Use Of Antidepressants In Children Research Articles

An Investigation of Diversity in Childhood and Adolescent Antidepressant Studies: A Systematic Review.

Objectives: Childhood mental illness is an ongoing public health crisis which is accompanied by an increase in antidepressant (i.e., serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors) use in children. Recent evidence highlighting the cultural differences in the utilization, efficacy, and tolerability of antidepressants in children underscores the need for diverse samples in studies examining antidepressant use. Furthermore, the American Psychological Association in recent years has emphasized the importance of including participants from diverse backgrounds in research studies, including investigations of medication efficacy. The present study, therefore, examined the demographic composition of samples used and reported in antidepressant efficacy and tolerability studies with children and adolescents experiencing anxiety and/or depression in the last decade. Methods: A systematic literature review utilizing two databases was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In line with the extant literature, antidepressants were operationalized as Sertraline, Duloxetine, Escitalopram, Fluoxetine, and Fluvoxamine. Results: Out of the 11 articles included in this review, 71% reported having a primarily adolescent sample (i.e., over 50% of the sample was 12 years or older). In addition, all studies omitted any transgender, genderqueer, or gender-nonconforming demographics, and one study omitted all racial demographic information. While 64% of studies only partially reported racial demographic information, 36% of studies omitted ethnicity demographics altogether. Conclusions: The present study addresses a gap in the literature by supporting a lack of diversity in studies examining antidepressant use in children and adolescents. Furthermore, it underscores the importance of future studies using a more diverse and representative sample. Limitations of the present study included limited generalizability and the lack of independent and blind reviewer process. Possible explanations for the lack of inclusion and suggestions on how to address these disparities are discussed.

Antidepressant use and off-label prescribing in primary care in Spain (2013–2018)

IntroductionRecent studies show an increase in the use of antidepressants in minors (younger than 18 years), although few antidepressants are indicated for this age group. The aim of our study was to calculate the annual prevalence of antidepressant use in children and adolescents and to review the adherence of prescription to current indications. MethodsStudy of the prevalence of antidepressant use in minors based on the records of the Electronic Database for Pharmacoepidemiologic Studies in Primary Care (BIFAP) of Spain for the 2013–2018 period, considering at least one prescription per year for each patient. ResultsThe prevalence of antidepressant prescription in patients from the BIFAP cohort increased between 2013 (7.97 prescriptions per 1000 patients) and 2018 (8.87 prescriptions per 1000 patients), in most groups and in both sexes. In this period, female patients received the most prescriptions, surpassing prescriptions in male patients by up to 2.5 points in the overall rates. In patients younger than 13 years, this trend was inverted and antidepressant use was higher in male patients. The prevalence of prescription rose with increasing patient age, as did the proportion of off-label prescriptions. The use of off-label medication decreased over time. ConclusionsThere was a gradual increase in the prevalence of antidepressant prescription in minors younger than 18 years, with a predominance of the female sex. The high proportion of unapproved medication use in this age group calls for more thorough investigation of the risk-benefit balance of these treatments and of safer treatment alternatives.

Utilización de antidepresivos y prescripción fuera de ficha técnica en atención primaria en España (2013-2018)

IntroductionRecent studies show an increase in the use of antidepressants in minors (younger than 18 years), although few antidepressants are indicated for this age group. The aim of our study was to calculate the annual prevalence of antidepressant use in children and adolescents and to review the adherence of prescription to current indications. MethodsStudy of the prevalence of antidepressant use in minors based on the records of the Electronic Database for Pharmacoepidemiologic Studies in Primary Care (BIFAP) of Spain for the 2013–2018 period, considering at least one prescription per year for each patient. ResultsThe prevalence of antidepressant prescription in patients from the BIFAP cohort increased between 2013 (7.97 prescriptions per 1000 patients) and 2018 (8.87 prescriptions per 1000 patients), in most groups and in both sexes. In this period, female patients received the most prescriptions, surpassing prescriptions in male patients by up to 2.5 points in the overall rates. In patients younger than 13 years, this trend was inverted and antidepressant use was higher in male patients. The prevalence of prescription rose with increasing patient age, as did the proportion of off-label prescriptions. The use of off-label medication decreased over time. ConclusionsThere was a gradual increase in the prevalence of antidepressant prescription in minors younger than 18 years, with a predominance of the female sex. The high proportion of unapproved medication use in this age group calls for more thorough investigation of the risk–benefit balance of these treatments and of safer treatment alternatives.

