises, période sans crise avant le traitement par stimulant, et faibles taux de crises au départ. CONCLUSIONS: Étant donné l'effet scolaire, social, émotionnel et fonctionnel du TDAH non traité, une approche vigilante de l'utilisation du MPH chez les enfants dont l'épilepsie est stable et qui sont aux prises avec les symptômes du TDAH est justifiée.

Translating Cognitive Behavioral Therapy for Anxious Youth to Rural-Community Settings via Tele-Psychiatry.

This study aimed to determine the feasibility of translating cognitive behavioral therapy for anxious youth to rural-community settings via tele-psychiatry training. A 20-week group-supervision training program was delivered to ten different groups from different agencies within Northern Ontario. Each group consisted of four to nine clinicians with child therapy background not specific to CBT (n = 78, 51% social workers, 49% other mental health disciplines). Clinicians were each required to treat an anxious youth under supervision. Changes in clinician knowledge and youth internalizing symptoms were measured. Northern Ontario clinicians showed significant gains on a child CBT-related knowledge test (t (1, 52) = -4.6, p < .001). Although youth treated by these clinicians showed a significant decrease in anxiety symptoms, possible response bias and the lack of a comparison group mandate further studies before generalizing our findings. Nevertheless, training local therapists in anxiety-focused CBT for children via a group supervision based tele-psychiatry model appears to be a feasible and well-received approach to knowledge translation to rural settings.

An innovative child CBT training model for community mental health practitioners in Ontario.

OBJECTIVE: Cognitive behavior therapy (CBT) for children has been shown efficacious, but community access to it is often limited by the lack of trained therapists. This study evaluated a child, CBT-focused, 20-session weekly group supervision seminar with a didactic component which was provided to community mental health practitioners by experienced CBT therapists from an academic center. METHODS: Twenty-two practitioners from four community mental health agencies completed the training in four groups (one for each agency); one group was trained by videoconference. The authors assessed outcomes immediately after the training and at 6-month follow-up using a mixed-method design including quantitative and qualitative methods to ensure a comprehensive evaluation. RESULTS: Participants' knowledge on a multiple-choice test of child CBT increased with training, as did their self-reported confidence using CBT and desire to do further child CBT. Therapist age and use of an intake diagnostic screen related to positive outcomes, and participants advocated for more structured training. CONCLUSION: Child CBT can be successfully taught to community practitioners using this training model, but refinement based on participant feedback and further studies that include direct observation of CBT skills are needed.

Stop signal and Conners' continuous performance tasks: test--retest reliability of two inhibition measures in ADHD children.

OBJECTIVE: To measure test-retest reliability of the Stop-Signal Task (SST) and the Conners' Continuous Performance Test (CPT) in children with ADHD. METHODS: 12 children with ADHD (age 11.46 +/-1.66) participated in the study. Primary outcome measures were stop-signal reaction time (SSRT) for the SST and CPT's commission errors (%FP). For each participant, we acquired three morning (8:00am) measurements and behavioral observations, separated by two 7-day intervals. Reliability of cognitive measures and behavioral observations was measured using the Intraclass-correlation coefficient (ICC). RESULTS: ICC values for SSRT and %FP were 0.72. Consistency of behavioral observations was much lower (ICC =0.41). CONCLUSION: Both the SST and the CPT yielded reliable measurements in ADHD children. Our findings lend further support to using these measures in the study of ADHD.

Association of attention-deficit/hyperactivity disorder with a candidate region for reading disabilities on chromosome 6p.

BACKGROUND: Reading disabilities (RD) and attention-deficit hyperactivity/disorder (ADHD) are two common childhood disorders that co-occur by chance more often than expected. Twin studies and overlapping genetic linkage findings indicate that shared genetic factors partially contribute to this comorbidity. Linkage of ADHD to 6p, an identified RD candidate locus, has previously been reported, suggesting the possibility of a pleiotropic gene at this locus. RD has been previously associated with five genes in the region, particularly DCDC2 and KIAA0319. METHODS: To test whether these genes also contribute to ADHD, we investigated markers previously associated with RD for association with ADHD and ADHD symptoms in a sample of families with ADHD (n = 264). Markers were located in two subregions, VMP/DCDC2 and KIAA0319/TTRAP. RESULTS: Across all analyses conducted, strong evidence for association was observed in the VMP/DCDC2 region. Association was equally strong with symptoms of both inattention and hyperactivity/impulsivity, suggesting that this locus contributes to both symptom dimensions. Markers were also tested for association with measures of reading skills (word identification, decoding); however, there was virtually no overlap in the markers associated with ADHD and those associated with reading skills in this sample. CONCLUSIONS: Overall this study supports a previous linkage study of ADHD indicating a risk gene for ADHD on 6p and points to VMP or DCDC2 as the most likely candidates.

Developing a risk-model of time to first-relapse for children and adolescents with a psychotic disorder.

