JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

From the Editor-in-Chief's Desk: Keeping Our Eyes on The Ball and a Call for Discontinuation Research
Croarkin PE
Mirtazapine-Associated Hyperkinetic Movements in a 17-Year-Old with Autism Spectrum Disorder and Chronic Catatonia: A Case Report
Berman L, Onyema I and Bieber E
Pain in Tourette Syndrome: A Comprehensive Review
Green B, Waters A and Jimenez-Shahed J
Recent survey data suggest that a high proportion of patients with Tourette syndrome (TS) experience pain, yet pain features in TS have not been previously investigated in a systematic manner. This article reviews the current understanding and impact of pain in TS as well as identifies possible areas for emphasis for future research on pain in TS. Using a comprehensive search strategy in two relevant research databases (PubMed and Scopus), we searched for relevant peer-reviewed, primary research articles, and review articles. Search terms used were Tourette syndrome, tic disorder, pain, pain management, sensory, and sensory gating. A total of 116 pertinent articles were identified. Pain is reported by 47%-60% of individuals with TS and may relate to different aspects of tic phenomenology or other causes. Pain is more prevalent among TS patients than in the general population and negatively impacts quality of life. To standardize future research efforts, we propose the following classification: tic-related immediate pain, tic-related delayed injury/pain, suppression-related pain, premonitory urge-related pain, and associated primary pain syndromes. Altered sensory gating and interoceptive processing abnormalities are possible mechanisms contributing to pain in TS but warrant further study. Despite pain prevalence, most TS clinical rating scales and outcome measures used in therapeutic studies do not incorporate sufficient information regarding pain. Therapies known to improve pain in non-TS conditions that are also reported to improve tics have not been investigated for their effects on pain among TS patients. TS can be associated with a chronic pain syndrome that negatively affects quality of life. Future research using a systematic framework is needed to better understand pain cause(s) and prevalence, develop appropriate assessment methods, establish outcome measures, and understand mechanisms of pain in TS. Such investigations are likely to lead to therapeutic options for this troublesome symptom.
Extended-Release Lithium Sulfate in Adolescents with Bipolar Disorder: Results from a Longitudinal Prospective Cohort Study
Placini F, Bargnesi F, Di Cicco D, Rinaldi D, Balestra S, Berloffa S, Viglione V, Fantozzi P, Tolomei G, Schirone G, Milone A, Masi G and Sesso G
Bipolar disorder (BD) in adolescence often associates with risky conducts, nonsuicidal self-injury (NSSI), and suicidal ideation. Lithium salts represent the first-line choice for BD in youth to manage manic symptoms and prevent both manic and depressive relapses. Our study aimed to assess efficacy and tolerability of extended-release lithium sulfate (ERLS) in youths with BD. A longitudinal perspective intervention study was thus conducted on a single cohort of 36 patients with BD aged 12-17 years treated with ERLS and followed up for 1 year. ERLS was titrated up to reach optimal plasma concentrations during the 3 months before baseline visit (T0). Then, patients underwent five follow-up visits after 1, 2, 3, 5, and 11 months and were administered with a battery of self- and parent-rated questionnaires and interviews to evaluate, at each timepoint, ERLS-related side effects, manic and depressive symptoms, emotional dysregulation (ED), NSSI and suicidality, and aggressiveness. Regular clinical assessments were also conducted, as well as blood tests, urinalysis, and EKG. Regression models were applied to examine the time course of outcome variables. Twenty-four patients completed the follow-up. Regressions showed a significant reduction of most dependent variables included in the models, including depressive symptoms (β = -0.0006; adj-p = 0.0007), aggressiveness (β = -0.0031; adj-p < 0.0001), ED (β = -0.0002; adj-p = 0.0497), and unstructured suicidal ideation (β = -0.0058; adj-p = 0.0340). Fine distal tremor, increased thirst, and diuresis were among the most frequently reported side effects. Findings from the present study support the use of ERLS as an effective and well-tolerated agent for the management of BD in youth, with a beneficial effect on associated severe symptoms, including NSSI and suicidality.