Tendencias suicidas asociadas al uso de antidepresivos en niños y adolescentes

INTRODUCTION Suicide is a public health problem in the infant and adolescent population and is one of the leading causes of death in that age range. Since the introduction of new classes of antidepressants in the early 1990s, concerns about the risk of suicidality associated with the use of these drugs in children and adolescents began to appear. Since then, numerous studies have been published in this regard, and several regulatory agencies have issued warnings concerning this possible increased risk. Despite this, the use of antidepressants in this population continues to increase. OBJECTIVE To analyse the evidence for the relationship between antidepressant use in children and adolescents and the risk of suicidality. In addition, to determine the relationship between this use and the onset of serious adverse events, as well as the treatment discontinuation due to such events. METHODS A literature search was carried out in MedLine and the Cochrane Library. Reviews were prioritised and, if necessary, the search was broadened to include randomised clinical trials. Studies concerning treatment with any antidepressant, irrespective of the diagnosis, compared with placebo, any non-pharmacological treatment or no treatment were analysed. Additionally, position papers from scientific societies and healthcare institutions were also identified. The prescriptions database of the Navarre Health Service was used to obtained information regarding antidepressant use in children and adolescents in Navarre, and the BIFAP (www.bifap.org) database was used to obtain this information for Navarre and Spain as a whole. CONCLUSIONS Current evidence indicates that antidepressants increase the risk of suicidality in children and adolescents. Therefore the use in this population should be restricted and they should only be used for the authorised indications. This risk is closely related to an increase in suicidal ideation. Indirect evidence suggests that the risk of suicidality may be higher with venlafaxine. There is insufficient evidence that any antidepressant reduces this risk. There is a large body of evidence that antidepressants increase the risk of serious adverse events and discontinuations due to adverse events under any indication in comparison with placebo. In the studies available, the safety is analysed when treatment starts and, in general, these are short-term studies, therefore the risk of this type of adverse event in the long term cannot be ruled out.

Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998-2017: A population-based cohort study.

The use of antidepressants in children and adolescents remains controversial. We examined trends over time and variation in antidepressant prescribing in children and young people in England and whether the drugs prescribed reflected UK licensing and guidelines. QResearch is a primary care database containing anonymised healthcare records of over 32 million patients from more than 1,500 general practices across the UK. All eligible children and young people aged 5-17 years in 1998-2017 from QResearch were included. Incidence and prevalence rates of antidepressant prescriptions in each year were calculated overall, for 4 antidepressant classes (selective serotonin reuptake inhibitors [SSRIs], tricyclic and related antidepressants [TCAs], serotonin and norepinephrine reuptake inhibitors [SNRIs], and other antidepressants), and for individual drugs. Adjusted trends over time and differences by social deprivation, region, and ethnicity were examined using Poisson regression, taking clustering within general practitioner (GP) practices into account using multilevel modelling. Of the 4.3 million children and young people in the cohort, 49,434 (1.1%) were prescribed antidepressants for the first time during 20 million years of follow-up. Males made up 52.0% of the cohorts, but only 34.1% of those who were first prescribed an antidepressant in the study period. The largest proportion of the cohort was from London (24.4%), and whilst ethnicity information was missing for 39.5% of the cohort, of those with known ethnicity, 75.3% were White. Overall, SSRIs (62.6%) were the most commonly prescribed first antidepressant, followed by TCAs (35.7%). Incident antidepressant prescribing decreased in 5- to 11-year-olds from a peak of 0.9 in females and 1.6 in males in 1999 to less than 0.2 per 1,000 for both sexes in 2017, but incidence rates more than doubled in 12- to 17-year-olds between 2005 and 2017 to 9.7 (females) and 4.2 (males) per 1,000 person-years. The lowest prescription incidence rates were in London, and the highest were in the South East of England (excluding London) for all sex and age groups. Those living in more deprived areas were more likely to be prescribed antidepressants after adjusting for region. The strongest trend was seen in 12- to 17-year-old females (adjusted incidence rate ratio [aIRR] 1.12, 95% confidence interval [95% CI] 1.11-1.13, p < 0.001, per deprivation quintile increase). Prescribing rates were highest in White and lowest in Black adolescents (aIRR 0.32, 95% CI 0.29-0.36, p < 0.001 [females]; aIRR 0.32, 95% CI 0.27-0.38, p < 0.001 [males]). The 5 most commonly prescribed antidepressants were either licensed in the UK for use in children and young people (CYP) or included in national guidelines. Limitations of the study are that, because we did not have access to secondary care prescribing information, we may be underestimating the prevalence and misidentifying the first antidepressant prescription. We could not assess whether antidepressants were dispensed or taken. Our analysis provides evidence of a continuing rise of antidepressant prescribing in adolescents aged 12-17 years since 2005, driven by SSRI prescriptions, but a decrease in children aged 5-11 years. The variation in prescribing by deprivation, region, and ethnicity could represent inequities. Future research should examine whether prescribing trends and variation are due to true differences in need and risk factors, access to diagnosis or treatment, prescribing behaviour, or young people's help-seeking behaviour.