Individuals treated for psychotic disorders and mood disorders with psychotic features have a high likelihood of relapse across the life course. This study examines the relapse rate and its associated predictors for children and adolescents experiencing a first-episode and develops a statistical risk-model for prediction of time to first-relapse. A multiyear, retrospective cohort design was used to track youth, under the age of 18 years, who experienced a first-episode of psychosis, and were admitted to 1 of 6 inpatient hospital psychiatric units (N = 87). Participants were followed for at least 2 years (M = 3.9, SD = 1.3) using survival analysis. Approximately 60% of subjects experienced relapse requiring hospital readmission by the end of follow-up, with 33% readmitted within the first year and 44% within 2 years. Median survival time was 34 months. Cox proportional hazards regression identified 4 key risk factors for relapse: medication nonadherence, female gender, receiving clinical treatment, and a decline in social support before first admission.

Mathematical learning disorder in school-age children with attention-deficit hyperactivity disorder.

OBJECTIVES: To explore the prevalence of mathematics disorder (MD) relative to reading disorders (RD) in school-age children with attention-deficit hyperactivity disorder (ADHD) and examine the effects of age, sex, cooccurring conduct disorder (CD), and ADHD subtype on this comorbidity. METHODS: Participants were school-age children (n = 476) with confirmed DSM-IV diagnosis of ADHD. The assessment included semistructured parent and teacher interviews and standardized measures of intelligence, academic attainment, and language abilities. Based on the presence or absence of concurrent learning disorders, we compared the emerging 4 groups: ADHD-only, ADHD + MD, ADHD + RD, and ADHD + MD + RD. RESULTS: Overall prevalence of comorbid ADHD + MD was 18.1%. Age, sex, ADHD subtypes, or comorbid CD did not affect the frequency of MD. Children with concurrent ADHD and either MD or RD attained lower IQ, language, and academic scores than those with ADHD alone. Children with ADHD + MD + RD were more seriously impaired and demonstrated distinct deficits in receptive and expressive language. CONCLUSION: MDs are relatively common in school-age children with ADHD and are frequently associated with RDs. Children with ADHD + MD + RD are more severely impaired. These deficits simply cannot be explained as consequences of ADHD and might have unique biological underpinnings, with implications for diagnostic classification and therapeutic interventions.

Cognitive and behavioral effects of multilayer-release methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to compare the pharmacodynamics of a new multilayer-release (MLR) formulation methylphenidate (MPH; Biphentin) with immediate-release (IR) MPH (Ritalin) in a double-blind, cross-over, placebo-controlled study in patients with attention-deficit/hyperactivity disorder (ADHD). METHOD: Patients were randomized to equivalent doses of MPH as MLR (once per day), IR (twice per day) or placebo. Each treatment was taken for 1 week prior to repeated behavioral and cognitive laboratory evaluations on a single day in each phase of the crossover. RESULTS: Two girls and 15 boys 6.8-15.3 years old (mean age 11.3 +/- 2.2 years) participated. Both MLR and IR MPH significantly reduced the Stop Signal Reaction Time (p = 0.0001, p = 0.0005), the Errors of Omission on the Continuous Performance Task (p = 0.0039, p = 0.0001), the IOWA-Conners Inattention/Overactivity Index (p = 0.0001, p = 0.0001), and increased the Clinical Global Impressions (CGI) Efficacy Index (p = 0.0001, p = 0.0017) and reduced the CGI Global Improvement Index (p = 0.0001, p = 0.0006) compared to placebo. Mild adverse events were experienced by 4, 6, and 3 patients on placebo, IR, and MLR MPH, respectively. CONCLUSIONS: MLR MPH given once daily produces equivalent improvements in behavioral and cognitive measures, and has a duration of effect at least as long as that of IR MPH given twice daily.

Association study for genes at chromosome 5p13-q11 in attention deficit hyperactivity disorder.

Linkage of attention deficit hyperactivity disorder (ADHD) to the short arm-centromeric region of chromosome 5 has been reported in multiple studies. The overlapping region (5p13-q11) contains a number of strong candidate genes for ADHD, based on their role in brain function or neurodevelopment. The aim of this study was to investigate some of the top candidates among these genes in relation to ADHD in a sample of 245 nuclear families from the Toronto area. We investigated the genes for the glial cell-derived neurotropic factor (GDNF), the fibroblast growth factor 10 (FGF10), islet-1 (ISL1), the hyperpolarized potassium channel (HCN1) and the integrin alpha 1 (ITGA1). In addition to these genes, we assessed the 3'region of the SLC1A3 gene, a glutamate transporter implicated in ADHD by a previous association study. A total of 36 polymorphisms were selected across the six genes. We performed family-based association and haplotype analyses. ADHD is a dimensional disorder, with symptoms of inattention and hyperactivity-impulsivity therefore, we also conducted quantitative analysis in relation to symptom scores for both dimensions. Single marker and haplotype analyses yielded little evidence of association for any of the genes tested in this study. Moreover, we were unable to replicate the positive association findings reported for SLC1A3. Our results suggest that these six genes are unlikely to be susceptibility genes in the chromosome 5p13-q11 region and other genes should now be considered for priority study.