From the Editor-in-Chief's Desk: Gratitude for Mentors and Colleagues
Croarkin PE
Incidence of Neuroleptic Malignant Syndrome During Antipsychotic Treatment in Children and Youth: A National Cohort Study
Ray WA, Fuchs DC, Olfson M, Stein CM, Murray KT, Daugherty J and Cooper WO
The incidence of neuroleptic malignant syndrome (NMS), a rare, potentially fatal adverse effect of antipsychotics, among children and youth is unknown. This cohort study estimated NMS incidence in antipsychotic users age 5-24 years and described its variation according to patient and antipsychotic characteristics. We used national Medicaid data (2004-2013) to identify patients beginning antipsychotic treatment and calculated the incidence of NMS during antipsychotic current use. Adjusted hazard ratios (HRs) assessed the independent contribution of patient and antipsychotic characteristics to NMS risk. The 1,032,084 patients had 131 NMS cases during 1,472,558 person-years of antipsychotic current use, or 8.9 per 100,000 person-years. The following five factors independently predicted increased incidence: age 18-24 years (HR [95% CI] = 2.45 [1.65-3.63]), schizophrenia spectrum and other psychotic disorders (HR = 5.86 [3.16-10.88]), neurodevelopmental disorders (HR = 7.11 [4.02-12.56]), antipsychotic dose >200mg chlorpromazine-equivalents (HR = 1.71 [1.15-2.54]), and first-generation antipsychotics (HR = 4.32 [2.74-6.82]). NMS incidence per 100,000 person-years increased from 1.8 (1.1-3.0) for those with none of these factors to 198.1 (132.8-295.6) for those with 4 or 5 factors. Findings were essentially unchanged in sensitivity analyses that restricted the study data to second-generation antipsychotics, children age 5-17 years, and the 5 most recent calendar years. In children and youth treated with antipsychotics, five factors independently identified patients with increased NMS incidence: age 18-24 years, schizophrenia spectrum and other psychotic disorders, neurodevelopmental disorders, first-generation drugs, and antipsychotic doses greater than 200 mg chlorpromazine-equivalents. Patients with 4 or 5 of these factors had more than 100 times the incidence of those with none. These findings could improve early identification of children and youth with elevated NMS risk, potentially leading to earlier detection and improved outcomes.
A Discrepancy in the Reports on Life Events Between Parents and Their Depressed Children Is Associated with Lower Responsiveness to SSRI Treatment
Amitai M, Etedgi E, Mevorach T, Kalimi R, Horesh N, Oschry-Bernstein N, Apter A, Benaroya-Milshtein N, Fennig S, Weizman A and Chen A
Exposure to a range of stressful life events (SLE) is implicated in youth psychopathology. Previous studies point to a discrepancy between parents'/children's reports regarding stressful life events. No study systematically assessed the correlation between such discrepancies and psychopathology in depressed youth. This study was designed to assess parent-youth discrepancies regarding stressful life events and its association with severity of psychopathology at baseline and response to selective serotonin reuptake inhibitor (SSRI) treatment in depressed youth. Reports regarding stressful life events were assessed in children/adolescents suffering from depressive/anxiety disorders using the life events checklist (LEC), a self-report questionnaire measuring the impact of negative life events (NLE) and positive life events (PLE), as reported by the children and their parents. The severity of depression/anxiety disorders and response to antidepressant treatment were evaluated and correlated with both measures of LEC. Participants were 96 parent-child dyads (39 boys, 57 girls) aged 6-18 years (mean = 13.90 years, SD = 2.41). Parents reported more NLE and higher severity of NLE events than their children (number of NLE: 7.51 ± 4.17 vs. 6.04 ± 5.32; Cumulative severity of NLE: 24.95 ± 14.83 vs. 17.24 ± 12.94). Discrepancy in PLE, but not NLE, was associated with more severe psychopathology and reduced response to treatment. Discrepancy in informant reports regarding life events in depressed/anxious youth, especially regarding PLE, is associated with more severe psychopathology and reduced response to pharmacotherapy. It is essential to use multiple reporters in assessing stressful life events in children.
Pharmacological Interventions for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Tourette Disorder: A Systematic Review and Network Meta-Analysis
Farhat LC, Behling E, Landeros-Weisenberger A, Macul Ferreira de Barros P, Polanczyk GV, Cortese S and Bloch MH
To evaluate the comparative efficacy of pharmacological interventions for children and adolescents with a dual diagnosis of persistent tic disorders or Tourette disorder and attention-deficit/hyperactivity disorder (TD + ADHD). We searched CENTRAL, Embase, PubMed, PsycInfo, Web of Sciences, ClinicalTrials.gov, and WHO ICTRP up to September 2023 to identify double-blinded randomized controlled trials (RCTs) assessing pharmacological interventions for children and adolescents with TD + ADHD. Outcomes were change in ADHD symptoms (primary) and tics (secondary) severity. Standardized mean difference (SMD) was calculated and pooled in random-effects network meta-analysis. The Confidence in Network Meta-Analysis framework was adopted to determine certainty of evidence. We included 8 RCTs involving 575 participants. Network meta-analyses demonstrated that α2 agonists (SMD, 95% confidence interval [CI] ADHD: -0.72 [-1.13 to -0.31]; TD: -0.70 [-0.96 to -0.45]) and stimulants + α2 agonists (ADHD: -0.84 [-1.54 to -0.13]; TD: -0.60 [-1.04 to -0.17]) were more efficacious than placebo for ADHD symptoms and tics severity. Stimulants alone were more efficacious than placebo for ADHD symptoms severity only, but they did not worsen tics (ADHD: -0.54 [-1.05 to -0.03]; TD: -0.22 [-0.49 to 0.05]). There were no significant differences between any pairs of medications that were found efficacious against placebo for ADHD symptoms or tics severity. Certainty in the evidence varied from low to very low. Stimulants are efficacious for ADHD symptoms severity and do not increase tics severity in TD + ADHD. α2 agonists are efficacious for both ADHD symptoms and tics severity in TD + ADHD. These findings should inform guidelines and help guide shared decision-making to choose a medication for children with TD + ADHD.