Placebos Are Part of the Solution, Not the Problem. An Exemplification of the Case of Antidepressants in Pediatric Chronic Pain Conditions.

Chronic pain is highly prevalent among adolescents and up to one in four youths will develop chronic pain (1). Also, more than 10% of hospitalized children and adolescents show features of chronic pain (2), which is inherently linked to emotional distress and functional disability (3). Interventions for chronic pediatric pain comprise a range of treatment approaches, among them antidepressants (ADs). Pharmacological treatment indications for pediatric populations are usually based on data extrapolated from adults where ADs are described to be effective and frequently used for the treatment of chronic pain (4–6). Furthermore, chronic pain is multi-faced, therefore the use of ADs may be utilized not only to address pain but also underlying or comorbid psychiatric symptoms such as depression, anxiety, or different sleep disorders (4, 7). However, although ADs are frequently used in clinical practice, a recent Cochrane review could only include four studies that examined the use of ADs in pediatric chronic non-cancer pain and was therefore not able to report effect sizes (4). In addition, the small to moderate effect sizes reported in many pediatric AD trials in the common psychiatric disorders are potentially due to large placebo effects, with effect sizes as high as high as 1.57 (Hedges g) (8). Moreover, the use of ADs in children and adolescents remains controversial (9), as severe adverse events—including an increased risk of suicidal thoughts and behaviors–have been reported, leading to a black box warning by the Food and Drug Administration (FDA) in 2004 (10). Placebo Effects and Mechanisms in Children and Adolescents To date, placebo effects in children and adolescents with clinical conditions are poorly understood. A review from 2013 concludes that from all citations found with the search term “placebo,” only around 2.5% discussed the placebo effect in children and adolescents, and most of them were conducted in the field of attention-deficit hyperactivity disorder (ADHD), depression and migraine (11). Existing literature reports generally higher placebo effects in pediatric populations compared to adults across different disorders (e.g., obsessive compulsive disorder, anxiety disorders, depression, and epilepsy) (11–14). For children with ADHD, Waschbusch et al. (15) reported average rates of positive response to placebo to be up to 20–30% in a review of drug treatments. Notably, while this is an interesting finding, it is not equivalent to a placebo effect which requires a no-treatment control group for comparison (16). It has been proposed that some of the psychological mechanisms underlying the placebo effect in children and adolescents are similar to those in adults, such as the patient-provider relationship, positive expectations (of parents and child), a plausible narrative, as well as a powerful ritual (11, 17–19), but the specific underlying mechanisms of placebo effects in children and adolescents remain poorly understood. It has, for example, been argued that placebo analgesia can be induced via social observational learning (20); children and adolescents may be more susceptible for social learning mechanisms by imitation and role models (11). Furthermore, it has been speculated that children aged 6 years or older have higher learning capacities than adults, at least for the process of associative learning. Associative learning, in turn, is a well-known underlying mechanism associated with placebo responses (11).

