Abstract

Introduction

Depression rates in children/adolescents in the United States have markedly increased over the last decade. In 2020, major depression disorder (MDD) affected 17% of adolescents aged 12 to 17 years, with suicide as the second leading cause of death for ages 10 to 14 years and the third leading cause for ages 15 to 24 years.^1–3 Unfortunately, it is estimated that only 41.6% of adolescents with MDD receive treatment.⁴

Treatment of MDD in children/adolescents is limited with psychotherapy and pharmacotherapy being the main treatment options.^5–7 Only 2 medications are approved by the FDA for MDD treatment in this population; fluoxetine (≥ 7 years old) and escitalopram (≥ 12 years old).^8,9 While other antidepressants are commonly used off-label for MDD in children/adolescents, some guidelines recommend against specific antidepressants (eg, paroxetine, venlafaxine) because of concerns for increased suicide in young adults.^6,10,11 In 2004, the FDA issued a black box warning for all antidepressants in youths from a meta-analysis, which revealed a 4% risk of new suicidal thinking/behaviors in youths taking an antidepressant compared with 2% in the placebo group.¹² Moreover, studies have found venlafaxine and paroxetine to be associated with an increased risk of suicidal behavior and ideations.¹³ This black box warning has complicated treatment for children/adolescents with MDD.

Three guidelines discuss MDD treatment in the child/adolescent population, which recommend psychotherapy and/or pharmacotherapy.^5–7 These guidelines recommend fluoxetine or other selective serotonin reuptake inhibitors, such as sertraline and escitalopram, as first-line pharmacotherapy.^5–7 The American Psychological Association 2019 Clinical Practice Guideline for the Treatment of Depression recommends either cognitive behavioral therapy, interpersonal psychotherapy, or fluoxetine as initial MDD treatment in adolescents.⁶ The National Institute for Health and Care Excellence 2019 Guideline for Depression in Children and Young People and the American Academy of Pediatrics Guidelines for Adolescent Depression in Primary Care recommend psychotherapy for mild depression and the addition of pharmacotherapy with selective serotonin reuptake inhibitors for moderate to severe depression similar to the American Psychological Association guidelines.^5,7 Unfortunately, these guidelines have limited recommendations for child/adolescent patients who fail to respond to antidepressants and/or psychotherapy.

In adults, antipsychotics (aripiprazole, brexpiprazole, cariprazine, olanzapine, and quetiapine) are approved as adjunctive MDD treatment.⁶ However, child/adolescent guidelines for MDD treatment have limited recommendations for their use, with only the National Institute for Health and Care Excellence Guidelines recommending augmentation with a second-generation antipsychotic in psychotic depression.⁷ Research with antipsychotics for use in depression in children/adolescents is limited to MDD with psychosis or bipolar depression.^14,15 While there is limited research for antipsychotic augmentation in child/adolescent MDD without psychosis, it is practiced clinically.^16,17 The use of antipsychotics can be associated with significant adverse effects in youths, including metabolic abnormalities (diabetes mellitus or weight gain), cardiac arrhythmias, dyslipidemia, hyperprolactinemia, and extrapyramidal symptoms.¹⁸

The objective of this study was to determine the frequency of prescribing antipsychotics for MDD in child/adolescent patients and what factors influence the utilization of an antipsychotic for children/adolescents diagnosed with MDD without psychosis.

Methods

Results

There were 3535 patients identified via the Healthcare Enterprise Repository for Ontological Narration as age younger than 18 years and admitted to inpatient psychiatry during the study period with a diagnosis of MDD. Of those patients, 1460 were randomly reviewed for 600 included patients. Full inclusion and exclusion criteria can be found in the Figure. There were 41 of 600 patients (6.8%) prescribed an antipsychotic with a diagnosis of MDD. The Table shows patient demographics and baseline characteristics. Patients were 70.2% female, with an average age of 14.2 years. Notable differences between groups include a higher incidence of patients identifying as male, sleep disturbances, posttraumatic stress disorder (PTSD), and disruptive mood dysregulation disorder (DMDD) in the antipsychotic group.