Beyond the Off-Label: A Systematic Review of What We Know About Clozapine Use for Children
Pimenta de Figueiredo T, de Almeida IR, de Freitas FAC, Kubrusly CHC, Alvim-Soares Júnior AM and de Miranda DM
It is essential not to delay behavior management and control for aggression, violence, and impulsive behavior in young people. Clozapine has been widely used in adolescents and adults to manage violence and aggression in Schizophrenia. However, there are limited data on the use of clozapine in children, and no systematic review has addressed its use in this population. To better understand the conditions under which clozapine is used as a therapeutic alternative for nonschizophrenic diagnoses and to assess the current evidence supporting its prescription to children, a systematic review was conducted. The review followed PRISMA guidelines and was registered in PROSPERO under the ID CRD42024537707. The review identified that all the studies used clozapine to address externalizing behavior, particularly aggressive behavior, and found positive outcomes supporting its use for treating children with treatment-resistant aggression. The studies also found that clozapine was well-tolerated in all cases. However, the studies were limited and mainly consisted of open trials without a control group. Further high-quality research is needed to establish precise guidelines for using clozapine in children.
Not Too Rare to Matter: The Incidence of Neuroleptic Malignant Syndrome in Children and Adolescents Treated with Antipsychotics
Bobo WV
Comparison of Psychiatric Readmission Rates for Child and Adolescent Patients on Long-Acting Injectable Antipsychotics Versus Oral Antipsychotics: A Mirror Study
Sun C, Temelie A, Goulding H, Clark C, Yabs M and Fabian T
Current literature shows a benefit in clinical outcomes when long-acting injectable antipsychotics (LAIAs) are utilized in adult patients with psychiatric disorders such as schizophrenia, schizoaffective disorder, and bipolar disorder. Literature regarding LAIA use in pediatric patients is sparse. The objective of this study is to compare the number of acute psychiatric admissions, psychiatric emergency services (PES) visits, and total number of days admitted to an acute psychiatric hospital 1 year prior to and 1-year post-mirror point of index hospitalization and LAIA initiation. This was a single-site retrospective mirror-image review of patients <18 years of age initiated on an LAIA during an acute psychiatric hospitalization between October 1, 2015, and October 31, 2022. The number of admissions to the acute psychiatric hospital, number of PES visits, and total number of days hospitalized at the acute psychiatric hospital were captured 1-year pre-index hospitalization admission and 1-year post-index hospitalization discharge, with LAIA administration during index hospitalization being the mirror point. Descriptive statistics and a two-tailed paired -test were utilized to analyze the data. There were 45 unique pediatric patients initiated on an LAIA during the specified timeframe. Across these 45 patients, there were 47 psychiatric admissions 1-year pre-index hospitalization and 38 psychiatric admissions 1-year post-index hospitalization discharge ( = 0.37). Additionally, there were 24 PES visits 1-year pre-index hospitalization admission and 16 PES visits 1-year post-index hospitalization discharge ( = 0.25). Finally, across the 45 patients, there were a total of 1040 days admitted to the acute psychiatric hospital in the 1-year prior to index hospitalization admission compared with 774 days admitted to the acute psychiatric hospital in the 1-year post-index hospitalization discharge ( = 0.48). In this cohort of pediatric patients initiated on an LAIA, there was a positive trend favoring LAIA therapy over oral antipsychotic therapy with LAIA injection as the mirror point; however, there was no statistically significant difference in the number of psychiatric admissions, number of PES visits, or total number of days admitted to an acute psychiatric hospital. Further studies are required to fully understand the impact of LAIA therapy on clinical outcomes for child and adolescent patients with psychiatric disorders.