The Impact of Placebo Response Rates on Clinical Trial Outcome: A Systematic Review and Meta-Analysis of Antidepressants in Children and Adolescents with Major Depressive Disorder.

Objective: The high placebo response rate may hamper the discovery of antidepressants in children and adolescents with major depressive disorder (MDD). The aim of the study was to clarify the relationship between the placebo response rate and clinical trial outcomes of the use of antidepressants in children and adolescents, and distinguish main factors responsible to placebo response rate. Methods: The PubMed and Cochrane Library databases were searched for double-blind randomized placebo-controlled trials of the new-generation antidepressants for the acute treatment of MDD in children and adolescents. The response rate differences (RDs) between placebo group and treatment group under different level of placebo response rate were pooled by random-effects meta-analysis. The classification thresholds for low, medium, and high placebo response rate were set at <40%, 40%-50%, and ≥50%, respectively. Predictors of placebo response rate were explored using meta-regression. Results: The analysis included 18 trials with 4365 participants. This study found that the lower the placebo response rate, the greater the efficacy differences between antidepressants and placebo. In the high, moderate, and low placebo response rate subgroups, the response RDs (95% CI) between antidepressants and placebo were 8 (1-14)%, 10 (2-17)%, and 21 (9-32)%, respectively. The meta-regression showed that the number of study sites was the factor most associated with placebo response rate, and that response rate increased 3% with every additional 10 study sites. Conclusions: The clinical outcome was related to the placebo response rates in the clinical trials of antidepressants in children and adolescents with MDD. The efficacy differences between antidepressants and placebo will be maximized when placebo response rates are reduced. The number of study sites was the factor most associated with the placebo response rates.

NICE guidance linked with rising antidepressant use in children

NICE guidance linked with rising antidepressant use in children

16.2 The Partnership Access Line: Prescribers’ Perspectives on Antidepressant Use in Children and Adolescents

We will review qualitative experiences from community providers using a statewide mental health consult service to gain prescriber perspectives on antidepressant use for youth.

Antidepressants for Children: A Meta-Analysis

To address the ongoing debate about the use of antidepressants in children and adolescents, researchers conducted a meta-analysis of data from 36

Evidence Weak for Antidepressant Use in Children and Adolescents.

Drugs have no clear advantages in this population.

Trends and patterns of antidepressant use in children and adolescents from five western countries, 2005–2012

Following the FDA black box warning in 2004, substantial reductions in antidepressant (ATD) use were observed within 2 years in children and adolescents in several countries. However, whether these reductions were sustained is not known. The objective of this study was to assess more recent trends in ATD use in youth (0−19 years) for the calendar years 2005/6–2012 using data extracted from regional or national databases of Denmark, Germany, the Netherlands, the United Kingdom (UK), and the United States (US). In a repeated cross-sectional design, the annual prevalence of ATD use was calculated and stratified by age, sex, and according to subclass and specific drug. Across the years, the prevalence of ATD use increased from 1.3% to 1.6% in the US data (+26.1%); 0.7% to 1.1% in the UK data (+54.4%); 0.6% to 1.0% in Denmark data (+60.5%); 0.5% to 0.6% in the Netherlands data (+17.6%); and 0.3% to 0.5% in Germany data (+49.2%). The relative growth was greatest for 15−19 year olds in Denmark, Germany and UK cohorts, and for 10−14 year olds in Netherlands and US cohorts. While SSRIs were the most commonly used ATDs, particularly in Denmark (81.8% of all ATDs), Germany and the UK still displayed notable proportions of tricyclic antidepressant use (23.0% and 19.5%, respectively). Despite the sudden decline in ATD use in the wake of government warnings, this trend did not persist, and by contrast, in recent years, ATD use in children and adolescents has increased substantially in youth cohorts from five Western countries.

Use of antidepressants in children soars by 50% in the UK

Use of antidepressants in children soars by 50% in the UK

The effect of antidepressants and antipsychotics on weight gain in children and adolescents.