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TABLE Patient demographics and baseline characteristics

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Escitalopram was the most prescribed antidepressant in the antipsychotic group (29.3%, 12/41 patients), followed by sertraline (26.8%, 11 patients). In the non-antipsychotic group, fluoxetine was most prescribed (29.7%, 166/559 patients), followed by escitalopram (24.1%, 135 patients) and sertraline (20.4%, 114 patients). There was a lower incidence of patients prescribed fluoxetine in the antipsychotic group compared with the non-antipsychotic group (4.9% vs 29.7%, P < .001). There were 2 of 41 patients (4.8%) in the antipsychotic group and 42 of 559 patients (7.6%) in the non-antipsychotic group that received a different antidepressant, including amitriptyline, bupropion, duloxetine, mirtazapine, and venlafaxine. In the antipsychotic group, 32.4% of patients were not prescribed an antidepressant, compared with 18.2% of patients in the non-antipsychotic group (P = .013). Of the 41 patients who received a scheduled antipsychotic for MDD, quetiapine was most prescribed (46% of patients), followed by aripiprazole (37%), olanzapine (10%), risperidone (5%), and lurasidone (2%).

Binomial logistic regression analysis was used to compare patients who were initiated on an antipsychotic with those who were not, based on relationship to length of stay, number of admissions, age, sex assigned at birth, gender identity, race, ethnicity, school, home life, insurance status, suicide attempt, Columbia Suicide Severity Rating Scale, symptoms of depression, and comorbidities. When holding all other variables constant, it was found that the odds of antipsychotic initiation increased by 1.28 for every 1-year increase in age (odds ratio [OR] 1.28; 95% CI = 1.045, 1.568; P = .017). It was also found that the odds of antipsychotic initiation increased by 3.28 for every admission after the initial admission within 1 year (OR 3.277; 95% CI = 2.283, 4.705; P < .001).

Discussion

This study, to our knowledge, is the first to assess the frequency of prescribing and factors associated with antipsychotic augmentation for child/adolescent MDD. This study found that an increased number of admissions within a year and increasing age increased the likelihood of being prescribed an antipsychotic for child/adolescent inpatients with MDD. Previous studies have found that a high number of previous admissions and poor prognosis increase psychiatric hospital readmission rates.²¹ Multiple admissions are probable markers of disease progression, highlighting the need for alternative or additional treatments. Other studies have found that older adolescent age is associated with the use of more psychotropic medications compared with younger children/adolescents.²² It is plausible that clinicians are more comfortable prescribing agents approved in adults as an adolescent’s age approaches adulthood.

In this study, child/adolescent patients with MDD who had comorbid PTSD or DMDD were more commonly prescribed antipsychotics. A study in adults also found that patients with MDD and comorbid PTSD were more likely to receive antipsychotic augmentation.²³ There is some evidence in adults for the use of adjunctive antipsychotics in treating PTSD in patients with hyperarousal or re-experiencing symptoms.²⁴ One study found that patients with childhood trauma are less likely to remit from symptoms of PTSD and have a longer time to remission.²⁵ This could explain augmentation with antipsychotics in younger patients with PTSD. DMDD, a childhood-specific psychiatric disorder, has been associated with increased use of antipsychotics outside of comorbid MDD.¹⁸ Other adult studies looking at factors associated with antipsychotic use for MDD found depression severity, medical comorbidities, alcohol use disorder, and obsessive-compulsive disorder were associated with antipsychotic use, which was not found in our child/adolescents study.^23,26 Depression severity, as shown by depressive symptoms in this study, was not different between groups, though it relied heavily on chart documentation. This study had a low incidence of obsessive-compulsive disorder and substance use disorders, making it difficult to find differences in these patient groups.