SYNGAP-1 Mutation And Catatonia: A Case Series and Systematic Review
Baldwin I, Cho A, Orenstein G, Wilner N, Nicoli D and Smith JR
Hyperactive catatonia is often unrecognized in pediatric patients due to its clinical heterogeneity, though it is often seen in children with neurodevelopmental disabilities, especially autism spectrum disorder (ASD). Emerging evidence implicates hyperactive catatonia in more cases of self-injury and aggression in ASD than previously thought. The study seeks to describe cases of hyperactive catatonia in SYNGAP-1 mutation and examine existing literature for symptomatic overlap between previously-described clinical and behavioral phenotypes of individuals with SYNGAP-1 mutations and catatonia. The study describes two cases of an adolescent and a young adult with SYNGAP-1 mutation and ASD presenting with hyperactive catatonia, which are the first reports of catatonia in individuals known to have a pathogenic variant in SYNGAP-1. A systematic review was undertaken during which 101 articles were screened. 13 articles were then examined for neurological and behavioral features present in participants with SYNGAP-1 mutations which are seen in catatonia. The systematic review demonstrates that clinical features suggestive of catatonia are frequently seen among individuals with SYNGAP-1 mutations, including verbal impairment, psychomotor symptoms, aggression, oral aversion, and incontinence. These features were also present in the cases of catatonia in SYNGAP-1 mutations presented here. Both patients showed clinical improvement with use of a long-acting benzodiazepine, and one patient showed benefit from electroconvulsive therapy. This symptomatic overlap revealed in the systematic review, including symptoms seen in the reported cases, raises the possibility that diagnoses of catatonia may have been missed in the past in individuals with SYNGAP-1 mutations. Self-injurious behavior and aggression, which are hallmarks of hyperactive catatonia, are commonly part of the behavioral phenotype of SYNGAP-1-related disorders. Clinicians should consider catatonia as a cause of such symptoms in individuals with SYNGAP-1 mutations, as effective treatment can result in significant improvement in safety and quality of life.
From the Editor-in-Chief's Desk: Harnessing Pharmacoepidemiology to Provide a Brighter Future for Children with Psychiatric Disorders
Croarkin PE
Quality of Life and Outcomes Associated with Adverse Effects in Pediatric Patients with Attention-Deficit/Hyperactivity Disorder and Their Parents/Caregivers
Schein J, Cloutier M, Gauthier-Loiselle M, Catillon M, Yu L, Libchaber B, Wang Y and Childress A
To assess quality of life and outcomes associated with adverse effects (AEs) in pediatric patients receiving pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) and their parents/caregivers. An online survey was conducted (10/13/2023-10/20/2023) among parents/caregivers recruited from Dynata's U.S. panel who lived with a pediatric patient (6-17 years) currently treated for ADHD. Patient and parent/caregiver characteristics and outcomes were descriptively reported. Patients were considered to have AEs if they experienced symptoms/complications in the past 30 days that appeared, worsened, or remained unchanged after initiating their latest ADHD treatment. Regression analyses were used to estimate correlations between the number of AEs and key outcomes, including patients' health-related quality of life (HRQoL; based on the Pediatric Quality of Life Inventory) and parents/caregivers' work and activity impairments (based on Work Productivity and Activity Impairment: Caregiver) and mental health (based on Patient Health Questionnaire-4). A total of 401 parents/caregivers from all U.S. regions completed the survey (caregiver median age: 38 years, 58.9% female; patient median age: 11 years; 37.7% female). In the 30 days prior to data collection, 66.8% of patients had AEs (overall mean: 1.2 AEs), with insomnia/sleep disturbances and decreased appetite/weight loss being the most frequently reported (14.2% and 11.7%, respectively). The number of AEs was significantly correlated with reduced patient's HRQoL (including reduced physical, emotional, and school functioning), increased parent/caregiver's work and activity impairment, and a higher likelihood of parents/caregivers having generalized anxiety disorder or major depressive disorder, respectively (all < 0.001). AEs are common among pediatric patients receiving pharmacological treatment for ADHD and are associated with poorer quality of life and outcomes in pediatric patients and their parents/caregivers. Therapies with better safety profiles may help improve patient's HRQoL and parent/caregiver outcomes.
Use of Long-Acting Injectable Antipsychotic Medication in Youth at Winnebago Mental Health Institute: A Clinical Pathway
Scharko AM, Mireski SJ, Casimir K, Goldstein B, Monese G, Pope K and Taleon A
Dopamine Transporter and Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study
Bishop JR, Zhou C, Gaedigk A, Krone B, Kittles R, Cook EH, Newcorn JH and Stein MA
Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter- also commonly known as ) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 ) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Genetic variations in and were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: = 0.058, Methylphenidate [MPH]: = 0.044). There was also a trend for the 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine ( = 0.029). Participants with 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Most children with ADHD who were CYP2D6 normal metabolizers or had 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of and with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.
Professor Alessandro Zuddas' Impact and Legacy: The Influential Networking and Human Connection Skills of a Passionate Scientist, Clinical Academic, and Pioneer in Child and Adolescent Psychopharmacology
Carucci S, Di Martino A, Castellanos FX, Masi G, Banaschewski T, Coghill D, Moreno C and Cortese S
Professor Alessandro Zuddas, from the University of Cagliari (Italy), passed away prematurely in July 2022. As a prominent figure in child and adolescent neuropsychiatry, he substantially influenced the fields of neurodevelopmental disorders and neuropsychopharmacology both nationally and internationally. Professor Zuddas was a renowned expert in basic and clinical research in child and adolescent psychopharmacology, an enlightened and stimulating educator, and a mentor to many students, residents, and senior colleagues. With his enthusiasm and unique ability to network, he contributed enormously to trace a path in the field that we continue to follow. His name will remain in the textbooks and articles he authored. Here, as colleagues and friends who had the honor to work with him, we provide our personal views of Alessandro's impact and legacy, which go far beyond his publications.