Psychiatric illness in the paediatric population is increasing and the weight effect of medications for these problems is often unclear. A comprehensive literature search was undertaken to identify studies reporting weight in relation to antipsychotic and antidepressant use in children and adolescents. From 636 articles, 42 were selected for review. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) do not cause weight gain and may lead to improvements in weight status over the short, but not, long term. Antipsychotics were generally associated with weight gain. In drug comparison studies, risperidone had a larger weight gain effect than lithium, divalproex sodium and pimozide. Studies assessing the weight-protective effects of augmentation therapy with metformin or topiramate show less weight gain with addition of these agents. In conclusion, prescribing of SSRIs and SNRIs may be associated with improvements in weight status in children and adolescents but trials assessing their use in obesity, outside of established psychiatric illness, are limited and still experimental. Youth prescribed antipsychotic medication should be monitored for exaggerated weight gain and in those where obesity is a pre-existing concern agents other than olanzapine, clozapine and risperidone may be advantageous.

More Youth Using Antipsychotics Concurrent With Other Medications

More Youth Using Antipsychotics Concurrent With Other Medications

Antidepressant Use in Children, Adolescents, and Young Adults: 10 Years After the Food and Drug Administration Black Box Warning

Depression in children, adolescents, and young adults can jeopardize health status, well-being, and development. Almost a decade ago, risks and benefits of antidepressant use in this group prompted the Food and Drug Administration (FDA) to ask manufacturers to include black box warnings on antidepressant prescriptions. This article reviews initial FDA decisions related to black box warnings for antidepressants in youth, reviews effects of the warnings, and considers clinical implications of prescribing antidepressants for treatment of youth depression. Health care providers must consider the risks and benefits of initiating antidepressant medication treatment, closely monitoring adherence, patient outcomes, and suicidal ideation.

Antidepressants for children with depression.

The Forum about treating depressed children presented in the previous issue of the journal[1],[2] highlighted several important issues about this controversial topic. Depression in children is a devastating disorder that effects psychosocial development and has long-term negative outcomes for both the patients and their families.[3]-[5] It has a relatively high prevalence of 1 to 2% in children and 3 to 8% in adolescents[3], but there are few randomized controlled trials on the efficacy of pharmacotherapy and other treatments for the disorder.[3]-[9] After the FDA's ‘black box’ warning about the potential suicide risk of antidepressant use in children in 2004, the diagnosis of pediatric depression in the United States decreased from 5 per 1000 managed care enrollees to 3 per 1000 and the prescription of antidepressants among treatment-naive patients with depression who were 5 to 21 years of age decreased by approximately 50%.[6] These changes following the FDA warning suggest that many children with depression were not being treated with appropriate medication. This hypothesis is supported by the increase in the suicide rates of children and adolescents – by 14% in the United States[10] and 25% in Canada[6]—in the years following the FDA warning compared to increasing antidepressant prescription use and a decline in suicide rates among children and youth in the years prior to the warning.[6],[7] The results of several reviews about the association between the treatment of pediatric depression with antidepressants and suicidality have questioned the appropriateness of the FDA warning.[5]-[11] Ecological studies have reported a beneficial effect of antidepressant prescription in children and adolescents. In the United States, suicide rates among children and adolescents decreased from 4.4 per 100,000 to 2.8 per 100,000 between 1999 and 2003, a period during which there was a substantial increase in the rates of prescription of selective serotonin reuptake inhibitor (SSRI) antidepressants for pediatric depression.[6] The Treatment for Adolescents with Depression Study (TADS) found that adolescents with major depressive disorder (MDD) show significant decreases in suicidality in all treatment arms but no significant difference in between those treated with fluoxetine and those treated with CBT.[12] More recent studies also indicate that antidepressants are modestly effective for the treatment of pediatric MDD and that the benefits outweigh the risks of suicidalilty.[11] Finally, the FDA's warning applied to all antidepressants, but it appears that the relationship between antidepressant use and suicidality in children and adolescents varies for the different types of antidepressants.[4] Despite the limited number of randomized controlled trials of pharmacotherapy for children with depressive disorders and the inconsistency of the results,[5] several studies found that SSRIs were significantly superior to placebo.[5],[6],[9]-[11] But some studies report antidepressants of limited use in children with depression.[9] Psychotherapy, especially CBT, and manipulation of the psychosocial context (including treatment of parental psychopathology) is considered effective for most children with mild or moderate depression,[7],[10] but usually needs to be augmented with antidepressants in those with severe depression.[9] Based on scientific reviews and expert consensus statements, several practice guidelines recommend using fluoxetine or escitalopram – both of which are approved by the FDA – as the first-line pharmacological treatment for children and adolescents with MDD if medication is indicated.[5]-[11] With appropriate monitoring for suicidality and other potential adverse events, patients with severe forms of pediatric MDD or with less severe MDD that does not respond to psychosocial interventions alone will often benefit from combined psychosocial and psychopharmacological interventions.