This study also found that males were more frequently prescribed antipsychotics, which is consistent with previous studies showing higher rates of antipsychotic use in males aged 11 to 17 years.²⁷ This increased use in males could be related to behavioral problems or conduct disorder. However, because of the retrospective nature of our study, we could not establish causality for males being prescribed antipsychotics.

Quetiapine and aripiprazole, both FDA approved for adult MDD adjunctive treatment, were the most prescribed antipsychotics in this study. Quetiapine is FDA approved for schizophrenia in patients 13 years and older and for bipolar–mania in those 10 years and older.²⁸ Additionally, aripiprazole has FDA approvals in children/adolescents for schizophrenia, Tourette’s syndrome, irritability in autism, and bipolar I disorder.^29,30 Previous studies evaluating off-label prescribing trends of antipsychotics in children/adolescents have found rates of antipsychotic prescribing increased in children/adolescents after new FDA approvals in both adults and children, which may explain their use in our study.³¹ Moreover, quetiapine is often prescribed off-label for sleep, which may account for its use in this study, as sleep disturbances were more commonly observed in the antipsychotic group.³²

Escitalopram and sertraline were both commonly prescribed antidepressants in both groups; however, there was a noticeable difference in fluoxetine prescribing. Fluoxetine was most commonly prescribed to patients in the non-antipsychotic group (29.7%), while it was only used in 4.9% of patients with antipsychotic augmentation. With fluoxetine being 1 of 2 FDA-approved antidepressants in children/adolescents, it is plausible that some patients who had antipsychotic augmentation had previously failed a trial of fluoxetine before switching to another antidepressant and the later initiation of an antipsychotic. An unexpected finding was the number of patients without antidepressant treatment in both groups. In the antipsychotic group, 32.4% of patients were not prescribed an antidepressant, compared with 18.2% in the non-antipsychotic group. This is concerning as antidepressants are the most studied pharmacologic treatment for child/adolescent MDD. It is possible that the patients who were not prescribed an antidepressant were receiving psychotherapy, had an intolerance to antidepressants, or their guardians did not consent to the medications recommended. Another explanation for the absence of antidepressants in the antipsychotic group may be that the physicians were attempting to rule out other psychiatric conditions, such as bipolar disorder, where antipsychotic monotherapy would be appropriate.

Investigators note several limitations of this study. This single-site study analyzed prescribing patterns for patients admitted to 1 facility in the Midwest. The retrospective nature of the study required reliance on documentation, which was not standardized and varied based on the provider for Columbia Suicide Severity Rating Scale scoring and symptoms of depression due to lack of utilization of a standardized rating scale, making it difficult to appropriately assess these endpoints. Provider preferences were not accounted for during analysis and may be considered a confounder. Guardian consent and nonpharmacologic-only recommendations were not accounted for when looking at those who received no medications. The dosing of pharmacologic agents and time from diagnosis to medication initiation were not collected and, therefore, could not be assessed. Specific indications for each medication and assessment of metabolic syndrome were not included in prescriber documentation, though it could have affected pharmacologic decision-making. Finally, we included patients diagnosed with DMDD in our study, which may have affected the results. Although there are no approved medications for the treatment of DMDD, antipsychotics, stimulants, or serotonergic antidepressants are commonly used for this diagnosis.³³

Conclusion

Despite limited evidence for antipsychotic efficacy for MDD in children/adolescents, antipsychotics were initiated in 6.8% of patients in this study. These results highlight the need for further research focused on evaluating the efficacy and safety of alternative treatments for MDD in children/adolescents, especially in patients who are refractory to guideline-recommended treatment with psychotherapy and/or antidepressants. Clinicians should consider the potential risks antipsychotics pose, including metabolic effects and extrapyramidal symptoms. Careful consideration and thoughtful treatment planning must occur before prescribing antipsychotics for children/adolescents with MDD because of the lack of sufficient evidence for efficacy, appropriate dosing, and long-term adverse effects.