Electronic Health Records for Research on Attention-Deficit/Hyperactivity Disorder Pharmacotherapy: A Comprehensive Review
Roy S, Arturi L, Parlatini V and Cortese S
Randomized controlled trials (RCTs) have shown that attention-deficit/hyperactivity disorder (ADHD) medications significantly reduce symptomatology at a group level, but individual response to ADHD medication is variable. Thus, developing prediction models to stratify treatment according to individual baseline clinicodemographic characteristics is crucial to support clinical practice. A potential valuable source of data to develop accurate prediction models is real-world clinical data extracted from electronic healthcare records (EHRs). Yet, systematic information regarding EHR data on ADHD is lacking. We conducted a comprehensive review of studies that included EHR reporting data regarding individuals with ADHD, with a specific focus on treatment-related data. Relevant studies were identified from PubMed, Ovid, and Web of Science databases up to February 24, 2024. We identified 103 studies reporting EHR data for individuals with ADHD. Among these, 83 studies provided information on the type of prescribed medication. However, dosage, duration of treatment, and ADHD symptom ratings before and after treatment initiation were only reported by a minority of studies. This review supports the potential use of EHRs to develop treatment response prediction models but emphasizes the need for more comprehensive reporting of treatment-related data, such as changes in ADHD symptom ratings and other possible baseline clinical predictors of treatment response.
Extension and Further Replication of the Reliability, Criterion Validity, and Treatment Sensitivity of the PANSS10 and PANSS20 for Pediatric Trials
Langfus JA, Youngstrom EA, Daniel D, Busner J and Findling RL
The Positive and Negative Syndrome Scale (PANSS) is a widely accepted outcome measure for pediatric schizophrenia trials; however, it has notable limitations. Psychometric investigations have shown a multifactorial structure and some items have limited utility assessing symptom severity in children. To address these issues, we developed and evaluated optimized 10- and 20-item PANSS short-forms (PANSS10 and PANSS20) using patient-level clinical trial data. This study further assesses these optimized forms using independent clinical trial data. We examined patient-level data from a randomized pediatric schizophrenia trial comparing paliperidone ER to aripiprazole. Data were accessed through the Yale Open Data Access (YODA) secure platform. Analyses included confirmatory factor analyses, graded response models, ω score reliability, internal consistency, sensitivity to change, and criterion validity versus the Clinical Global Impressions of Severity (CGI-S). Bland-Altman analyses examined score calibration versus the 30-item PANSS and inclusion cut scores. Participants ( = 288) were ages 12 to 17 years ( = 15.3, SD = 1.46; 66% male). Total scores for the PANSS10 and PANSS20 showed strong correlations with the 30-item PANSS (0.90 and 0.97, respectively). Average inter-item correlations were 0.10 and 0.14 and ω reliabilities were 0.74 and 0.85. Both PANSS10 and PANSS20 scores showed reliability >0.80-2.3 to 4.5 SD and -3.0 to 6.0 SD about mean symptom severity, respectively. Sensitivity to treatment was also similar (partial squared 0.23 and 0.22), as was correlation with CGI-S at baseline (0.45 and 0.48; not significantly different). The mean item-average discrepancy with the 30-item PANSS was 0.095 for PANSS10 and 0.033 for PANSS20. The optimized PANSS forms continue to show impressive reliability, validity, and calibration compared with the 30-item PANSS. Researchers should consider replacing the 30-item PANSS with the PANSS10 as a clinical outcome and screening measure due to its length and psychometric performance.