Off‐label antidepressant use in children and adolescents compared with young adults: extent and level of evidence

To estimate the degree of, and level of evidence supporting, off-label antidepressant (AD) prescribing for children and adolescents compared with young adults. Retrospective cohort study utilizing medical and pharmacy claims data from US-managed care plans, 1997-2009. Patients aged 5-24 years, with at least one (index) AD claim during a period of continuous enrollment. Drug-diagnosis pairs, on the basis of medical claims within 30 days pre-index or post-index AD, were grouped as (1) Food and Drug Administration (FDA)-approved or (2) off-label with one of three evidence categories based on Micromedex®2.0: favorable, inconclusive or limited-to-none (Thomson Micromedex, Greenwood Village, CO, USA). Over the study period, 290 816 subjects met eligibility criteria: 17% 5-12 years old, 40% 13-18 years old, and 43% 19-24 years old. Sertraline was the most commonly prescribed index AD (19-23%). Psychiatrists more often prescribed the AD for children (31%) and adolescents (35%) versus young adults (17%). Only 28% of all subjects had a diagnosis consistent with an FDA-approved indication within 30 days pre-index and post-index AD. Children less than 13 years old were less likely to have had an FDA-approved indication (5-10%). Most off-label prescribing had inconclusive to no evidence supporting efficacy. The lack of evidence was especially pronounced for younger children. Trends were consistent over the study period. Increasing the time period for potential indications pre-index and post-index AD did not result in significantly reduced off-label rates. Pediatric off-label AD prescribing occurs frequently without a strong evidence base, highlighting a need to generate additional evidence to ensure safe and effective use.

Efficacy and safety of antidepressant drug treatment in children and adolescents

Depression and anxiety are common disorders in youth that can have profound influences on functioning and even mortality. In the late 1990s, large controlled trials began demonstrating the efficacy of selective serotonin reuptake inhibitors for these conditions in the pediatric population. By 2003, regulatory agencies began warning the public of unrecognized risk and misrepresented benefit. The current review article summarizes a series of published and unpublished efficacy and safety data regarding antidepressant use in children and adolescents. The resulting complex synthesis suggests that these medications may offer mild-to-moderate benefit, with notable exceptions depending on medication and indication, but they may also heighten the risk for suicidal ideation and parasuicidal behavior. However, reviewed epidemiological data does not demonstrate a relationship between newer antidepressant prescription and completed suicide in large populations of youth. In conclusion, this breadth of mixed research data is applied to clinical decision making.

Antidepressant use in children and adolescents: Practice touch points to guide paediatricians

Depression in children and youth is common, and requires an understanding of its developmental character and associated comorbid conditions. Initial treatment of mild depression involves active supportive measures with a focus on symptom reduction and improved daily function. Where pharmacotherapy is warranted, evidence supports the use of selective serotonin reuptake inhibitor (SSRI) antidepressants, particularly fluoxetine, to manage moderate/severe depression. SSRI treatment should include a comprehensive management plan in the context of interdisciplinary care, an understanding of its pharmacology and clearly articulated goals for symptom reduction, functional status tracking (school, home and peers) and monitoring for the emergence of suicidal ideation/behaviour. For children with more severe symptoms or complicating factors (comorbid conditions), referral to mental health clinicians should be considered. Use of an SSRI should be associated with family/patient education about medication effects, specific social and health goals that promote self-esteem, improved function and close monitoring for adverse effects.