The Association of Antidepressants in Late Pregnancy with Postpartum Hemorrhage: Systematic Review of Controlled Observational Studies
Bobo WV, Moore KM, Betcher HK, Larish AM, Stoppel CM, VandeVoort JL, Chauhan M, Athreya AP and Talati A
Despite advances in obstetric care, postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Prior reviews of studies published through 2016 suggest an association of antidepressant use during late pregnancy and increased risk of PPH. However, a causal link between prenatal antidepressants and PPH remains controversial. This systematic literature review aimed to synthesize the empirical evidence on the association of antidepressant exposure in late pregnancy with the risk of PPH, including studies published before and after 2016. A systematic literature search was conducted using PubMed, OVID Medline, EMBASE, SCOPUS, PsycINFO, and CINAHL from inception to September 9, 2023. Original, peer-reviewed studies (published in English) that reported on the frequency or risk of PPH in women with evidence of antidepressant use during pregnancy and included at least one control group were included. Twenty studies (eight published after 2016) met inclusion criteria, most of which focused on the risks of PPH associated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The main findings from the individual studies were mixed, but the majority documented statistically significant associations of PPH with late prenatal exposure, especially for exposures occurring within 30 days of delivery, compared with unexposed deliveries. Fourteen studies addressed underlying antidepressant indications or their correlates. Few studies focused on prenatal antidepressants and the risk of well-defined severe PPH or on antidepressant dose changes and general PPH risk. None examined competing risks of antidepressant discontinuation on mental health outcomes. Late pregnancy exposure to antidepressants may be a minor risk factor for PPH, but it is unclear to what extent reported associations are causal in nature, as opposed to correlational (effects related to nonpharmacological factors including maternal indication). For patients needing antidepressants during pregnancy, current evidence does not favor routinely discontinuing antidepressants specifically to reduce the risk of PPH.
Deprescribing Antidepressants in Children and Adolescents: A Systematic Review of Discontinuation Approaches, Cross-Titration, and Withdrawal Symptoms
Stimpfl JN, Walkup JT, Robb AS, Alford AE, Stahl SM, McCracken JT, Stancil SL, Ramsey LB, Emslie GJ and Strawn JR
Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly used to treat depressive, anxiety, and obsessive-compulsive disorders in youth. Yet, data on discontinuing these medications, withdrawal symptoms, and strategies to switch between them are limited. We searched PubMed and ClinicalTrials.gov through June 1, 2024, to identify randomized controlled trials assessing antidepressant discontinuation in youth. We summarized pediatric pharmacokinetic data to inform tapering and cross-titration strategies for antidepressants and synthesized these data with reports of antidepressant withdrawal. Our search identified 528 published articles, of which 28 were included. In addition, 19 records were obtained through other methods, with 14 included. The corpus of records included 13 randomized, double-blind, placebo-controlled trials (3026 patients), including SSRIs (K = 10), SNRIs (K = 4), and TCAs (K = 1), ranging from 4 to 35 weeks. Deprescribing antidepressants requires considering clinical status, treatment response, and, in cross-titration cases, the pharmacokinetics and pharmacodynamics of both medications. Antidepressant withdrawal symptoms are related to the pharmacokinetics of the medication, which vary across antidepressants and may include irritability, palpitations, anxiety, nausea, sweating, headaches, insomnia, paresthesia, and dizziness. These symptoms putatively involve changes in serotonin transporter expression and receptor sensitivity, impacting the serotonin, dopamine, and norepinephrine pathways. Although approaches to deprescribing antidepressants in pediatric patients are frequently empirically guided, accumulating data related to the course of relapse and withdrawal symptoms, as well as the pharmacokinetic and pharmacodynamic properties of medications, should inform these approaches. Recommendations within this review support data-informed discussions of deprescribing-including when and how-that are critically important in the clinician-family-patient relationship.
A Short-Term Group Telehealth Cognitive Behavioral Therapy Intervention for Youth with Autism and Anxiety: A Pilot Study
Rivelis E and Valicenti-McDermott M
Children with autism often present with comorbid anxiety disorders. Cognitive behavioral therapy (CBT) is an effective, evidence-based approach to treating anxiety, but information on youth with autism and anxiety is limited. Coping Cat is a 16-week CBT intervention for children with anxiety but its use in a group telehealth format in an urban, predominantly Hispanic population is limited. (a) To examine the feasibility and preliminary effectiveness of a short-term CBT telehealth group for youth with autism and anxiety disorders in an urban, predominantly Hispanic population and (b) to examine satisfaction with the intervention. Single-arm pilot study that consisted of a 16-week telehealth CBT group therapy was based on a modified Coping Cat curriculum. Youth with autism and anxiety disorders who were on a waitlist for psychotherapy at an urban developmental center were invited to participate. Anxiety was assessed pre- and posttreatment using the Screen for Child Anxiety Related Emotional Disorders, parent and self-report. Eighteen children were enrolled; 16 children completed the program. Mean age was 11 ± 2.5 years (8-15 years); 89% males, 61% Hispanic. There was a significant reduction in pre-post intervention in symptoms of overall anxiety (parent: 41.0 ± 18.5 to 31.0 ± 16.3 ≤ 0.003, self: 25.9 ± 12.8 to 14.1 ± 7.8 ≤ 0.001), panic disorder (parent: 8.1 ± 7.0 to 4.1 ± 4.2 = 0.013, self: 5.1 ± 4.8 to 0.8 ± 0.9 = 0.004), and separation anxiety disorder (parent: 7.5 ± 4.8 to 5.7 ± 4.4 = 0.041, self: 5.8 ± 3.3 to 3.8 ± 2.4 = 0.018) as per parent and self-reports. Self-report data also revealed a significant reduction in symptoms of social anxiety disorder (6.5 ± 3.5 to 3.9 ± 2.7 ≤ 0.001). Parents and children reported satisfaction with the group. In this small, predominantly Hispanic population of youth with autism and anxiety disorder, 89% of families were compliant with a group telehealth CBT intervention. Parents and youth reported a significant reduction in anxiety symptoms and program satisfaction. A modified group CBT program via telehealth represents a feasible intervention for youth with autism and anxiety disorders.
Naltrexone Treatment for Multiple Substance Use Disorders in an Adolescent Boy
Organista D, Rosewater J, Bez Y and Coffey BJ
From the Editor-in-Chief's Desk: Maximizing Adherence, Digital Platforms, and Early Response for Precision Pediatric Psychopharmacology
Croarkin PE
Metabolic Monitoring for Children and Adolescents Prescribed Second-Generation Antipsychotics: A Qualitative Study with Child Psychiatrists
Sanyal S, Rowan PJ, Ochoa-Perez M, Calarge C, Aparasu R, Abughosh S and Chen H
Professional guidelines recommend that providers routinely monitor children prescribed second-generation antipsychotics (SGA) to reduce the risk of adverse metabolic events associated with the medication. Despite this guidance, many studies show low rates of monitoring compliance. In this study, we interviewed child psychiatrists for their views of possible barriers to monitoring. Semi-structured qualitative interviews, developed according to the Regehr model of influences upon patient-provider decision making, were conducted with child and adolescent psychiatrists in current practice and recruited by convenience and snowball sampling. Interviews were conducted through internet video meetings and were recorded. Interview data were analyzed following Framework Analysis qualitative methods. We recruited and completed interviews with 17 psychiatrists. Patient-level barriers included travel difficulties, limited family time for health care appointments, patient fear of blood draws, and more. Provider-level barriers included professional judgment versus guideline guidance, perceived family burden, assumption of low-risk, short-term SGA use, and more. Organizational level barriers included lack of organizational mandates or incentives, limited appointment time per patient, lack of care coordination, lack of co-located labs, personnel turnover, and more. Barriers at the social and cultural level include stigma and low health literacy. These practicing prescribers provided a wide range of possible barriers to metabolic monitoring in children and adolescents prescribed SGAs. The next step is to explore which may be present in certain settings, and to pilot quality improvement interventions. Addressing barriers can reduce risk of metabolic disorders arising from long-term use of SGAs in children and adolescents.
Pharmacological Treatment of Tourette Disorder in Children
Can A, Vermilion J, Mink JW and Morrison P
Tourette disorder (TD) is a neurodevelopmental disorder characterized by childhood onset of tics lasting more than one year, with multiple motor tics and at least one phonic tic at some point during the course of the symptoms. Treatment of tics may include psychoeducation, non-pharmacologic treatment, or pharmacologic treatment. We review pharmacologic treatment here. We performed a literature review on pharmacologic treatments for TD. There is no current evidence to suggest that medications impact the prognosis of tic disorders, so current clinical guidelines recommend reassurance of the patient and family and monitoring if there is no change in function or quality of life due to tics. If treatment is indicated, it must be chosen based on the needs of each individual patient. Comprehensive behavioral intervention for tics (CBIT) is considered first-line management for most individuals with bothersome tics, especially if they are mild to moderate in severity. Pharmacotherapy should be considered when tics are impairing daily functioning, causing social problems, accompanied by other neuropsychiatric symptoms, or when the patient is not likely to benefit from CBIT. Current recommended pharmacotherapy options include alpha-2 adrenergic agonists, dopamine modulators, GABAergic medications, dopamine depleters, and botulinum toxin injections. Additionally, there are other novel medications that are being studied in ongoing clinical trials. This review summarizes available pharmacotherapy options for TD in children. It provides an overview of new medications and offers guidance to physicians when selecting appropriate treatments. If medications are indicated for tic management, treatment should be chosen based on the needs of the individual patient.
From the Editor-in-Chief's Desk: Are Omega-3 Fatty Acid Supplements an Effective, Safe, and Scalable Treatment for Depression in Children and Adolescents?
Croarkin PE
Long-Acting Injectable Antipsychotic Medication Use in Youth: A Systematic Review of the Literature Along with MedWatch Safety Data and Prescriber Attitudes
Scharko AM, Sieracki R and Mireski SJ
Long-acting injectable (LAI) antipsychotic medications are being prescribed to children and adolescents along a broad age range from 2 to 17 years old. However, there is no U.S. Food and Drug Administration (FDA) approved indication for the use of any LAI in a pediatric population. The goal of this article is to perform a systematic literature review regarding the use of LAIs in a pediatric population, to obtain pediatric LAI safety data, and to survey prescriber attitudes regarding LAI use in youth. A search for relevant articles between June 1986 and June 2021 was conducted. Safety data were obtained from FDA MedWatch postmarketing adverse event reports regarding LAI use in children and adolescents. A survey of practicing Child and Adolescent Psychiatrists in Wisconsin was done regarding the use of LAIs in youth. The predominant reasons for LAI use in youth were illness severity and treatment noncompliance. Twenty-six of 30 identified studies and reports favored LAI use in youth, but were of low to very low quality. Overall, 587 FDA MedWatch reports between June 1986 and June 2021 were identified. Most adverse events occurred in modest numbers. Extrapyramidal symptoms accounted for 18% of all MedWatch reports, neuroleptic malignant syndrome accounted for 3% of all reports, and deaths accounted for 2% of all reports. The concern for safety was reflected in prescriber survey results along with a recognition that LAIs can be helpful to target severe psychiatric symptoms and address treatment noncompliance. No randomized controlled studies were found. Identified published studies and reports were of low to very low quality. However, it appeared reasonable that the use of LAIs in a select group of pediatric patients can be helpful to target severe psychiatric symptoms and to enhance treatment compliance.
Description, Implementation, and Efficacy of the Comprehensive Behavioral Intervention for Tics as First-Line Treatment for Tourette and Other Tic Disorders
Kohler K, Rosen N and Piacentini J
To provide an evidence-based review of the Comprehensive Behavioral Intervention for Tic (CBIT) disorders. For close to a century, behavioral interventions for managing tics associated with Tourette and other tic disorders (TDs) were incorrectly considered ineffective and dangerous by the professional community, due, in large part, to unfounded fears that efforts to suppress tics would lead to a host of negative psychological, and even physical, outcomes (e.g., symptom substitution, tic rebound). Spurred by a growing body of research to the contrary, the Comprehensive Behavioral Treatment for Tics (CBIT) was developed to provide a tolerable and effective nonpharmacological treatment option, alone or in combination with medication, for youth and adults with tics associated with Tourette or other TDs. CBIT combines two evidence-based practices, habit reversal training (HRT) to address the urge-tic relationship and a functional intervention to identify and neutralize tic-related environmental factors. Based on positive findings from two large-scale randomized controlled trials that involved a total of 248 8-69-year olds with Tourette or chronic TD, CBIT has been designated as a first-line treatment, when available, for treating tics by the American Academy of Neurology and the European and Canadian medical academies. CBIT has demonstrated acute and durable efficacy when delivered alone or in combination with medication, in person, or via telehealth, and in the presence or absence of common comorbid conditions. Additional research is needed to develop and test treatment guidelines for the use of CBIT in combination with pharmacologic, neuromodulatory, and other intervention modalities.
Long-Acting Injectable Antipsychotic Initiation in Child and Adolescent Patients with Psychiatric Disorders
Sun C, Temelie A, Goulding H, Clark C, Yabs M and Fabian T
There are currently no long-acting injectable antipsychotics (LAIAs) that are approved by the Food and Drug Administration for use in child and adolescent patients, however these agents are used off-label for the treatment of various psychiatric disorders. This study aims to describe the initiation and maintenance dosing strategies of LAIAs in child and adolescent psychiatry inpatients. This was a single-site retrospective chart review of patients less than 18 years of age initiated on an LAIA during an acute psychiatric hospitalization between October 1, 2015, and October 31, 2022. Patient demographics and hospital encounter information were collected and analyzed using descriptive statistics. Of the 6402 unique pediatric patients discharged from the acute psychiatric hospital within the specified timeframe, 45 (0.7%) were newly initiated on an LAIA. The average age was 15.6 years (range 10-17), with a greater proportion of male ( = 26, 57.8%) and Black or African American ( = 27, 60%) patients. The LAIA agents prescribed included paliperidone palmitate ( = 21, 46.7%), aripiprazole monohydrate ( = 15, 33.3%), aripiprazole lauroxil ( = 7, 15.6%), haloperidol decanoate ( = 1, 2.2%), and risperidone microspheres ( = 1, 2.2%). Primary diagnosis via International Classification of Diseases-10 code at discharge included schizophrenia spectrum and other psychotic disorders ( = 19, 42.2%); bipolar disorder ( = 14, 31.1%); disruptive, impulse control, and conduct disorders ( = 6, 13.3%); autistic disorder ( = 5, 11.1%); and attention-deficit/hyperactivity disorder ( = 1, 2.2%). Seventeen patients (37.8%) received a loading dose regimen and/or a maintenance dose regimen that differed from adult package-insert dosing. The mean length of stay was 23.7 days, and 14 patients (31.1%) were readmitted to the psychiatric hospital within 6 months of discharge. The mean number of days to readmission was 71.9 days. This retrospective study is the first to focus on LAIA initiation and maintenance dosing strategies of multiple agents in both a child and adolescent patient population. Further research is required to evaluate the impact of LAIAs on clinical outcomes in this patient population.